Campath: Package Insert and Label Information

CAMPATH- alemtuzumab injection
Genzyme Corporation

Infusion-Related Reactions: CAMPATH administration can result in serious, including fatal, infusion-related reactions. Carefully monitor patients during infusions and withhold CAMPATH for Grade 3 or 4 infusion-related reactions. Gradually escalate CAMPATH to the recommended dose at the initiation of therapy and after interruption of therapy for 7 or more days [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

Immunosuppression/Infections: Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving CAMPATH. Administer prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Schedule and Administration

• Administer as an intravenous infusion over 2 hours. Do not administer as intravenous push or bolus.
• Recommended Dosing Regimen
  • Gradually escalate to the maximum recommended single dose of 30 mg. Escalation is required at initiation of dosing or if dosing is held ≥7 days during treatment. Escalation to 30 mg ordinarily can be accomplished in 3 to 7 days.
  • Escalation Strategy:

    –

    Administer 3 mg daily until infusion-related reactions are ≤ Grade 2 [see Adverse Reactions (6.1)].

    –

    Then administer 10 mg daily until infusion-related reactions are ≤ Grade 2.

    –

    Then administer 30 mg/day three times per week on alternate days (e.g., Mon-Wed-Fri). The total duration of therapy, including dose escalation, is 12 weeks.

• Single doses of greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.

2.2 Recommended Concomitant Medications

• Premedicate with diphenhydramine (50 mg) and acetaminophen (500–1000 mg) 30 minutes prior to first infusion and each dose escalation. Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
• Administer trimethoprim/sulfamethoxazole double strength (DS) twice daily 3 times per week (or equivalent) as Pneumocystis jirovecii pneumonia (PCP) prophylaxis.
• Administer famciclovir 250 mg BID or equivalent as herpetic prophylaxis.

Continue PCP and herpes viral prophylaxis for a minimum of 2 months after completion of CAMPATH or until the CD4+ count is ≥200 cells/µL, whichever occurs later [see Warnings and Precautions (5.3)].

2.3 Dosage Modification

• Withhold CAMPATH during serious infection or other serious adverse reactions until resolution.
• Discontinue CAMPATH for autoimmune anemia or autoimmune thrombocytopenia.
• There are no dose modifications recommended for lymphopenia.

Dose Modification for Neutropenia or Thrombocytopenia [see Warnings and Precautions (5.1)]

Hematologic Values	Dosage Modification *
* If the delay between dosing is ≥7 days, initiate therapy at CAMPATH 3 mg and escalate to 10 mg and then to 30 mg as tolerated [see Dosage and Administration (2.1)].
ANC <250/μL and/or platelet count ≤25,000/μL
For first occurrence:	Withhold CAMPATH therapy. Resume CAMPATH at 30 mg when ANC ≥500/μL and platelet count ≥50,000/μL.
For second occurrence:	Withhold CAMPATH therapy. Resume CAMPATH at 10 mg when ANC ≥500/μL and platelet count ≥50,000/μL.
For third occurrence:	Discontinue CAMPATH therapy.
≥50% decrease from baseline in patients initiating therapy with a baseline ANC ≤250/μL and/or a baseline platelet count ≤25,000/μL
For first occurrence:	Withhold CAMPATH therapy. Resume CAMPATH at 30 mg upon return to baseline value(s).
For second occurrence:	Withhold CAMPATH therapy. Resume CAMPATH at 10 mg upon return to baseline value(s).
For third occurrence:	Discontinue CAMPATH therapy.

2.4 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, discard the vial. DO NOT SHAKE VIAL.

Use aseptic technique during the preparation and administration of CAMPATH. Withdraw the necessary amount of CAMPATH from the vial into a syringe.

• To prepare the 3 mg dose, withdraw 0.1 mL into a 1 mL syringe calibrated in increments of 0.01 mL.
• To prepare the 10 mg dose, withdraw 0.33 mL into a 1 mL syringe calibrated in increments of 0.01 mL.
• To prepare the 30 mg dose, withdraw 1 mL in either a 1 mL or 3 mL syringe calibrated in 0.1 mL increments.

Inject syringe contents into 100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution. Discard syringe.

The vial contains no preservatives and is intended for single use only. DISCARD VIAL including any unused portion after withdrawal of dose.

Use within 8 hours after dilution. Store diluted CAMPATH at room temperature between 15°C to 30°C (59°F to 86°F) or refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light.

2.5 Incompatibilities

CAMPATH is compatible with polyvinylchloride (PVC) bags and PVC or polyethylene-lined PVC administration sets. Do not add or simultaneously infuse other drug substances through the same intravenous line.

3 DOSAGE FORMS AND STRENGTHS

Injection: 30 mg/1 mL as a clear, colorless solution in single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Cytopenias

Severe, including fatal, autoimmune anemia and thrombocytopenia, and prolonged myelosuppression have been reported in patients receiving CAMPATH.

In addition, hemolytic anemia, pure red cell aplasia, bone marrow aplasia, and hypoplasia have been reported after treatment with CAMPATH at the recommended dose. Single doses of CAMPATH greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia.

Withhold CAMPATH for severe cytopenias (except lymphopenia). Discontinue for autoimmune cytopenias or recurrent/persistent severe cytopenias (except lymphopenia) [see Dosage and Administration (2.3)]. No data exist on the safety of CAMPATH resumption in patients with autoimmune cytopenias or marrow aplasia [see Adverse Reactions (6.1)].

Obtain complete blood counts (CBC) at weekly intervals during CAMPATH therapy and more frequently if worsening anemia, neutropenia, or thrombocytopenia occurs. Assess CD4+ counts after treatment until recovery to ≥200 cells/µL [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.2 Infusion-Related Reactions

Adverse reactions occurring during or shortly after CAMPATH infusion include pyrexia, chills/rigors, nausea, hypotension, urticaria, dyspnea, rash, emesis, and bronchospasm [see Adverse Reactions (6.1)]. In clinical trials, the frequency of infusion-related reactions was highest in the first week of treatment. Monitor for the signs and symptoms listed above and withhold infusion for Grade 3 or 4 infusion-related reactions.

The following serious, including fatal, infusion-related reactions have been identified in postmarketing reports: syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arrest, cardiac arrhythmias, myocardial infarction, acute cardiac insufficiency, cardiac arrest, angioedema, and anaphylactoid shock.

Initiate CAMPATH according to the recommended dose-escalation scheme [see Dosage and Administration (2.1)]. Premedicate patients with an antihistamine and acetaminophen prior to each dose. Institute appropriate medical management (e.g., glucocorticoids, epinephrine, meperidine) for infusion-related reactions as needed [see Dosage and Administration (2.2)]. If therapy is interrupted for 7 or more days, reinstitute CAMPATH with gradual dose escalation [see Dosage and Administration (2.1)].

5.3 Immunosuppression/Infections

CAMPATH treatment results in severe and prolonged lymphopenia with a concomitant increased incidence of opportunistic infections [see Adverse Reactions (6.1)]. Administer PCP and herpes viral prophylaxis during treatment with CAMPATH and for a minimum of 2 months after completion of CAMPATH or until the CD4+ count is ≥200 cells/µL, whichever occurs later [see Dosage and Administration (2.2)]. Prophylaxis does not eliminate these infections.

Routinely monitor patients for CMV infection during treatment with CAMPATH and for at least 2 months following completion of CAMPATH. Withhold CAMPATH 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). Initiate therapeutic ganciclovir (or equivalent) for CMV infection or confirmed CMV viremia.

Epstein-Barr virus (EBV) infection, including severe and fatal EBV-associated hepatitis, has been reported in patients who received CAMPATH.

Monitor for sign and symptoms of EBV infections. Withhold CAMPATH for EBV reactivation or severe infection.

Administer only irradiated blood products to avoid transfusion associated Graft versus Host Disease (TAGVHD), unless emergent circumstances dictate immediate transfusion.

In patients who received CAMPATH as initial therapy, recovery of CD4+ counts to ≥200 cells/µL occurred by 6 months following completion of CAMPATH; however, at 2 months post treatment, the median was 183 cells/µL. In previously treated patients who received CAMPATH, the median time to recovery of CD4+ counts to ≥200 cells/µL was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months [see Adverse Reactions (6)].

5.4 Immunization

The safety of immunization with live viral vaccines following CAMPATH therapy has not been studied. Do not administer live viral vaccines to patients or infants born to patients receiving CAMPATH. The ability to generate an immune response to any vaccine following CAMPATH therapy has not been studied.

6 ADVERSE REACTIONS

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

• Cytopenias [see Warnings and Precautions (5.1)]
• Infusion-Related Reactions [see Warnings and Precautions (5.2)]
• Immunosuppression/Infections [see Warnings and Precautions (5.3)]

6.1 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.

The most common adverse reactions with CAMPATH are: infusion-related 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-related reactions, and immunosuppression/infections.

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-Related Reactions

Infusion-related 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-related 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 to 5 sepsis ranged from 3% to 10% across studies and was higher in previously treated patients. Grade 3 to 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: 69–90 mg).

Table 1: Per Patient Incidence of Selected * Adverse Reactions in Treatment Naive B-CLL Patients

		CAMPATH (n=147)		Chlorambucil (n=147)
		All Grades † %	Grades 3–4 %	All Grades %	Grades 3–4 %
* 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.
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.