Gemzar Side Effects

Generic Name: gemcitabine

Please note - some side effects for Gemzar 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 Gemzar - for the Consumer

Gemzar

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 Gemzar:

Abnormal skin sensations; bleeding; blood in the urine; constipation; diarrhea; drowsiness; flu-like symptoms (fever, weakness, loss of appetite, headache, cough, chills, and muscle aches); hair loss; infection (fever, chills, sore throat); itching; loss of appetite; nausea; reaction at the injection site; sleepiness; small red spots under the skin; swelling of the hands or feet; vomiting.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abdominal pain; confusion; dark urine; difficulty breathing; difficulty urinating or decreased amount of urine; irregular or absent menstrual periods; irregular heartbeat; joint or muscle pain; numbness in the arms or legs; painful or frequent urination; seeing or hearing strange things; seizures; shortness of breath; sores on the mouth or lips; unusual bruising or bleeding; unusual tiredness; yellowing of the skin or eyes.

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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Gemzar Side Effects - for the Professional

Gemzar

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.

Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.

Gemzar has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs.

Single-Agent Use:

Myelosuppression is the principal dose-limiting toxicity with Gemzar therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

The data in Table 4 are based on 979 patients receiving Gemzar as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemzar starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of Gemzar therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the Gemzar arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories.

Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemzar WHO Grades (% incidence)a

a Grade based on criteria from the World Health Organization (WHO).
b N=699-974; all patients with laboratory or non-laboratory data.
c N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data.
d N=979.
e Regardless of causality.
f Table includes non-laboratory data with incidence for all patients ≥10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
	All Patientsb			Pancreatic Cancer Patientsc			Discontinuations (%)d
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4	All Patients
Laboratorye
Hematologic
Anemia	68	7	1	73	8	2	<1
Leukopenia	62	9	<1	64	8	1	<1
Neutropenia	63	19	6	61	17	7	-
Thrombocytopenia	24	4	1	36	7	<1	<1
Hepatic							<1
ALT	68	8	2	72	10	1
AST	67	6	2	78	12	5
Alkaline Phosphatase	55	7	2	77	16	4
Bilirubin	13	2	<1	26	6	2
Renal							<1
Proteinuria	45	<1	0	32	<1	0
Hematuria	35	<1	0	23	0	0
BUN	16	0	0	15	0	0
Creatinine	8	<1	0	6	0	0
Non-laboratoryf
Nausea and Vomiting	69	13	1	71	10	2	<1
Fever	41	2	0	38	2	0	<1
Rash	30	<1	0	28	<1	0	<1
Dyspnea	23	3	<1	10	0	<1	<1
Diarrhea	19	1	0	30	3	0	0
Hemorrhage	17	<1	<1	4	2	<1	<1
Infection	16	1	<1	10	2	<1	<1
Alopecia	15	<1	0	16	0	0	0
Stomatitis	11	<1	0	10	<1	0	<1
Somnolence	11	<1	<1	11	2	<1	<1
Paresthesias	10	<1	0	10	<1	0	0

Hematologic — In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with Gemzar, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during Gemzar therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Gastrointestinal — Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.

Hepatic — In clinical trials, Gemzar was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to Gemzar or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)].

Renal — In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemzar in clinical trials. Four patients developed HUS on Gemzar therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemzar therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)].

Fever — The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that Gemzar may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable.

Rash — Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients.

Pulmonary — In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with Gemzar therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, Gemzar should be discontinued. Early use of supportive care measures may help ameliorate these conditions.

Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema.

Flu-like Symptoms — “Flu syndrome” was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.

Infection — Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).

Alopecia — Hair loss, usually minimal, was reported by 15% of patients.

Neurotoxicity — There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.

Extravasation — Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemzar is not a vesicant.

Allergic — Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemzar should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)].

Cardiovascular — During clinical trials, 2% of patients discontinued therapy with Gemzar due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)].

Combination Use in Non-Small Cell Lung Cancer:

In the Gemzar plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of Gemzar injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of Gemzar plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions.

In the Gemzar plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of Gemzar injections and 16% of cisplatin injections in the Gemzar plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of Gemzar plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the Gemzar plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the Gemzar plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with Gemzar plus cisplatin treatment (~90%) compared to that with the Gemzar monotherapy (~60%). With combination therapy Gemzar dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.

Table 5 presents the safety data from the Gemzar plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the Gemzar plus cisplatin arm.

Myelosuppression occurred more frequently on the combination arm, and in 4 possibly treatment-related deaths myelosuppression was observed. Sepsis was reported in 4% of patients on the Gemzar plus cisplatin arm compared to 1% on the cisplatin arm. Platelet transfusions were required in 21% of patients on the combination arm and <1% of patients on the cisplatin arm. Hemorrhagic events occurred in 14% of patients on the combination arm and 4% on the cisplatin arm. However, severe hemorrhagic events were rare. Red blood cell transfusions were required in 39% of the patients on the Gemzar plus cisplatin arm, versus 13% on the cisplatin arm. The data suggest cumulative anemia with continued Gemzar plus cisplatin use.

Nausea and vomiting despite the use of antiemetics occurred more often with Gemzar plus cisplatin therapy (78%) than with cisplatin alone (71%). In studies with single-agent Gemzar, a lower incidence of nausea and vomiting (58% to 69%) was reported. Renal function abnormalities, hypomagnesemia, neuromotor, neurocortical, and neurocerebellar toxicity occurred more often with Gemzar plus cisplatin than with cisplatin monotherapy. Neurohearing toxicity was similar on both arms.

Cardiac dysrrhythmias of Grade 3 or greater were reported in 7 (3%) patients treated with Gemzar plus cisplatin compared to one (<1%) Grade 3 dysrrhythmia reported with cisplatin therapy. Hypomagnesemia and hypokalemia were associated with one Grade 4 arrhythmia on the Gemzar plus cisplatin combination arm.

Table 6 presents data from the randomized study of Gemzar plus cisplatin versus etoposide plus cisplatin in 135 patients with NSCLC. One death (1.5%) was reported on the Gemzar plus cisplatin arm due to febrile neutropenia associated with renal failure which was possibly treatment-related. No deaths related to treatment occurred on the etoposide plus cisplatin arm. The overall incidence of Grade 4 neutropenia on the Gemzar plus cisplatin arm was less than on the etoposide plus cisplatin arm (28% versus 56%). Sepsis was experienced by 2% of patients on both treatment arms. Grade 3 anemia and Grade 3/4 thrombocytopenia were more common on the Gemzar plus cisplatin arm. RBC transfusions were given to 29% of the patients who received Gemzar plus cisplatin versus 21% of patients who received etoposide plus cisplatin. Platelet transfusions were given to 3% of the patients who received Gemzar plus cisplatin versus 8% of patients who received etoposide plus cisplatin. Grade 3/4 nausea and vomiting were also more common on the Gemzar plus cisplatin arm. On the Gemzar plus cisplatin arm, 7% of participants were hospitalized due to febrile neutropenia compared to 12% on the etoposide plus cisplatin arm. More than twice as many patients had dose reductions or omissions of a scheduled dose of Gemzar as compared to etoposide, which may explain the differences in the incidence of neutropenia and febrile neutropenia between treatment arms. Flu syndrome was reported by 3% of patients on the Gemzar plus cisplatin arm with none reported on the comparator arm. Eight patients (12%) on the Gemzar plus cisplatin arm reported edema compared to one patient (2%) on the etoposide plus cisplatin arm.

Table 5: Selected CTC-Graded Adverse Reactions From Comparative Trial of Gemzar Plus Cisplatin Versus Single-Agent Cisplatin in NSCLC CTC Grades (% incidence)a

a Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse reactions with incidence ≥10% in either arm.
b N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gemzar at 1000 mg/m2 on Days 1, 8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days.
c N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.
d Regardless of causality.
e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
f Non-laboratory events were graded only if assessed to be possibly drug-related.
	Gemzar plus Cisplatinb			Cisplatinc
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Laboratoryd
Hematologic
Anemia	89	22	3	67	6	1
RBC Transfusione	39			13
Leukopenia	82	35	11	25	2	1
Neutropenia	79	22	35	20	3	1
Thrombocytopenia	85	25	25	13	3	1
Platelet Transfusionse	21			<1
Lymphocytes	75	25	18	51	12	5
Hepatic
Transaminase	22	2	1	10	1	0
Alkaline Phosphatase	19	1	0	13	0	0
Renal
Proteinuria	23	0	0	18	0	0
Hematuria	15	0	0	13	0	0
Creatinine	38	4	<1	31	2	<1
Other Laboratory
Hyperglycemia	30	4	0	23	3	0
Hypomagnesemia	30	4	3	17	2	0
Hypocalcemia	18	2	0	7	0	<1
Non-laboratoryf
Nausea	93	25	2	87	20	<1
Vomiting	78	11	12	71	10	9
Alopecia	53	1	0	33	0	0
Neuro Motor	35	12	0	15	3	0
Neuro Hearing	25	6	0	21	6	0
Diarrhea	24	2	2	13	0	0
Neuro Sensory	23	1	0	18	1	0
Infection	18	3	2	12	1	0
Fever	16	0	0	5	0	0
Neuro Cortical	16	3	1	9	1	0
Neuro Mood	16	1	0	10	1	0
Local	15	0	0	6	0	0
Neuro Headache	14	0	0	7	0	0
Stomatitis	14	1	0	5	0	0
Hemorrhage	14	1	0	4	0	0
Dyspnea	12	4	3	11	3	2
Hypotension	12	1	0	7	1	0
Rash	11	0	0	3	0	0

Table 6: Selected WHO-Graded Adverse Reactions From Comparative Trial of Gemzar Plus Cisplatin Versus Etoposide Plus Cisplatin in NSCLC WHO Grades (% incidence)a

a Grade based on criteria from the World Health Organization (WHO).
b N=67-69; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gemzar at 1250 mg/m2 on Days 1 and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.
c N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.
d Regardless of causality.
e Percent of patients receiving transfusions. Percent transfusions are not WHO-graded events.
f Non-laboratory events were graded only if assessed to be possibly drug-related.
g Pain data were not collected.
	Gemzar plus Cisplatinb			Etoposide plus Cisplatinc
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Laboratoryd
Hematologic
Anemia	88	22	0	77	13	2
RBC Transfusionse	29			21
Leukopenia	86	26	3	87	36	7
Neutropenia	88	36	28	87	20	56
Thrombocytopenia	81	39	16	45	8	5
Platelet Transfusionse	3			8
Hepatic
ALT	6	0	0	12	0	0
AST	3	0	0	11	0	0
Alkaline Phosphatase	16	0	0	11	0	0
Bilirubin	0	0	0	0	0	0
Renal
Proteinuria	12	0	0	5	0	0
Hematuria	22	0	0	10	0	0
BUN	6	0	0	4	0	0
Creatinine	2	0	0	2	0	0
Non-laboratoryf,g
Nausea and Vomiting	96	35	4	86	19	7
Fever	6	0	0	3	0	0
Rash	10	0	0	3	0	0
Dyspnea	1	0	1	3	0	0
Diarrhea	14	1	1	13	0	2
Hemorrhage	9	0	3	3	0	3
Infection	28	3	1	21	8	0
Alopecia	77	13	0	92	51	0
Stomatitis	20	4	0	18	2	0
Somnolence	3	0	0	3	2	0
Paresthesias	38	0	0	16	2	0

Combination Use in Breast Cancer:

In the Gemzar plus paclitaxel versus paclitaxel study, dose reductions occurred with 8% of Gemzar injections and 5% of paclitaxel injections on the combination arm, versus 2% on the paclitaxel arm. On the combination arm, 7% of Gemzar doses were omitted and <1% of paclitaxel doses were omitted, compared to <1% of paclitaxel doses on the paclitaxel arm. A total of 18 patients (7%) on the Gemzar plus paclitaxel arm and 12 (5%) on the paclitaxel arm discontinued the study because of adverse reactions. There were two deaths on study or within 30 days after study drug discontinuation that were possibly drug-related, one on each arm.

Table 7 presents the safety data occurrences of ≥10% (all grades) from the Gemzar plus paclitaxel versus paclitaxel study in breast cancer.

Table 7: Adverse Reactions From Comparative Trial of Gemzar Plus Paclitaxel Versus Single-Agent Paclitaxel in Breast Cancera CTC Grades (% incidence)

a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%).
b Regardless of causality.
c Non-laboratory events were graded only if assessed to be possibly drug-related.
	Gemzar plus Paclitaxel (N=262)			Paclitaxel (N=259)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Laboratoryb
Hematologic
Anemia	69	6	1	51	3	<1
Neutropenia	69	31	17	31	4	7
Thrombocytopenia	26	5	<1	7	<1	<1
Leukopenia	21	10	1	12	2	0
Hepatobiliary
ALT	18	5	<1	6	<1	0
AST	16	2	0	5	<1	0
Non-laboratoryc
Alopecia	90	14	4	92	19	3
Neuropathy-sensory	64	5	<1	58	3	0
Nausea	50	1	0	31	2	0
Fatigue	40	6	<1	28	1	<1
Myalgia	33	4	0	33	3	<1
Vomiting	29	2	0	15	2	0
Arthralgia	24	3	0	22	2	<1
Diarrhea	20	3	0	13	2	0
Anorexia	17	0	0	12	<1	0
Neuropathy-motor	15	2	<1	10	<1	0
Stomatitis/pharyngitis	13	1	<1	8	<1	0
Fever	13	<1	0	3	0	0
Rash/desquamation	11	<1	<1	5	0	0

The following are the clinically relevant adverse reactions that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (Gemzar plus paclitaxel versus paclitaxel): febrile neutropenia (5.0% versus 1.2%), infection (0.8% versus 0.8%), dyspnea (1.9% versus 0), and allergic reaction/hypersensitivity (0 versus 0.8%).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Combination Use in Ovarian Cancer:

In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse reactions between arms (10.9% versus 9.8%, respectively).

Table 8 presents the adverse reactions (all grades) occurring in ≥10% of patients in the ovarian cancer study.

Table 8: Adverse Reactions From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence)

a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%).
b Regardless of causality.
c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.
	Gemzar plus Carboplatin (N=175)			Carboplatin (N=174)
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4
Laboratoryb
Hematologic
Neutropenia	90	42	29	58	11	1
Anemia	86	22	6	75	9	2
Leukopenia	86	48	5	70	6	<1
Thrombocytopenia	78	30	5	57	10	1
RBC Transfusionsc	38			15
Platelet Transfusionsc	9			3
Non-laboratoryb
Nausea	69	6	0	61	3	0
Alopecia	49	0	0	17	0	0
Vomiting	46	6	0	36	2	<1
Constipation	42	6	1	37	3	0
Fatigue	40	3	<1	32	5	0
Neuropathy-sensory	29	1	0	27	2	0
Diarrhea	25	3	0	14	<1	0
Stomatitis/pharyngitis	22	<1	0	13	0	0
Anorexia	16	1	0	13	0	0

In addition to blood product transfusions as listed in Table 8, myelosuppression was also managed with hematopoietic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoietic agents: 7.3% and 3.9%, respectively).

The following are the clinically relevant adverse reactions, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse reactions (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Gemzar. 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 drug exposure.

These adverse reactions have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar.

Cardiovascular — Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disorders — Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skin — Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepatic — Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Hepatic veno-occlusive disease has been reported.

Pulmonary — Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renal — Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS.

Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported [see Warnings and Precautions (5.8)].

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Myelosuppression is the major dose-limiting factor associated with gemcitabine therapy.

Dosage adjustments for hematologic toxicity are frequently necessary. Less than 1% of patients have had to discontinue therapy for either anemia, leukopenia, or thrombocytopenia. Grade 3/4 thrombocytopenia was more common in the elderly, especially older women.

The risk for thrombotic thrombocytopenic purpura increases as the cumulative dose of gemcitabine approaches 20,000 mg/m2.

Hematologic side effects including anemia (68%), leukopenia (62%), neutropenia (63%), thrombocytopenia (24%), petechiae (16%), thrombotic thrombocytopenic purpura (0.015% to 1.4%), and sepsis (less than 1%) have been reported. Red blood cell transfusions were required by 19% of patients.

Gastrointestinal

Gastrointestinal side effects including nausea and vomiting (69%), diarrhea (19%) and stomatitis (11%) have been reported. A case of severe anal pruritus has also been reported.

If the patient is not vomiting due to their disease state, nausea can generally be prevented by administration of prochlorperazine or low-dose oral serotonin antagonists and glucocorticoid therapy. One study of 790 patients found the rate of WHO grade 3 nausea and vomiting at a frequency of 22% in patients under 65 years of age, and 12% in patients 65 years of age or older.

Hepatic

No evidence of increased hepatic toxicity has been reported with longer duration or greater total cumulative dose.

Hepatic side effects including transient elevations in ALT (68%), AST (67%), alkaline phosphatase (55%), bilirubin (13%), and GGT have been reported. Serious hepatotoxicity including liver failure and death have been reported very rarely.

Renal

Renal side effects including proteinuria (45%), hematuria (35%), renal failure, hemolytic-uremic syndrome (0.25%), and nephrotoxicity have been reported.

Renal failure may not be reversible, even upon discontinuation of therapy.

Other

The flu-like symptoms usually take place a few hours after drug administration. The symptoms are usually self-limiting and recovery is generally within 24 to 48 hours. Less than 1% of patients discontinued use due to flu-like symptoms. Some patients get relief from nonsteroidal anti-inflammatory drugs or acetaminophen.

Out of the five reported cases of distal ischemic changes, four of those case related to combination chemotherapy with cisplatin and gemcitabine, while one case was of gemcitabine as a single agent in first-line therapy.

Other side effects including fever (41%), frequently associated with other flu-like symptoms, has been reported. There was a 16% incidence of infection among the patients with fever. Both fever and asthenia have frequently been reported as isolated effects. Flu syndrome (19%), including fever, asthenia, anorexia, headache, cough, chills, and myalgia has been reported. Insomnia, rhinitis, sweating, and malaise have been reported infrequently. Vasculitis and gangrene have been reported very rarely. Five cases of distal ischemic changes have been reported.

A pattern of tissue injury typically associated with radiation toxicity has also been reported in association with the use of gemcitabine.

Dermatologic

Rash was generally a macular or finely granular maculopapular pruritic eruption, mild to moderate in severity, involving the trunk and extremities. Alopecia is usually minimal.

Dermatologic side effects including rash (30%), alopecia (15%), pruritus (13%), and radiation recall have been reported. Cellulitis has been reported rarely. Severe skin reactions including desquamation and bullous skin eruptions have been reported very rarely. Two cases of pseudocellulitis have been reported. A case of linear immunoglobulin A bullous dermatosis has also been reported.

Respiratory

Some of the dyspnea reported may have been due to underlying disease. Forty percent of the study population consisted of lung cancer patients, while some of the other study patients had pulmonary manifestations of other malignancies.

Different patterns of lung injury may be related to gemcitabine. A rapid response following the administration of corticosteroids would mean the respiratory problem was probably due to a hypersensitivity reaction.

Respiratory side effects including dyspnea (23%), sometimes accompanied by bronchospasm (<2%) have been reported. Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome has been reported rarely. Respiratory failure and death have been reported very rarely (in some patients, despite the discontinuation of therapy).

Nervous system

Less than 1% of the paresthesias have been severe.

Nervous system side effects including paresthesias (10%) have been reported.

Local

Local side effects including "injection-site-related events" (4%) have been reported by the manufacturer.

Hypersensitivity

Hypersensitivity side effects including anaphylactoid reactions have been reported rarely.

Cardiovascular

Many of the patients that suffered cardiovascular effects had a prior history of cardiovascular disease. Two percent of patients discontinued therapy due to these effects. Less than 1% of patients discontinued due to edema.

Cardiovascular side effects including peripheral edema (20%), edema (13%), cerebrovascular accident, hypotension, hypertension, and generalized edema (less than 1%) have been reported. Atrial fibrillation has been reported rarely. Congestive heart failure, myocardial infarction, and arrhythmias (predominantly supraventricular in nature) have been reported very rarely.

Immunologic

Immunologic side effects including a scleroderma-like reaction have been reported.

Oncologic

Long term animal studies to evaluate carcinogenic potential have not been conducted.

Oncologic side effects have been reported in animal studies. Gemcitabine induced forward mutations in vitro in a mouse lymphoma assay and was clastogenic in an in vivo micronucleus assay.

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