Campath Side Effects

Generic Name: alemtuzumab

Please note - some side effects for Campath may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Campath - for the Consumer

Campath

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Campath:

Anxiety; diarrhea; fatigue; headache; loss of appetite; muscle pain; nausea; stomach pain; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Campath:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); chest pain; fast or irregular heartbeat; lightheadedness when sitting or standing up; numbness of an arm or leg; rigid muscles; severe dizziness, lightheadedness, or fainting; shortness of breath or wheezing; signs of infection (eg, chills, fever, sore throat); sores or ulcers on the lips or mouth; sudden, severe headache, vomiting, or sweating; swelling of the legs or feet; symptoms of blood problems (eg, unusual bruising or bleeding, severe or persistent tiredness or weakness, sluggishness, unusually pale skin, yellowing of the skin or eyes); vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Campath Side Effects - for the Professional

Campath

The following adverse reactions are discussed in greater detail in other sections of the label:

• Cytopenias [see WARNINGS AND PRECAUTIONS (5.1)]
• Infusion Reactions [see WARNINGS AND PRECAUTIONS (5.2)]
• Immunosuppression/Infections [see WARNINGS AND PRECAUTIONS (5.3)]

The most common adverse reactions with Campath are: infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), infections (CMV viremia, CMV infection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most common serious adverse reactions are cytopenias, infusion reactions, and immunosuppression/infections.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Campath in 296 patients with CLL of whom 147 were previously untreated and 149 received at least 2 prior chemotherapy regimens. The median duration of exposure was 11.7 weeks for previously untreated patients and 8 weeks for previously treated patients.

Lymphopenia: Severe lymphopenia and a rapid and sustained decrease in lymphocyte subsets occurred in previously untreated and previously treated patients following administration of Campath. In previously untreated patients, the median CD4+ was 0 cells/μL at one month after treatment and 238 cells/μL [25-75% interquartile range 115 to 418 cells/μL at 6 months post-treatment [see WARNINGS AND PRECAUTIONS (5.3)].

Neutropenia: In previously untreated patients, the incidence of Grade 3 or 4 neutropenia was 42% with a median time to onset of 31 days and a median duration of 37 days. In previously treated patients, the incidence of Grade 3 or 4 neutropenia was 64% with a median duration of 28 days. Ten percent of previously untreated patients and 17% of previously treated patients received granulocyte colony stimulating factors.

Anemia: In previously untreated patients, the incidence of Grade 3 or 4 anemia was 12% with a median time to onset of 31 days and a median duration of 8 days. In previously treated patients, the incidence of Grade 3 or 4 anemia was 38%. Seventeen percent of previously untreated patients and 66% of previously treated patients received either erythropoiesis stimulating agents, transfusions or both.

Thrombocytopenia: In previously untreated patients, the incidence of Grade 3 or 4 thrombocytopenia was 14% with a median time to onset of 9 days and a median duration of 14 days. In previously treated patients, the incidence of Grade 3 or 4 thrombocytopenia was 52% with a median duration of 21 days. Autoimmune thrombocytopenia was reported in 2% of previously treated patients with one fatality.

Infusion reactions: Infusion reactions, which included pyrexia, chills, hypotension, urticaria, and dyspnea, were common. Grade 3 and 4 pyrexia and/or chills occurred in approximately 10% of previously untreated patients and in approximately 35% of previously treated patients. The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses of Campath. All patients were pretreated with antipyretics and antihistamines; additionally, 43% of previously untreated patients received glucocorticoid pre-treatment.

Infections: In the study of previously untreated patients, patients were tested weekly for CMV using a PCR assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. CMV infection occurred in 16% (23/147) of previously untreated patients; approximately one-third of these infections were serious or life threatening. In studies of previously treated patients in which routine CMV surveillance was not required, CMV infection was documented in 6% (9/149) of patients; nearly all of these infections were serious or life threatening.

Other infections were reported in approximately 50% of patients across all studies. Grade 3 - 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 - 4 febrile neutropenia ranged from 5 to 10% across studies and was higher in previously treated patients. Infection-related fatalities occurred in 2% of previously untreated patients and 16% of previously treated patients. There were 198 episodes of other infection in 109 previously untreated patients; 16% were bacterial, 7% were fungal, 4% were other viral, and in 73%, the organism was not identified.

Cardiac: Cardiac dysrhythmias occurred in approximately 14% of previously untreated patients. The majority were tachycardias and were temporally associated with infusion; dysrhythmias were Grade 3 or 4 in 1% of patients.

Previously Untreated Patients

Table 1 contains selected adverse reactions observed in 294 patients randomized (1:1) to receive Campath or chlorambucil as first line therapy for B-CLL. Campath was administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks. The median duration of therapy was 11.7 weeks with a median weekly dose of 82 mg (25-75% interquartile range: 69 mg – 90 mg).

Table 1

Per Patient Incidence of Selected* Adverse Reactions in Treatment Naive B-CLL Patients
		Campath (n=147)		Chlorambucil (n=147)
*    Adverse reactions occurring at a higher relative frequency in the Campath arm †    NCI CTC version 2.0 for adverse reactions; NCI CTCAE version 3.0 for laboratory values ‡    CMV viremia (without evidence of symptoms) includes both cases of single PCR positive test results and of confirmed CMV viremia (≥ 2 occasions in consecutive samples 1 week apart).  For the latter, ganciclovir (or equivalent) was initiated per protocol.
		All Grades†   %	Grades 3-4 %	All Grades %	Grades 3-4 %
Blood and Lymphatic System Disorders	Lymphopenia	97	97	9	1
	Neutropenia	77	42	51	26
	Anemia	76	13	54	18
	Thrombocytopenia	71	13	70	14
General Disorders and Administration Site Conditions	Pyrexia	69	10	11	1
	Chills	53	3	1	0
Infections and Infestations	CMV viremia‡	55	4	8	0
	CMV infection	16	5	0	0
	Other infections	74	21	65	10
Skin and Subcutaneous Tissue Disorders	Urticaria	16	2	1	0
	Rash	13	1	4	0
	Erythema	4	0	1	0
Vascular Disorders	Hypotension	16	1	0	0
	Hypertension	14	5	2	1
Nervous System Disorders	Headache	14	1	8	0
	Tremor	3	0	1	0
Respiratory, Thoracic and Mediastinal Disorders	Dyspnea	14	4	7	3
Gastrointestinal Disorders	Diarrhea	10	1	4	0
Psychiatric Disorders	Insomnia	10	0	3	0
	Anxiety	8	0	1	0
Cardiac Disorders	Tachycardia	10	0	1	0

Previously Treated Patients

Additional safety information was obtained from 3 single arm studies of 149 previously treated patients with CLL administered 30 mg Campath intravenously three times weekly for 4 to 12 weeks (median cumulative dose 673 mg [range 2 – 1106 mg]; median duration of therapy 8.0 weeks). Adverse reactions in these studies not listed in Table 1 that occurred at an incidence rate of > 5% were fatigue, nausea, emesis, musculoskeletal pain, anorexia, dysesthesia, mucositis, and bronchospasm.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Using an ELISA assay, anti-human antibodies (HAHA) were detected in 11 of 133 (8.3%) previously untreated patients. In addition, two patients were weakly positive for neutralizing activity. Limited data suggest that the anti-Campath antibodies did not adversely affect tumor response. Four of 211 (1.9%) previously-treated patients were found to have antibodies to Campath following treatment.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Campath with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions were identified during post-approval use of Campath. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Campath exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Campath.

Fatal infusion reactions: [see WARNINGS AND PRECAUTIONS (5.2)].

Cardiovascular: congestive heart failure, cardiomyopathy, decreased ejection fraction (some patients had been previously treated with cardiotoxic agents).

Immune disorders: Goodpasture’s syndrome, Graves’ disease, aplastic anemia, Guillain Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness, fatal transfusion associated Graft versus Host Disease.

Infections: Epstein-Barr Virus (EBV) including EBV-associated lymphoproliferative disorder, progressive multifocal leukoencephalopathy (PML), re-activation of latent viruses.

Metabolic: tumor lysis syndrome

Neurologic: optic neuropathy

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Side Effects by Body System - for Healthcare Professionals

General

The major adverse effects associated with alemtuzumab have included infusion-related reactions, hematologic toxicity, and infections.

Alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, rash, syncope, pulmonary infiltrates, ARDS, respiratory arrest, cardiac arrhythmias, myocardial infarction, and cardiac arrest. Some cases of cardiac adverse events have resulted in death.

Hematologic

Median CD4+ lymphocyte counts were 2/mcL 4 weeks after begin of alemtuzumab therapy, 207/mcL two months after discontinuation, and 470/mcL six months after discontinuation. CD8+ cells followed a similar pattern of change. In some patients, CD4+ and CD8+ counts did not return to baseline levels within 1 year after discontinuation.

Hematologic side effects include myelosuppression, which is the major toxicity associated with alemtuzumab and has been fatal in rare cases. The following grade 3 or 4 severity effects have been reported in 93 B-CLL trial patients: anemia (47%), autoimmune hemolytic anemia (1%), neutropenia (70%), thrombocytopenia (52%), autoimmune thrombocytopenia (2%, 1 fatal). Six percent of patients discontinued alemtuzumab permanently due to pancytopenia/marrow hypoplasia, and 2% of these cases were fatal.

The following adverse events were reported in 149 B-CLL trial patients (including the 93 above): neutropenia (85% any grade, 64% grade 3/4), anemia (80% any grade, 38% grade 3/4), pancytopenia (5% any grade, 3% grade 3/4), thrombocytopenia (72% any grade, 50% grade 3/4), purpura (8%), and epistaxis (7% any grade, 1% grade 3/4). Additional serious side effects reported in B-CLL and other trials have included agranulocytosis, aplasia, decreased haptoglobin, lymphadenopathy, marrow depression, coagulation disorder, disseminated intravascular coagulation, hematoma, pulmonary embolism, thrombocythemia, hemolysis, hemolytic anemia, splenic infarction, and splenomegaly.

Immunologic

Immunologic side effects have included infections in 43% of 93 B-CLL patients who had received anti-infective prophylaxis: sepsis (12%), pneumonia (15%), opportunistic infections (17%), neutropenic fever (10%), aplastic anemia, and chronic inflammatory demyelinating polyradiculoneuropathy. Eighteen percent of infections were fatal. Development of antibodies to alemtuzumab has occurred in 1.9% (4 of 211) of patients. Postmarketing experiences have included fatal transfusion associated graft versus host disease.

Types of infections reported in the 93 B-CLL patients have included Candida, CMV, Aspergillosis, Mucomycosis, Cryptococcal pneumonia, Listeria monocytogenes meningitis, disseminated Herpes zoster, Herpes simplex, Torulopsis pneumonia, and PCP pneumonia. Infections reported in other trials have included abscess, bacterial infection, Herpes zoster infection, Pneumocystis carinii infection, otitis media, Tuberculosis infection, interstitial pneumonitis, progressive multifocal leukoencephalopathy, and other viral infections.

Postmarketing experiences have included Epstein-Barr virus lymphoproliferative disorder and reactivation of latent viruses.

Respiratory

An initial dose of 80 mg caused acute bronchospasm, cough, shortness of breath, followed by anuria and death in one patient. Tumor lysis syndrome may have been a factor.

Respiratory side effects reported in B-CLL patients have included dyspnea (26% any grade, 9% grade 3/4), cough (25% any grade, 2% grade 3/4), bronchitis/pneumonitis (21% any grade, 13% grade 3/4), pneumonia (16% any grade, 10% grade 3/4), pharyngitis (12%), bronchospasm (9% any grade, 2% grade 3/4), and rhinitis (7%). Serious effects reported in other trials have included asthma, bronchitis, chronic obstructive pulmonary disease, hemoptysis, hypoxia, pleural effusion, pleurisy, pneumothorax, pulmonary edema, pulmonary fibrosis, pulmonary infiltration, respiratory depression, respiratory insufficiency, sinusitis, stridor, and throat tightness. A case of diffuse alveolar hemorrhage has also been reported.

Gastrointestinal

Gastrointestinal side effects reported in B-CLL patients have included nausea (54%), vomiting (41%), diarrhea (22%), stomatitis/ulcerative stomatitis/mucositis (14%), abdominal pain (11%), dyspepsia (10%), and constipation (9%). Serious gastrointestinal effects which have been reported in other trials include: duodenal ulcer, esophagitis, gingivitis, gastroenteritis, GI hemorrhage, hematemesis, hemorrhoids, intestinal obstruction, intestinal perforation, melena, paralytic ileus, peptic ulcer, pseudomembranous colitis, colitis, pancreatitis, and peritonitis.

Nervous system

Nervous system side effects reported in B-CLL patients have included headache (24%), dysthesias (15%), dizziness (12%), and tremor (7%). Serious nervous system effects which have been reported in other trials include: abnormal gait, aphasia, coma, grand mal convulsions, paralysis, meningitis, and syncope.

Cardiovascular

Cardiovascular side effects reported in B-CLL patients have included hypotension (32% any grade, 5% grade 3/4), hypertension (11% any grade, 2% grade 3/4), and tachycardia/SVT (11% any grade, 3% grade 3/4). Serious effects which have been reported in other trials include: cardiac failure, cyanosis, atrial fibrillation, cardiac arrest, ventricular arrhythmia, ventricular tachycardia, angina pectoris, coronary artery disorder, myocardial infarction, pericarditis, cerebral hemorrhage, cerebrovascular disorder, deep vein thrombosis, increased capillary fragility, intracranial hemorrhage, phlebitis, subarachnoid hemorrhage, cardiomyopathy and thrombophlebitis. Decreased ejection fraction has been reported in patients previously treated with cardiotoxic agents. Postmarketing experiences have included reports of congestive heart failure.

Musculoskeletal

Musculoskeletal side effects reported in B-CLL patients have included myalgias (11%). Serious side effects reported in other trials have included arthritis or worsening arthritis, arthropathy, bone fracture, myositis, muscle atrophy, muscle weakness, osteomyelitis, polymyositis, asthenia, skeletal pain, back pain, and chest pain.

Psychiatric

Psychiatric side effects reported in B-CLL patients have included insomnia (10%), depression (7%), and somnolence (5%). Serious effects reported in other trials have included confusion, hallucinations, nervousness, abnormal thinking and apathy.

Dermatologic

Dermatologic side effects reported in B-CLL patients have included rashes (40% any grade, 3% grade 3/4), urticaria (30% any grade, 5% grade 3/4), pruritus (24% any grade), and increased sweating (19%). Serious effects reported in other trials include angioedema, bullous eruption, cellulitis, and purpuric rash.

Endocrine

Endocrine side effects have included serious cases of hyperthyroidism.

Hepatic

Hepatic side effects have included serious cases of hyperbilirubinemia, hepatic failure, hepatocellular damage, hypoalbuminemia, and biliary pain.

Metabolic

Metabolic side effects have included serious cases of acidosis, aggravated diabetes mellitus, dehydration, fluid overload, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, and respiratory alkalosis, edema, peripheral edema, and hypovolemia.

Oncologic

Oncologic side effects have included cases of malignant lymphoma, malignant testicular neoplasm, prostatic cancer, plasma cell dyscrasia, secondary leukemia, squamous cell carcinoma, transformation to aggressive lymphoma, transformation or prolymphocytic leukemia. A case of Epstein-Barr virus positive lymphoproliferative disorder has also been reported.

Genitourinary

Genitourinary side effects have included cases of cervical dysplasia.

Other

Other side effects have included decreased hearing, taste loss, ascites, influenza-like syndrome, mouth edema, rigors, fever, pain, malaise, and temperature change sensation.

Renal

Renal side effects have included serious cases of abnormal renal function, acute renal failure, facial edema, hematuria, toxic nephropathy, ureteric obstruction, urinary retention, and urinary tract infection.

Ocular

Ocular side effects have included cases of endophthalmitis.

Hypersensitivity

Hypersensitivity reactions have included allergic and anaphylactoid reactions.

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