Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2400
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Gemzar (Injection, Powder, Lyophilized, For Solution)
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| dailymed-instance:dosage |
Gemzar is
for intravenous use only.<br/>Adults:<br/>Single���Agent
Use:: Pancreatic
Cancer���Gemzar should
be administered by intravenous infusion at a dose of 1000 mg/mover
30 minutes once weekly for up to 7 weeks
(or until toxicity necessitates reducing or holding a dose), followed by a
week of rest from treatment. Subsequent cycles should consist of infusions
once weekly for 3 consecutive weeks out of every 4 weeks. Dose
Modifications���Dosage adjustment is based upon the degree
of hematologic toxicity experienced by the patient .
Clearance in women and the elderly is reduced and women were somewhat less
able to progress to subsequent cycles (see Human
Pharmacokinetics under CLINICAL PHARMACOLOGY and PRECAUTIONS). Patients receiving Gemzar should
be monitored prior to each dose with a complete blood count (CBC),
including differential and platelet count. If marrow suppression is detected,
therapy should be modified or suspended according to the guidelines in Table 13. Laboratory evaluation of renal and hepatic function, including
transaminases and serum creatinine, should be performed prior to initiation
of therapy and periodically thereafter. Gemzar should be administered with caution in patients with evidence of significant
renal or hepatic impairment as there is insufficient information from clinical
studies to allow clear dose recommendation for these patient populations. Patients treated with Gemzar who complete an entire cycle of therapy may have the dose for subsequent
cycles increased by 25%, provided that the absolute granulocyte
count (AGC) and platelet nadirs exceed 1500 x 10/L
and 100,000 x 10/L,
respectively, and if non���hematologic toxicity has not been greater than
WHO Grade 1. If patients tolerate the subsequent course of Gemzar at
the increased dose, the dose for the next cycle can be further increased by 20%,
provided again that the AGC and platelet nadirs exceed 1500 x 10/L
and 100,000 x 10/L,
respectively, and that non���hematologic toxicity has not been greater
than WHO Grade 1.<br/>Combination
Use:: Non���Small
Cell Lung Cancer���Two schedules have been
investigated and the optimum schedule has not been determined .
With the 4���week schedule, Gemzar should
be administered intravenously at 1000 mg/mover
30 minutes on Days 1, 8, and 15 of each
28���day cycle. Cisplatin should be administered intravenously at 100 mg/mon
Day 1 after the infusion of Gemzar.
With the 3���week schedule, Gemzar should
be administered intravenously at 1250 mg/mover
30 minutes on Days 1 and 8 of each 21���day cycle. Cisplatin
at a dose of 100 mg/mshould
be administered intravenously after the infusion of Gemzar on
Day 1. See prescribing information for cisplatin administration
and hydration guidelines. Dose
Modifications���Dosage adjustments for hematologic toxicity
may be required for Gemzar and
for cisplatin. Gemzar dosage
adjustment for hematological toxicity is based on the granulocyte and platelet
counts taken on the day of therapy. Patients receiving Gemzar should
be monitored prior to each dose with a complete blood count (CBC),
including differential and platelet counts. If marrow suppression is detected,
therapy should be modified or suspended according to the guidelines in Table 13. For cisplatin dosage adjustment, see manufacturer's
prescribing information. In general, for severe (Grade 3 or 4)
non���hematological toxicity, except alopecia and nausea/vomiting, therapy
with Gemzar plus
cisplatin should be held or decreased by 50% depending on
the judgment of the treating physician. During combination therapy with cisplatin,
serum creatinine, serum potassium, serum calcium, and serum magnesium should
be carefully monitored (Grade 3/4 serum creatinine toxicity
for Gemzar plus
cisplatin was 5% versus 2% for
cisplatin alone). Breast
Cancer���Gemzar should
be administered intravenously at a dose of 1250 mg/mover
30 minutes on Days 1 and 8
of each 21���day cycle. Paclitaxel should be administered at 175 mg/mon
Day 1 as a 3���hour intravenous infusion before Gemzar administration.
Patients should be monitored prior to each dose with a complete blood count,
including differential counts. Patients should have an absolute granulocyte
count���1500 x 10/L
and a platelet count���100,000 x 10/L
prior to each cycle. Dose
Modifications���Gemzar dosage
adjustments for hematological toxicity is based on the granulocyte and platelet
counts taken on Day 8 of therapy. If marrow suppression is
detected, Gemzar dosage
should be modified according to the guidelines in Table 14. In general, for severe (Grade 3 or 4)
non���hematological toxicity, except alopecia and nausea/vomiting, therapy
with Gemzar should
be held or decreased by 50% depending on the judgment of the treating physician.
For paclitaxel dosage adjustment, see manufacturer's prescribing information. Ovarian Cancer���Gemzar should
be administered intravenously at a dose of 1000 mg/mover
30 minutes on Days 1 and 8 of each 21���day
cycle. Carboplatin AUC 4 should be administered intravenously
on Day 1 after Gemzar administration.
Patients should be monitored prior to each dose with a complete blood count,
including differential counts. Patients should have an absolute granulocyte
count���1500 x 10/L
and a platelet count���100,000 x 10/L prior to each cycle. Dose Modifications���Gemzar dosage
adjustments for hematological toxicity within a cycle of treatment is based
on the granulocyte and platelet counts taken on Day 8 of
therapy. If marrow suppression is detected, Gemzar dosage
should be modified according to guidelines in Table 15. In general, for severe (Grade 3 or
4) non���hematological toxicity, except nausea/vomiting, therapy with Gemzar should
be held or decreased by 50% depending on the judgment of the treating physician.
For carboplatin dosage adjustment, see manufacturer's prescribing information. Dose
adjustment for Gemzar in
combination with carboplatin for subsequent cycles is based upon observed
toxicity. The dose of Gemzar in
subsequent cycles should be reduced to 800 mg/mon
Days 1 and 8 in case of any of the following hematologic
toxicities: If any of the above toxicities recur after
the initial dose reduction, for the subsequent cycle, Gemzar should
be given on Day 1 only at 800 mg/m. Gemzar may
be administered on an outpatient basis.<br/>Instructions for Use/Handling: The recommended diluent for reconstitution of Gemzar is
0.9% Sodium Chloride Injection without preservatives. Due
to solubility considerations, the maximum concentration for Gemzar upon
reconstitution is 40 mg/mL. Reconstitution at concentrations
greater than 40 mg/mL may result in incomplete dissolution,
and should be avoided. To reconstitute, add 5 mL of 0.9% Sodium
Chloride Injection to the 200���mg vial or 25 mL of 0.9% Sodium
Chloride Injection to the 1���g vial. Shake to dissolve. These dilutions
each yield a gemcitabine concentration
of 38 mg/mL which includes accounting for the displacement
volume of the lyophilized powder (0.26 mL for the 200���mg
vial or 1.3 mL for the 1���g vial). The total volume
upon reconstitution will be 5.26 mL or 26.3 mL,
respectively. Complete withdrawal of the vial contents will provide 200 mg
or 1 g of gemcitabine, respectively. The appropriate amount of drug may be administered as prepared
or further diluted with 0.9% Sodium Chloride Injection to
concentrations as low as 0.1 mg/mL. Reconstituted Gemzar is
a clear, colorless to light straw���colored solution. After reconstitution
with 0.9% Sodium Chloride Injection, the pH of the resulting
solution lies in the range of 2.7 to 3.3.
The solution should be inspected visually for particulate matter and discoloration,
prior to administration, whenever solution or container permit. If particulate
matter or discoloration is found, do not administer. When prepared as directed, Gemzar solutions
are stable for 24 hours at controlled room temperature 20��to 25��C (68��to 77��F) [See USP].
Discard unused portion. Solutions of reconstituted Gemzar should
not be refrigerated, as crystallization may occur. The compatibility of Gemzar with
other drugs has not been studied. No incompatibilities have been observed
with infusion bottles or polyvinyl chloride bags and administration sets. Unopened vials of Gemzar are
stable until the expiration date indicated on the package when stored at controlled
room temperature 20��to 25��C (68��to 77��F)
[See USP]. Caution should be exercised in handling and preparing Gemzar solutions.
The use of gloves is recommended. If Gemzar solution contacts the skin or mucosa, immediately wash the skin thoroughly
with soap and water or rinse the mucosa with copious amounts of water. Although
acute dermal irritation has not been observed in animal studies, 2 of
3 rabbits exhibited drug���related systemic toxicities
(death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption. Procedures for proper handling and disposal of anti���cancer drugs
should be considered. Several guidelines on this subject have been published.There
is no general agreement that all of the procedures recommended in the guidelines
are necessary or appropriate.
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| dailymed-instance:descripti... |
Gemzar (gemcitabine HCl)
is a nucleoside analogue that exhibits antitumor activity. Gemcitabine HCl
is 2���-deoxy-2���,2���-difluorocytidine monohydrochloride (�����isomer). The structural formula is as follows: The empirical formula for gemcitabine HCl
is CHFNO���HCl. It has a molecular weight of 299.66. Gemcitabine HCl is a white to off���white solid. It is soluble
in water, slightly soluble in methanol, and practically insoluble in ethanol
and polar organic solvents. The clinical formulation is supplied in a sterile form
for intravenous use only. Vials of Gemzar contain
either 200 mg or 1 g of gemcitabine HCl
(expressed as free base) formulated with mannitol (200 mg or
1 g, respectively) and sodium acetate (12.5 mg or
62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric
acid and/or sodium hydroxide may have been added for pH adjustment.
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| dailymed-instance:clinicalP... |
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA
synthesis (S���phase) and also blocking the progression of cells through
the G1/S���phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP)
and triphosphate (dFdCTP) nucleosides. The cytotoxic effect
of gemcitabine is
attributed to a combination of two actions of the diphosphate
and the triphosphate nucleosides, which leads to inhibition of DNA synthesis.
First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for
catalyzing the reactions that generate the deoxynucleoside triphosphates for
DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes
a reduction in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate
competes with dCTP for incorporation into DNA. The reduction in the intracellular
concentration of dCTP (by the action of the diphosphate) enhances the incorporation
of gemcitabine triphosphate
into DNA (self���potentiation). After the gemcitabine nucleotide
is incorporated into DNA, only one additional nucleotide
is added to the growing DNA strands. After this addition, there is inhibition
of further DNA synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide
and repair the growing DNA strands (masked chain termination). In CEM T
lymphoblastoid cells, gemcitabine induces
internucleosomal DNA fragmentation, one of the characteristics of programmed
cell death. Gemcitabine demonstrated dose���dependent synergistic activity with cisplatin in vitro.
No effect of cisplatin on gemcitabine triphosphate accumulation or DNA double���strand breaks was observed. In vivo, gemcitabine showed
activity in combination with cisplatin against the LX���1 and CALU���6
human lung xenografts, but minimal activity was seen with the NCI���H460
or NCI���H520 xenografts. Gemcitabine was synergistic with cisplatin in the Lewis lung murine xenograft. Sequential
exposure to gemcitabine 4 hours before cisplatin produced the greatest interaction.<br/>Human Pharmacokinetics: Gemcitabine disposition
was studied in 5 patients who received a single 1000 mg/m/30 minute
infusion of radiolabeled drug. Within one (1) week,
92% to 98% of the dose was recovered, almost
entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2������deoxy���2���,2������difluorouridine
(dFdU), accounted for 99% of the excreted dose. The metabolite
dFdU is also found in plasma. Gemcitabine plasma protein binding is negligible. The pharmacokinetics
of gemcitabine were
examined in 353 patients, about 2/3 men,
with various solid tumors. Pharmacokinetic parameters were derived using data
from patients treated for varying durations of therapy given weekly with periodic
rest weeks and using both short infusions (<70 minutes)
and long infusions (70 to 285 minutes).
The total Gemzar dose
varied from 500 to 3600 mg/m. Gemcitabine pharmacokinetics
are linear and are described by a 2���compartment model. Population pharmacokinetic
analyses of combined single and multiple dose studies showed
that the volume of distribution of gemcitabine was
significantly influenced by duration of infusion and gender. Clearance was
affected by age and gender. Differences in either clearance or volume of distribution
based on patient characteristics or the duration of infusion result in changes
in half���life and plasma concentrations. Table 1 shows
plasma clearance and half���life of gemcitabine following
short infusions for typical patients by age and gender. Gemcitabine half���life
for short infusions ranged from 42 to 94 minutes,
and the value for long infusions varied from 245 to 638 minutes,
depending on age and gender, reflecting a greatly increased volume of distribution
with longer infusions. The lower clearance in women and the elderly results
in higher concentrations of gemcitabine for any given dose. The volume of
distribution was increased with infusion length. Volume of distribution of gemcitabine was
50 L/mfollowing infusions lasting<70 minutes, indicating that gemcitabine,
after short infusions, is not extensively distributed into tissues. For long
infusions, the volume of distribution rose to 370 L/m,
reflecting slow equilibration of gemcitabine within the tissue compartment. The maximum plasma
concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes
after discontinuation of the infusions and the metabolite is excreted in urine
without undergoing further biotransformation. The metabolite did not accumulate
with weekly dosing, but its elimination is dependent on renal excretion, and
could accumulate with decreased renal function. The effects of
significant renal or hepatic insufficiency on the disposition of gemcitabine have
not been assessed. The active metabolite, gemcitabine triphosphate,
can be extracted from peripheral blood mononuclear cells. The half���life
of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to
19.4 hours.<br/>Drug Interactions: When Gemzar (1250 mg/mon
Days 1 and 8) and cisplatin (75 mg/mon
Day 1) were administered in NSCLC patients, the clearance
of gemcitabine on
Day 1 was 128 L/hr/mand
on Day 8 was 107 L/hr/m.
The clearance of cisplatin in the same study was reported to be 3.94 mL/min/mwith
a corresponding half���life of 134 hours . Analysis
of data from metastatic breast cancer patients shows that, on average, Gemzar has
little or no effect on the pharmacokinetics (clearance and
half���life) of paclitaxel and paclitaxel has little or no effect on the
pharmacokinetics of Gemzar. Data from NSCLC patients demonstrate
that Gemzar and
carboplatin given in combination does not alter the pharmacokinetics of Gemzar or
carboplatin compared to administration of either single-agent. However,
due to wide confidence intervals and small sample size, interpatient variability
may be observed.
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Vials: 200 mg white, lyophilized powder in a
10���mL size sterile single use vial (No. 7501)NDC 0002���7501���01 1 g white, lyophilized powder in a 50���mL
size sterile single use vial (No. 7502)NDC 0002���7502���01 Store at controlled room temperature 20��to 25��C (68��to 77��F). The USP has defined controlled room temperature as���A temperature
maintained thermostatically that encompasses the usual and customary working
environment of 20��to 25��C (68��to 77��F);
that results in a mean kinetic temperature calculated to be not more than
25��C; and that allows for excursions between 15��and 30��C (59��and 86��F) that are experienced in pharmacies, hospitals,
and warehouses.���
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General: Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer
chemotherapeutic agents. Most adverse events are reversible and do not need
to result in discontinuation, although doses may need to be withheld or reduced.
There was a greater tendency in women, especially older women, not to proceed
to the next cycle.<br/>Laboratory Tests: Patients receiving Gemzar should
be monitored prior to each dose with a complete blood count (CBC),
including differential and platelet count. Suspension or modification of therapy
should be considered when marrow suppression is detected . Laboratory evaluation of renal and hepatic function should be performed
prior to initiation of therapy and periodically thereafter .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long���term animal studies to evaluate the carcinogenic potential
of Gemzar have
not been conducted. Gemcitabine induced
forward mutations in vitro in
a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse
micronucleus assay. Gemcitabine was
negative when tested using the Ames, in vivo sister chromatid exchange,
and in vitro chromosomal
aberration assays, and did not cause unscheduled DNA synthesisin vitro. Gemcitabine IP
doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/mbasis)in male mice had an effect on fertility with moderate to severe hypospermatogenesis,
decreased fertility, and decreased implantations. In female mice, fertility
was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV
(about 1/200 the human dose on a mg/mbasis) and
fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV
(about 1/1300 the human dose on a mg/mbasis).<br/>Pregnancy: Category D. See WARNINGS.<br/>Nursing Mothers: It is not known whether Gemzar or
its metabolites are excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions from Gemzar in
nursing infants, the mother should be warned and a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother and the potential risk to the infant.<br/>Elderly Patients: Gemzar clearance
is affected by age (see CLINICAL
PHARMACOLOGY). There is no evidence, however,
that unusual dose adjustments (i.e., other than those already
recommended in DOSAGE AND ADMINISTRATION) are necessary in patients over 65,
and in general, adverse reaction rates in the single���agent safety database
of 979 patients were similar in patients above and below 65.
Grade 3/4 thrombocytopenia was more common in the elderly. In the randomized clinical trial
of Gemzar in
combination with carboplatin for recurrent ovarian cancer ,
125 women treated with Gemzar plus carboplatin were<65 years
and 50 were���65 years.
Similar effectiveness was observed between older and younger women. There
was significantly higher Grade 3/4 neutropenia in women 65 years
of age or older. Overall, there were no substantial differences in toxicity
profile of Gemzar plus
carboplatin based on age.<br/>Gender: Gemzar clearance
is affected by gender (see CLINICAL
PHARMACOLOGY). In the single���agent safety
database (N=979 patients), however, there is no evidence
that unusual dose adjustments (i.e., other than those already
recommended in the DOSAGE
AND ADMINISTRATION section) are necessary in women. In general,
in single���agent studies of Gemzar,
adverse reaction rates were similar in men and women, but women, especially
older women, were more likely not to proceed to a subsequent cycle and to
experience Grade 3/4 neutropenia and thrombocytopenia.<br/>Pediatric Patients: The effectiveness of Gemzar in
pediatric patients has not been demonstrated. Gemzar was
evaluated in a Phase 1 trial in pediatric patients with refractory
leukemia and determined that the maximum tolerated dose was 10 mg/m/min
for 360 minutes three times weekly followed
by a one-week rest period. Gemzar was
also evaluated in a Phase 2 trial in patients with relapsed
acute lymphoblastic leukemia (22 patients) and acute myelogenous
leukemia (10 patients) using 10 mg/m/min
for 360 minutes three times weekly followed
by a one week rest period. Toxicities observed included bone
marrow suppression, febrile neutropenia, elevation of serum transaminases,
nausea, and rash/desquamation, which were similar to those reported in adults.
No meaningful clinical activity was observed in this Phase 2
trial.<br/>Patients with Renal or Hepatic Impairment: Gemzar should
be used with caution in patients with preexisting renal impairment or hepatic
insufficiency as there is insufficient information from clinical studies to
allow clear dose recommendation for these patient populations. Administration
of Gemzar in
patients with concurrent liver metastases or a preexisting medical
history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation
of the underlying hepatic insufficiency.<br/>Drug Interactions: No specific drug interaction studies have been conducted. For information
on the pharmacokinetics of Gemzar and
cisplatin in combination, see Drug
Interactions under CLINICAL
PHARMACOLOGY.<br/>Radiation Therapy: A pattern of tissue injury typically associated with radiation toxicity
has been reported in association with concurrent and non���concurrent
use of Gemzar. Non���concurrent
(given>7 days apart)���Analysis of the data does not indicate
enhanced toxicity when Gemzar is
administered more than 7 days before or after radiation, other than radiation
recall. Data suggest that Gemzar can
be started after the acute effects of radiation have resolved or at least
one week after radiation. Concurrent
(given together or���7 days apart)���Preclinical
and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality
therapy is dependent on many different factors, including dose of Gemzar,
frequency of Gemzar administration,
dose of radiation, radiotherapy planning technique, the target tissue, and
target volume. In a single trial, where Gemzar at a dose of 1000 mg/mwas administered concurrently
for up to 6 consecutive weeks with therapeutic thoracic radiation to patients
with non���small cell lung cancer, significant toxicity in the form of
severe, and potentially life���threatening mucositis, especially esophagitis
and pneumonitis was observed, particularly in patients receiving large volumes
of radiotherapy [median treatment volumes 4795 cm].
Subsequent studies have been reported and suggest that Gemzar administered
at lower doses with concurrent radiotherapy has predictable and less severe
toxicity. However, the optimum regimen for safe administration of Gemzar with
therapeutic doses of radiation has not yet been determined in all tumor types.
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| dailymed-instance:overdosag... |
There
is no known antidote for overdoses of Gemzar. Myelosuppression, paresthesias, and severe rash were the principal toxicities
seen when a single dose as high as 5700 mg/mwas
administered by IV infusion over 30 minutes
every 2 weeks to several patients in a Phase 1
study. In the event of suspected overdose, the patient should be monitored
with appropriate blood counts and should receive supportive therapy, as necessary.
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| dailymed-instance:genericMe... |
Gemcitabine hydrochloride
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| dailymed-instance:fullName |
Gemzar (Injection, Powder, Lyophilized, For Solution)
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| dailymed-instance:adverseRe... |
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 and are
described in DOSAGE
AND ADMINISTRATION. The data in Table 7 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/m.
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 events 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 events are
listed in Table 7, regardless of causality.
Non���laboratory adverse events listed in Table 7 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
events under the Renal, Pulmonary, and Infection categories. Table 8 presents the data from the comparative trial
of Gemzar and
5���FU in pancreatic cancer for the same adverse events as those in Table 7, regardless of incidence. 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). 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 Hepatic under Post���marketing
experience). 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 Renal under Post���marketing
experience). 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 Pulmonary under Post���marketing
experience). 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
. 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
Cardiovascular under Post���marketing experience). 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
events 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 events. With a median of 2 cycles
of cisplatin treatment, 61 of 260 patients (23%)
experienced 78 hospitalizations due to possibly treatment���related
adverse events. 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 events. 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 events. 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
events 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 9 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 slightly 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 10 presents
data from the randomized study of Gemzar plus
cisplatin versus etoposide plus cisplatin in 135 patients
with NSCLC for the same WHO���graded adverse events as those in Table 8. 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. 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 events. There were two deaths
on study or within 30 days after study drug discontinuation
that were possibly drug���related, one on each arm. Table 11 presents
the safety data occurrences of���10% (all grades) from the Gemzar plus
paclitaxel versus paclitaxel study in breast cancer. The following are the clinically relevant
adverse events that occurred in>1% and<10% (all grades) of patients on
either arm. In parentheses are the incidences of Grade 3
and 4 adverse events (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 events between arms
(10.9% versus 9.8%, respectively). Table 12 presents the adverse events (all grades) occurring
in���10% of patients
in the ovarian cancer study. In
addition to blood product transfusions as listed in Table 12,
myelosuppression was also managed with hematopoetic agents. These agents were
administered more frequently with combination therapy than with monotherapy
(granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic
agents: 7.3% and 3.9%, respectively). The
following are the clinically relevant adverse events, 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 events
(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 events have been identified during
post���approval use of Gemzar.
These events 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. 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 Radiation
Therapy under PRECAUTIONS).
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Caution���Prolongation of the infusion time beyond 60 minutes
and more frequent than weekly dosing have been shown to increase
toxicity (see CLINICAL
STUDIES). Hematology���Gemzar can
suppress bone marrow function as manifested by leukopenia, thrombocytopenia,
and anemia (see ADVERSE
REACTIONS), and myelosuppression is usually the
dose���limiting toxicity. Patients should be monitored for myelosuppression
during therapy. See DOSAGE AND ADMINISTRATION for
recommended dose adjustments. Pulmonary���Pulmonary toxicity has been reported with the use of Gemzar.
In cases of severe lung toxicity, Gemzar therapy
should be discontinued immediately and appropriate supportive care measures
instituted (see
Pulmonary under Single���Agent Use and under Post���marketing
experience in ADVERSE REACTIONS). 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 (see
Renal under Single���Agent Use and under Post���marketing
experience in ADVERSE REACTIONS). Hepatic���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 Hepatic under Single���Agent
Use and
under Post���marketing experience in ADVERSE REACTIONS). Pregnancy���Pregnancy Category D. Gemzar can cause fetal harm when administered to a pregnant woman. Gemcitabine is
embryotoxic causing fetal malformations (cleft palate, incomplete ossification)
at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended
human dose on a mg/mbasis). Gemcitabine is
fetotoxic causing fetal malformations (fused pulmonary artery, absence of
gall bladder) at doses of 0.1 mg/kg/day in rabbits (about
1/600 the recommended human dose on a mg/mbasis).
Embryotoxicity was characterized by decreased fetal viability, reduced live
litter sizes, and developmental delays. There are no studies of Gemzar in
pregnant women. If Gemzar is
used during pregnancy, or if the patient becomes pregnant while taking Gemzar,
the patient should be apprised of the potential hazard to the fetus.
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Therapeutic
Indications:<br/>Ovarian
Cancer: Gemzar in
combination with carboplatin is indicated for the treatment of patients with
advanced ovarian cancer that has relapsed at least 6 months
after completion of platinum���based therapy.<br/>Breast Cancer: Gemzar in
combination with paclitaxel is indicated for the first���line treatment
of patients with metastatic breast cancer after failure of prior anthracycline���containing
adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.<br/>Non���Small Cell Lung Cancer: Gemzar is
indicated in combination with cisplatin for the first���line treatment
of patients with inoperable, locally advanced (Stage IIIA
or IIIB), or metastatic (Stage IV) non���small
cell lung cancer.<br/>Pancreatic Cancer: Gemzar is
indicated as first���line treatment for patients with locally advanced
(nonresectable Stage II or Stage III) or
metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar is
indicated for patients previously treated with 5���FU.
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Gemzar
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