Alemtuzumab

Campath is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).

Across all clinical experience, the reported maximum single dose received was 90 mg. Bone marrow aplasia, infections, or severe infusions reactions occurred in patients who received a dose higher than recommended.

One patient received an 80 mg dose by IV infusion and experienced acute bronchospasm, cough, and dyspnea, followed by anuria and death. Another patient received two 90 mg doses by IV infusion one day apart during the second week of treatment and experienced a rapid onset of bone marrow aplasia.

There is no known specific antidote for Campath overdosage. Treatment consists of drug discontinuation and supportive therapy.

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 C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

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.

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.

Call your doctor for instructions if you miss an appointment for your alemtuzumab injection.

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

Storage

Parenteral

2–8°C.1 Do not freeze; if accidentally frozen, thaw at 2–8°C before administration.1 Protect from direct sunlight.1

Following dilution, may store at 15–30°C or under refrigeration (2–8°C); use within 8 hours.1 5 Protect from light.1

2–8°C in original carton; protect from light.a Do not freeze or shake.a

Following dilution, may store at room temperature (15–30°C) or under refrigeration (2–8°C) for up to 8 hours; protect from light.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

No incompatibilities observed between alemtuzumab solution and PVC bags, PVC or polyethylene-lined PVC administration sets.1

Parenteral

Acute graft-versus-host disease (steroid refractory) (treatment)

Data from a limited number of patients in two studies (one phase II and one retrospective) suggest that alemtuzumab may be beneficial for the treatment of steroid refractory acute graft-versus-host disease (aGVHD) [Martinez 2009], [Schnitzler 2009]. Additional data may be necessary to further define the role of alemtuzumab in this condition.

Autoimmune hemolytic anemia, chronic lymphocytic leukemia (CLL)-induced

Data from a limited number of patients and clinical experience suggests alemtuzumab may be beneficial for the treatment of CLL-induced autoimmune hemolytic anemias [Karlsson 2007], [ Osterborg 2009]. Additional data may be necessary to further define the role of alemtuzumab in this condition.

B-cell chronic lymphocytic leukemia (B-CLL) (subcutaneous [off-label route])

Data from two phase II open-label clinical trials support the subcutaneous use of alemtuzumab in the treatment of B-CLL [Lundin 2002], [ Stilgenbauer 2009].

Solid organ transplantation: Heart transplant (induction)

Data from a single center retrospective review suggests that alemtuzumab may be beneficial for prevention of rejection in heart transplant recipients when used in combination with decreased maintenance immunosuppression [Teuteberg 2010]. Additional data may be necessary to further define the role of alemtuzumab in this condition.

Solid organ transplantation: Lung transplant (induction)

A retrospective analysis of data obtained from the United Network for Organ Sharing (UNOS) registry supports the use of alemtuzumab as induction therapy in patients receiving double lung transplants [Furuya 2016]. Data from other studies also support the use of alemtuzumab in the prevention of rejection in lung transplant recipients when followed by decreased maintenance immunosuppression [Jaksch 2014], [Shyu 2011], [Whited 2015]. Additional data may be necessary to further define the role of alemtuzumab in this condition.

Solid organ transplantation: Renal transplant (induction)

Data from a large, prospective, multicenter randomized study supports the use of alemtuzumab as induction therapy (followed by reduced maintenance immunosuppression) in the prevention of renal transplant rejection [Haynes 2014].

Stem cell transplant (allogeneic) conditioning regimen

Data from two studies support the use of alemtuzumab in conditioning regimens for allogeneic stem cell transplantation [Mead 2010 ], [Van Biesen 2009]. Additional trials may be necessary to further define the role of alemtuzumab in this setting.

T-cell prolymphocytic leukemia (T-PLL)

Data from two studies support the use of alemtuzumab in the treatment of T-cell prolymphocytic leukemia [Deardon 2001], [Keating 2002].

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

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. May be given through peripheral IV.

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.

Concerns related to adverse effects:

• Autoimmune effects: [US Boxed Warning (Lemtrada)]: Alemtuzumab causes serious, sometimes fatal, autoimmune conditions, such as immune thrombocytopenia and antiglomerular 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 antiglomerular basement membrane disease. Glomerular nephropathies require urgent evaluation; may lead to renal failure if not treated. Prompt intervention is necessary for autoimmune cytopenias. Immune thrombocytopenia (formerly known as 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: [US 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: [US 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: [US 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: [US 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: [US 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.

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.

You should not receive alemtuzumab if you are allergic to it.

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

• any type of bacterial, fungal, or viral infection (including herpes, cytomegalovirus, HIV, or AIDS);
• if you are allergic to mouse or hamster proteins; or
• if you have regular blood transfusions.

FDA pregnancy category C. It is not known whether alemtuzumab will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while receiving this medication.

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

Do not receive a "live" vaccine while receiving alemtuzumab. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

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

Data not available