A1, A2, B, C1, C2, D, E, F, G-H, I-K, L, M, N, O, P1, P2, Q-R, S, T, U-V, W-Z

Herceptin Side Effects, and Drug Interactions - Trastuzumab

SIDE EFFECTS

A total of 958 patients have received HERCEPTIN^® (Trastuzumab) alone or in combination with chemotherapy. Data in the table below are based on the experience with the recommended dosing regimen for HERCEPTIN in the randomized controlled clinical trial in 234 patients who received HERCEPTIN in combination with chemotherapy and four open-label studies of HERCEPTIN as a single agent in 352 patients at doses of 10-500 mg administered weekly.

Cardiac Failure/Dysfunction: For a description of cardiac toxicities, see WARNINGS.

Anemia and Leukopenia: An increased incidence of anemia and leukopenia was observed in the treatment group receiving HERCEPTIN and chemotherapy, especially in the HERCEPTIN and AC subgroup, compared with the treatment group receiving chemotherapy alone. The majority of these cytopenic events were mild or moderate in intensity, reversible, and none resulted in discontinuation of therapy with HERCEPTIN.

Hematologic toxicity is infrequent following the administration of HERCEPTIN as a single agent, with an incidence of Grade III toxicities for WBC, platelets, hemoglobin all 1%. No Grade IV toxicities were observed.

Diarrhea: Of patients treated with HERCEPTIN as a single agent, 25% experienced diarrhea. An increased incidence of diarrhea, primarily mild to moderate in severity, was observed in patients receiving HERCEPTIN in combination with chemotherapy.

Infection: An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, was observed in patients receiving HERCEPTIN in combination with chemotherapy.

Infusion-Associated Symptoms: During the first infusion with HERCEPTIN, a symptom complex most commonly consisting of chills and/or fever was observed in about 40% of patients. The symptoms were usually mild to moderate in severity and were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of HERCEPTIN infusion). HERCEPTIN discontinuation was infrequent. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, rash, and asthenia. The symptoms occurred infrequently with subsequent HERCEPTIN infusions.

Table 4

Adverse Events Occurring in ³5% of Patients or at
Increased Incidence in the HERCEPTIN Arm of the Randomized Study
(Percent of Patients)

	Single Agent n = 352	HERCEPTIN Paclitaxel n = 91	Paclitaxel Alone n = 95	HERCEPTIN AC n = 143	AC Alone n = 135
Body as a Whole
Pain	47	61	62	57	42
Asthenia	42	62	57	54	55
Fever	36	49	23	56	34
Chills	32	41	4	35	11
Headache	26	36	28	44	31
Abdominal pain	22	34	22	23	18
Back pain	22	34	30	27	15
Infection	20	47	27	47	31
Flu syndrome	10	12	5	12	6
Accidental injury	6	13	3	9	4
Allergic Reaction	3	8	2	4	2
Cardiovascular
Tachycardia	5	12	4	10	5
Congestive heart failure	7	11	1	28	7
Digestive
Nausea	33	51	9	76	77
Diarrhea	25	45	29	45	26
Vomiting	23	37	28	53	49
Nausea and vomiting	8	14	11	18	9
Anorexia	14	24	16	31	26
Heme & Lymphatic
Anemia	4	14	9	36	26
Leukopenia	3	24	17	52	34
Metabolic
Peripheral edema	10	22	20	20	17
Edema	8	10	8	11	5
Musculoskeletal
Bone pain	7	24	18	7	7
Arthralgia	6	37	21	8	9
Nervous
Insomnia	14	25	13	29	15
Dizziness	13	22	24	24	18
Paresthesia	9	48	39	17	11
Depression	6	12	13	20	12
Peripheral neuritis	2	23	16	2	2
Neuropathy	1	13	5	4	4
Respiratory
Cough increased	26	41	22	43	29
Dyspnea	22	27	26	42	25
Rhinitis	14	22	5	22	16
Pharyngitis	12	22	14	30	18
Sinusitis	9	21	7	13	6
Skin
Rash	18	38	18	27	17
Herpes simplex	2	12	3	7	9
Acne	2	11	3	3	< 1
Urogenital
Urinary tract infection	5	18	14	13	7

Other Serious Adverse Events

The following other serious adverse events occurred in at least one of the 958 patients treated with HERCEPTIN:

Body as a Whole: cellulitis, anaphylactoid reaction, ascites, hydrocephalus, radiation injury, deafness, amblyopia

Cardiovascular: vascular thrombosis, pericardial effusion, heart arrest, hypotension, syncope, hemorrhage, shock arrhythmia

Digestive: hepatic failure, gastroenteritis, hematemesis, ileus, intestinal obstruction, colitis, esophageal ulcer, stomatitis, pancreatitis, hepatitis

Endocrine: hypothyroidism

Hematological: pancytopenia, acute leukemia, coagulation disorder, lymphangitis

Metabolic: hypercalcemia, hypomagnesemia, hyponatremia, hypoglycemia, growth retardation, weight loss

Musculoskeletal: pathological fractures, bone necrosis, myopathy

Nervous: convulsion, ataxia, confusion, manic reaction

Respiratory: apnea, pneumothorax, asthma, hypoxia, laryngitis

Skin: herpes zoster, skin ulceration

Urogenital: hydronephrosis, kidney failure, cervical cancer, hematuria, hemorrhagic cystitis, pyelonephritis

DRUG INTERACTIONS

There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of paclitaxel in combination with HERCEPTIN resulted in a two-fold decrease in HERCEPTIN clearance in a non-human primate study and in a 1.5-fold increase in HERCEPTIN serum levels in clinical studies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

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