alemtuzumab (Rx)

>10% (Campath)

Rigors (86%)

Fever (85%)

Neutropenia (85%)

Anemia (80%)

Thrombocytopenia (72%)

Nausea (54%)

Vomiting (41%)

Rash (40%)

Fatigue (34%)

Dyspnea (26%)

Cough (25%)

Headache (24%)

Pruritus (24%)

Sepsis (24%)

Skeletal pain (24%)

Diarrhea (22%)

Anorexia (20%)

Excessive sweating (19%)

Pneumonia (16%)

Dysthesias (15%)

Stomatitis (14%)

Asthenia (13%)

Edema (13%)

Dizziness (12%)

Abdominal pain (11%)

Herpes simplex (11%)

Hypertension (11%)

Myalgias (11%)

Tachycardia, SVT (11%)

>10% (Lemtrada)

Infusion reactions, all (92%)

Infections, all (71%)

Rash (53%)

Headache (52%)

Pyrexia (29%)

Nasopharyngitis (25%)

Nausea (21%)

Urinary tract infection (19%)

Fatigue (18%)

Insomnia (16%)

Upper respiratory tract infection (16%)

Herpes viral infection (16%)

Urticaria (16%)

Pruritus (14%)

Thyroid gland disorders (13%)

Fungal infection (13%)

Arthralgia (12%)

Pain in extremity (12%)

Back pain (12%)

Diarrhea (12%)

Sinusitis (11%)

Oropharyngeal pain (11%)

1-10% (Campath)

Chest/back pain (10%)

Dyspepsia (10%)

Insomnia (10%)

Bronchospasm (9%)

Constipation (9%)

Depression (7%)

Epistaxis (7%)

Moniliasis (8%)

Pancytopenia (5%)

Somnolence (5%)

1-10% (Lemtrada)

Paresthesia (10%)

Dizziness (10%)

Abdominal pain (10%)

Flushing (10%)

Vomiting (10%)

Cough (9%)

Chills (9%)

Dysgeusia (8%)

Influenza (8%)

Dermatitis (8%)

Dyspepsia (8%)

Blood in urine (8%)

Dyspnea (8%)

Tachycardia (8%)

Anxiety (7%)

Muscular weakness (7%)

Bronchitis (7%)

Chest discomfort (7%)

Muscle spasm (6%)

Myalgia (6%)

Decreased CD4 and CD8 lymphocytes (6%)

Asthenia (5%)

Infusion reactions, serious (3%)

Infections, serious (3%)

Immune thrombocytopenia (2%)

HPV infection (2%)

<1% (Lemtrada)

Pneumonitis (0.5%)

Glomerular nephropathies (0.3%)

Thyroid cancer (0.3%)

Melanoma (0.3%)

Active/latent tuberculosis (0.3%)

Hemolytic anemia (0.2%)

Pancytopenia (0.2%)

Neutropenia (0.1%)

Postmarketing Reports

Campath

• Fatal infusion reactions
• Cardiovascular: CHF, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents)
• Cerebrovascular disorders: Cervicocephalic arterial dissection, stroke, including hemorrhagic and ischemic stroke
• Gastrointestinal: Acute acalculous cholecystitis
• Immune disorders: Goodpasture’s syndrome, Graves disease, aplastic anemia, Guillain Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, autoimmune hepatitis, vasculitis, hemophagocytic lymphohistiocytosis, sarcoidosis, fatal transfusion-associated
• GVHD Infections: Epstein-Barr virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), reactivation of latent viruses
• Metabolic: Tumor lysis syndrome
• Neurologic: Optic neuropathy
• Renal and urinary disorders: Glomerular nephropathies
• Endocrine disorders: Hypothyroidism, hyperthyroidism, and thyroiditis

Lemtrada

• Cerebrovascular disorders: Stroke, including hemorrhagic and ischemic stroke and cervicocephalic arterial dissection
• Gastrointestinal system disorders: Cholecystitis, including acalculous cholecystitis and acute acalculous cholecystitis
• Immune system disorders: Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis
• Pulmonary system disorders: Pulmonary alveolar hemorrhage
• Thrombotic thrombocytopenia purpura
• Musculoskeletal and connective tissue disorders: Adult-onset Still’s disease

Contraindications

Campath: None

Lemtrada

• Patients infected with HIV,
• Hypersensitivity or anaphylactic reactions to alemtuzumab or excipients
• Active infection

Cautions

Therapy associated with moderate emetic potential in adults in the oncology setting; may recommend antiemetics to prevent nausea and vomiting

Leukoencephalopathy (PML) reported; withhold therapy immediately for symptoms suggestive of PML

Campath

• Treatment results in severe and prolonged lymphopenia along with an increased incidence of opportunistic infections
• Prophylaxis does not eliminate these infections; routinely monitor for CMV infection during treatment and for ≥2 months following completion; withhold treatment for serious infections and during antiviral treatment for CMV infection or confirmed CMV viremia (defined as polymerase chain reaction (PCR) positive CMV in ≥2 consecutive samples obtained 1 week apart)
• Unless an emergency, administer only irradiated blood products to avoid transfusion-associated graft versus host disease
• Hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia reported after treatment
• Safety of immunization with live viral vaccines has not been studied; do not administer live viral vaccines to patients who have recently therapy
• Serious infusion reactions (pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, bronchospasm) reported
• Monitor thyroid-stimulating hormone (TSH) at baseline and every 2-3 months during treatment

Lemtrada

• Therapy can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage infusion reactions (including anaphylaxis, cerebrovascular, cardiac and respiratory emergencies); therapy causes cytokine release syndrome, resulting in infusion reactions that can be life-threatening; in majority of cases, time to onset may occur within 1 to 3 days of infusion
• During postmarketing use, cases of vasculitis, autoimmune hepatitis, and Guillain-Barre syndrome reported
• Autoantibody formation may occur and increase risk of serious autoimmune conditions (eg, thyroid disorders, immune thrombocytopenia, hemolytic anemia, pancytopenia, glomerular nephropathies, connective tissue disorders, and acquired hemophilia A)
• Thrombotic thrombocytopenia purpura (TTP) reported, characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological sequelae, fever, and renal impairment; TTP is associated with high morbidity and mortality rates if not recognized and treated early; discontinue treatment if confirmed or alternate etiology for signs and symptoms cannot be established
• Chronic inflammatory demyelinating polyradiculoneuropathy reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmune disorders, generally at higher and more frequent doses than recommended in MS
• Therapy may increase risk of other autoimmune conditions because of the broad range of autoantibody formation with therapy
• Autoimmune hepatitis causing clinically significant liver injury, including acute liver failure requiring transplant, reported; prior to starting treatment, obtain serum transaminases (ALT and AST) and total bilirubin levels; obtain transaminase levels and total bilirubin levels periodically until 48 months after last dose
• Infusion reactions are common (92%) and may be serious or life-threatening; premedication with corticosteroids is required and monitoring
• May increase risk for malignancies, including thyroid cancer, melanoma, lymphoproliferative disorders, and lymphoma; patients and healthcare providers should monitor for symptoms of thyroid cancer including a new lump or swelling in the neck, pain in the front of the neck, persistent hoarseness or other voice changes, trouble swallowing or breathing, or a constant cough not due to an upper respiratory tract infection
• Obtain thyroid function tests, such as TSH levels, prior to initiation of treatment and every 3 months thereafter until 48 months after the last infusion; continue to test thyroid function after 48 months if clinically indicated or in case of pregnancy
• Pneumonitis reported; advice patients to contact physician with symptoms of SOB, cough, wheezing, chest pain/tightness, or hemoptysis
• Cases of pulmonary alveolar hemorrhage, myocardial ischemia, myocardial infarction, stroke (including ischemic and hemorrhagic stroke), and cervicocephalic (eg, vertebral, carotid) arterial dissection reported; reactions may occur following any of the doses during treatment course; patients should be informed about the signs and symptoms and advised to seek immediate medical attention if any of these symptoms occur
• Cases of severe and fatal neutropenia reported within 2 months of infusion; some cases resolved with receiving granulocyte-colony stimulating factor treatment
• Increased vigilance and monitoring is warranted in patients previously treated with alemtuzumab (Campath) for CLL who receive Lemtrada for MS; additive and chronic autoimmune effects may occur
• May increase risk of acute acalculous cholecystitis; symptoms of acute acalculous cholecystitis include abdominal pain, abdominal tenderness, fever, nausea, vomiting; leukocytosis and abnormal liver enzymes are also commonly observed; if acute acalculous cholecystitis is suspected, evaluate and treat promptly
• In postmarketing setting, cases of cervicocephalic (eg, vertebral, carotid) arterial dissection involving multiple arteries reported within 3 days of administration
• 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
• Concomitant use with antineoplastic or immunosuppressive therapies could increase risk of immunosuppression
• During postmarketing use, cases of autoimmune encephalitis (AIE) reported; AIE can present with a variety of clinical manifestations, including subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and seizures; therapy should be discontinued if AIE is confirmed by presence of neural autoantibodies or an alternate etiology cannot be established

• Hemophagocytic lymphohistiocytosis

  • Patients who develop early manifestations of pathologic immune activation should be evaluated immediately and a diagnosis of hemophagocytic lymphohistiocytosis (HLH) considered; discontinue therapy if alternate etiology for signs and symptoms cannot be established
  • HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation; it is associated with high mortality rates if not recognized early and treated
  • Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms (e.g., mental status changes, ataxia, or seizures), cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities
  • Hemophagocytosis may be seen on histologic examination of bone marrow, spleen, or lymph nodes; in cases of HLH reported with therapy, most patients presented with fever, elevated ferritin, transaminitis, hypertriglyceridemia, and all patients required hospitalization
  • Although the small number of cases limits the ability to draw conclusions pertaining to mean or range of latency for HLH, symptoms have been reported to occur within approximately thirteen months to thirty-three months following the initiation of treatment
  • Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered
  • Discontinue therapy if an alternate etiology for signs or symptoms cannot be established

• Acquired hemophilia A

  • Cases of acquired hemophilia A (anti-Factor VIII antibodies) reported; patients typically present with spontaneous subcutaneous hematomas and extensive bruising, although hematuria, epistaxis, gastrointestinal or other types of bleeding may occur
  • Obtain a coagulopathy panel including aPTT in patients who present with such symptoms; patients should be informed about signs and symptoms of acquired hemophilia A and advised to seek immediate medical attention if any of these symptoms occur

• Infections

  • Infections reported, including herpes viral infections, HPV, tuberculosis, fungal infections (especially oral and vaginal candidiasis), and listeria meningitis; patients with HBV or HCV were excluded from clinical trials
  • In postmarketing setting, serious, sometimes fatal, opportunistic infections reported, including aspergillosis, coccidioidomycosis, histoplasmosis, Pneumocystis jirovecii pneumonia, nocardiosis, and cytomegalovirus infections
  • Epstein-Barr virus (EBV) infection, including severe and fatal EBV-associated hepatitis, reported; monitor for sign and symptoms of EBV infections; withhold therapy for EBV reactivation or severe infection
  • Avoid or adequately heat foods that are potential sources of Listeria monocytogenes (eg, deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry)

• Adult-onset Still’s disease

  • During postmarketing use, Adult Onset Still’s Disease (AOSD) reported; AOSD is a rare inflammatory condition that requires urgent evaluation and treatment
  • Patients with AOSD may have a combination of the following signs and symptoms: fever, arthritis, rash, and leukocytosis in the absence of infections, malignancies, and other rheumatic conditions; patients with manifestations of AOSD should be evaluated immediately and treatment discontinued if an alternate etiology for signs or symptoms cannot be established

Pregnancy

Campath: Unknown whether drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity; administer to a pregnant woman only if clearly needed

Lemtrada

• There is a pregnancy surveillance program; if exposure occurs during pregnancy, healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2
• No adequate data on developmental risk associated with use in pregnant women
• When administer during organogenesis, drug was embryolethal in pregnant huCD52 transgenic mice
• Auto-antibodies may develop after administration; placental transfer of antithyroid antibodies resulting in neonatal Graves’ disease reported

• Contraception

  • Women of childbearing potential should use effective contraceptive measures during treatment and for 4 months following that course of treatment

• Infertility

  • In huCD52 transgenic mice, administration prior to and during the mating period resulted in adverse effects on sperm parameters in males and reduced number of corpora lutea and implantations in females

• Clinical considerations

  • Alemtuzumab induces persistent thyroid disorders, untreated hypothyroidism in pregnant women increases the risk for miscarriage and may have effects on the fetus including mental retardation and dwarfism
  • In mothers with Graves’ disease, maternal thyroid stimulating hormone receptor antibodies may transfer to a developing fetus and can cause neonatal Graves’ disease

Lactation

No data on presence of alemtuzumab in human milk, effects on the breastfed infant, or effects of the drug on milk production

Lemtrada: Alemtuzumab was detected in the milk of lactating huCD52 transgenic mice administered drug

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Recombinant monoclonal antibody against CD52 (lymphocyte antigen); promotes antibody-dependent lysis

Pharmacokinetics

Half-Life: 12 days

Vd: 14.1 L; largely confined to blood and interstitial space

Metabolism: unknown

Excretion: unknown

IV Incompatibilities

Do not admix with any other drug; do not administer simultaneously in the same IV line

IV Compatibilities

0.9% NaCl

D5W

Campath: Polyvinylchloride (PVC) bags and PVC or polyethylene-lined PVC administration sets

IV Preparation

Visually inspect for particulate matter and discoloration; if particulate matter is present or solution is discolored, do use vial

Do not shake vial

Withdraw the necessary amount from the vial into a syringe

Campath

• To prepare 3-mg or 10-mg dose, withdraw calculated amount into a 1-mL syringe calibrated in increments of 0.01 mL
• To prepare 30-mg dose, withdraw 1 mL in either a 1-mL or 3-mL syringe

Lemtrada

• Withdraw 1.2 mL from vial into a syringe
• Inject syringe contents into 100 mL sterile 0.9% NaCl USP or D5W
• Gently invert bag to mix solution

Premedication and Infection Prophylaxis

Campath

• Premedicate with diphenhydramine 50 mg and acetaminophen 500-1000 mg PO 30 minutes before first infusion and each dose escalation
• Administer trimethoprim/sulfamethoxazole DS PO BID 3x/week (or equivalent) for Pneumocystis jiroveci pneumonia (PCP) prophylaxis
• Administer famciclovir 250 mg PO BID (or equivalent) as herpetic prophylaxis
• Continue PCP and herpes viral prophylaxis for a minimum of 2 months after treatment completion or until the CD4+ count is ≥200 cells/mcL, whichever occurs later
• Monitor CBC, platelets, CD4+ counts qWeek

Lemtrada

• Corticosteroids: Premedication with high-dose corticosteroids (eg, 1,000 mg methylprednisolone) immediately before alemtuzumab IV infusion and for the first 3 days of each treatment course
• Herpes prophylaxis: Administer antiviral prophylaxis for herpetic viral infections starting on the first day of each treatment course and continue for a minimum of 2 months following or until CD4+ count is ≥200 cells/microL

IV Administration

Administer by IV infusion only, do NOT give as IV push or bolus

Campath: Administer over 2 hr

Lemtrada: Administer over 4 hr; extend duration of infusion if clinically warranted

Do not shake prior to use

Storage

Unopened vials: Refrigerate at 2-8°C (36-46°F)

Diluted solution: Start infusion within 8 hr after dilution (no preservatives); may store at room temperature or refrigerate at 2-8°C (36-46°F)

Do not freeze or shake

Store in original carton to protect from light