SIDE EFFECTS
: Adverse events that occurred during clinical trials of
CYTOVENE-IV solution and CYTOVENE capsules are summarized
below, according to the participating study subject population.
Subjects With AIDS: Three controlled, randomized, phase
3 trials comparing CYTOVENE-IV and CYTOVENE capsules for
maintenance treatment of CMV retinitis have been completed.
During these trials, CYTOVENE-IV or CYTOVENE capsules
were prematurely discontinued in 9% of subjects because
of adverse events. In a placebo-controlled, randomized,
phase 3 trial of CYTOVENE capsules for prevention of CMV
disease in AIDS, treatment was prematurely discontinued
because of adverse events, new or worsening intercurrent
illness, or laboratory abnormalities in 19.5% of subjects
treated with CYTOVENE capsules and 16% of subjects receiving
placebo. Laboratory data and adverse events reported during
the conduct of these controlled trials are summarized
below.
Laboratory Data:
| Selected
Laboratory Abnormalities in Trials for
Treatment of CMV Retinitis and Prevention
of CMV Disease |
|
|
|
CMV
Retinitis Treatment* |
CMV
Disease Prevention$ |
| Treatment |
CYTOVENE
Capsules#
3000 mg/day |
CYTOVENE-IV## mg/kg/day |
CYTOVENE
Capsules||
3000 mg/day |
Placebo& |
| Subjects,
number |
320 |
175 |
478 |
234 |
Neutropenia:
<500 ANC/µL
500 <749
750
<1000 |
18%
17%
19% |
25%
14%
26% |
10%
16%
22% |
6%
7%
16% |
Anemia:
Hemoglobin:
<6.5
g/dL
6.5 <8.0
8.0 <9.5 |
2%
10%
25% |
5%
16%
26% |
1%
5%
15% |
<1%
3%
16% |
Maximum
Serum Creatinine:
>2.5
mg/dL
>1.5 <2.5 |
1%
12% |
2%
14% |
1%
19% |
2%
11% |
*
Pooled data from Treatment Studies,
ICM 1653, Study ICM 1774 and Study AVI 034.
# Mean time on
therapy = 91 days, including allowed reinduction
treatment periods
## Mean
time on therapy = 103 days, including allowed
reinduction treatment periods
$
Data from Prevention Study, ICM 1654
|| Mean time on ganciclovir
= 269 days
& Mean
time on placebo = 240 days
(See
discussion of clinical trials under INDICATIONS
AND USAGE.) |
|
Adverse Events: The following table shows selected
adverse events reported in 5% or more of the subjects in
three controlled clinical trials during treatment with either
CYTOVENE-IV solution (5 mg/kg/day) or CYTOVENE capsules
(3000 mg/day), and in one controlled clinical trial in which
CYTOVENE capsules (3000 mg/day) were compared to placebo
for the prevention of CMV disease.
|
Selected Adverse Events
Reported in > 5% of Subjects in
Three Randomized Phase 3 Studies Comparing CYTOVENE
Capsules to CYTOVENE-IV Solution for Maintenance
Treatment of CMV Retinitis and in One Phase 3
Randomized Study Comparing Cytovene Capsules to
Placebo for Prevention of CMV Disease |
|
|
Maintenance Treatment Studies |
Prevention Study |
| Body
System |
Adverse
Event |
Capsules
(n=326) |
IV
(n=179) |
Capsules
(n=478) |
Placebo
(n=234) |
Body
as a
Whole
Digestive
System
Hemic and
Lymphatic
System
Nervous System
Other
Catheter Related*
|
Fever
Infection
Chills
Sepsis
Diarrhea
Anorexia
Vomiting
Leukopenia
Anemia
Thrombocytopenia
Neuropathy
Sweating
Pruritus
Total Catheter Events
Catheter Infection
Catheter Sepsis |
38%
9%
7%
4%
41%
15%
13%
29%
19%
6%
8%
11%
6%
6%
4%
1% |
48%
13%
10%
15%
44%
14%
13%
41%
25%
6%
9%
12%
5%
22%
9%
8% |
35%
8%
7%
3%
48%
19%
14%
17%
9%
3%
21%
14%
10%
–
–
– |
33%
4%
4%
2%
42%
16%
11%
9%
7%
1%
15%
12%
9%
–
–
– |
| *Some
of these events also appear under other body systems. |
The following events were frequently observed in clinical
trials but occurred with equal or greater frequency in
placebo-treated subjects: abdominal pain, nausea, flatulence,
pneumonia, paresthesia, rash.
Retinal Detachment: Retinal detachment has been
observed in subjects with CMV retinitis both before and
after initiation of therapy with ganciclovir. Its relationship
to therapy with ganciclovir is unknown. Retinal detachment
occurred in 11% of patients treated with CYTOVENE-IV solution
and in 8% of patients treated with CYTOVENE capsules.
Patients with CMV retinitis should have frequent ophthalmologic
evaluations to monitor the status of their retinitis and
to detect any other retinal pathology.
Transplant Recipients: There have been
three controlled clinical trials of CYTOVENE-IV solution
and one controlled clinical trial of CYTOVENE capsules
for the prevention of CMV disease in transplant recipients.
Laboratory data and adverse events reported during
these trials are summarized below.
Laboratory Data: The following table shows the frequency
of granulocytopenia (neutropenia) and thrombocytopenia observed:
|
Controlled
Trials — Transplant Recipients
|
|
|
CYTOVENE-IV |
CYTOVENE
Capsules |
|
|
Heart
Allograft* |
Bone
Marrow Allograft# |
Liver
Allograft## |
|
|
CYTOVENE-IV
(n=76) |
Placebo
(n=73) |
CYTOVENE-IV
(n=57) |
Control
(n=55) |
CYTOVENE
Capsules
(n=150) |
Placebo
(n=154) |
| Neutropenia |
|
|
|
|
|
|
Minimum
ANC
<500/µL
Minimum ANC
500-1000/µL |
4%
3% |
3%
8% |
12%
29% |
6%
17% |
3%
3% |
1%
2% |
TOTAL
ANC
<1000/µL |
7% |
11% |
41% |
23% |
6% |
3% |
| Thrombocytopenia |
|
|
|
|
|
|
Platelet
count
<25,000/µL
Platelet count
25,000-50,000/µL |
3%
5% |
1%
3% |
32%
25% |
28%
37% |
0%
5% |
3%
3% |
TOTAL
Platelet
<50,000/µL |
8% |
4% |
57% |
65% |
5% |
6% |
*
Study ICM 1496. Mean duration of treatment = 28 days
# Study ICM 1570 and ICM 1689. Mean duration
of treatment = 45 days
## Study GAN040. Mean duration of ganciclovir treatment
= 82 days
(See discussion of clinical trials under INDICATIONS
AND USAGE.) |
The following table shows the
frequency of elevated serum creatinine values in these controlled
clinical trials:
| Controlled Trials — Transplant Recipients
|
| |
CYTOVENE-IV
|
CYTOVENE
Capsules |
| |
Heart
Allograft
ICM 1496 |
Bone
Marrow Allograft
ICM 1570 |
Bone
Marrow Allograft
ICM 1689 |
Liver
Allograft
Study 040 |
Maximum
Serum
Creatinine
Levels |
CYTOVENE-IV
(n=76) |
Placebo
(n=73) |
CYTOVENE-IV
(n=20) |
Control
(n=20) |
CYTOVENE-IV
(n=37) |
Placebo
(n=35) |
CYTOVENE
Capsules
(n=150) |
Placebo
(n=154) |
Serum
Creatinine
>2.5mg/dL |
18%
|
4%
|
20%
|
0%
|
0%
|
0%
|
16%
|
10%
|
Serum
Creatinine
>1.5 -<2.5 mg/dL |
58%
|
69%
|
50%
|
35%
|
43%
|
44%
|
39%
|
42%
|
In 3 out of 4 trials, patients receiving either CYTOVENE-IV
solution or CYTOVENE capsules had elevated serum creatinine
levels when compared to those receiving placebo. Most
patients in these studies also received cyclosporine.
The mechanism of impairment of renal function is not known.
However, careful monitoring of renal function during therapy
with CYTOVENE-IV solution or CYTOVENE capsules is essential,
especially for those patients receiving concomitant agents
that may cause nephrotoxicity.
General: Other adverse events that were
thought to be "probably" or "possibly"
related to CYTOVENE-IV solution or CYTOVENE capsules in
controlled clinical studies in either subjects with AIDS
or transplant recipients are listed below. These events
all occurred in at least 3 subjects.
Body as a Whole: abdomen enlarged, asthenia,
chest pain, edema, headache, injection site inflammation,
malaise, pain
Digestive System: abnormal liver function test,
aphthous stomatitis, constipation, dyspepsia, eructation
Hemic and Lymphatic System: pancytopenia
Respiratory System: cough increased, dyspnea
Nervous System: abnormal dreams, anxiety, confusion,
depression, dizziness, dry mouth, insomnia, seizures,
somnolence, thinking abnormal, tremor
Skin and Appendages: alopecia, dry skin
Special Senses: abnormal vision, taste perversion,
tinnitus, vitreous disorder
Metabolic and Nutritional Disorders: creatinine
increased, SGOT increased, SGPT increased, weight loss
Cardiovascular System: hypertension, phlebitis,
vasodilatation
Urogenital System: creatinine clearance decreased,
kidney failure, kidney function abnormal, urinary frequency
Musculoskeletal System: arthralgia, leg cramps,
myalgia, myasthenia
The following adverse events reported in patients receiving
ganciclovir may be potentially fatal: gastrointestinal
perforation, multiple organ failure, pancreatitis and
sepsis.
Adverse Events Reported During Postmarketing Experience
With CYTOVENE-IV and CYTOVENE Capsules: The following
events have been identified during postapproval use of
the drug. Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot
be made. These events have been chosen for inclusion due
to either the seriousness, frequency of reporting, the
apparent causal connection or a combination of these factors:
acidosis, allergic reaction, anaphylactic reaction, arthritis,
bronchospasm, cardiac arrest, cardiac conduction abnormality,
cataracts, cholelithiasis, cholestasis, congenital anomaly,
dry eyes, dysesthesia, dysphasia, elevated triglyceride
levels, encephalopathy, exfoliative dermatitis, extrapyramidal
reaction, facial palsy, hallucinations, hemolytic anemia,
hemolytic uremic syndrome, hepatic failure, hepatitis,
hypercalcemia, hyponatremia, inappropriate serum ADH,
infertility, intestinal ulceration, intracranial hypertension,
irritability, loss of memory, loss of sense of smell,
myelopathy, oculomotor nerve paralysis, peripheral ischemia,
pulmonary fibrosis, renal tubular disorder, rhabdomyolysis,
Stevens-Johnson syndrome, stroke, testicular hypotrophy,
Torsades de Pointes, vasculitis, ventricular tachycardia
DRUG INTERACTIONS
: Didanosine: At an oral dose of 1000 mg of CYTOVENE
every 8 hours and didanosine, 200 mg every 12 hours, the
steady-state didanosine AUC0-12 increased 111
± 114% (range: 10% to 493%) when didanosine was administered
either 2 hours prior to or concurrent with administration
of CYTOVENE (n=12 patients, 23 observations). A decrease
in steady-state ganciclovir AUC of 21 ± 17% (range: -44%
to 5%) was observed when didanosine was administered 2 hours
prior to administration of CYTOVENE, but ganciclovir AUC
was not affected by the presence of didanosine when the
two drugs were administered simultaneously (n=12). There
were no significant changes in renal clearance for either
drug.
When the standard intravenous ganciclovir induction dose
(5 mg/kg infused over 1 hour every 12 hours) was coadministered
with didanosine at a dose of 200 mg orally every 12 hours,
the steady-state didanosine AUC0-12 increased
70 ± 40% (range: 3% to 121%, n=11) and Cmax
increased 49 ± 48% (range: -28% to 125%). In a separate
study, when the standard intravenous ganciclovir maintenance
dose (5 mg/kg infused over 1 hour every 24 hours) was
coadministered with didanosine at a dose of 200 mg orally
every 12 hours, didanosine AUC0-12 increased
50 ± 26% (range: 22% to 110%, n=11) and Cmax
increased 36 ± 36% (range: -27% to 94%) over the first
didanosine dosing interval. Didanosine plasma concentrations
(AUC12-24) were unchanged during the dosing
intervals when ganciclovir was not coadministered. Ganciclovir
pharmacokinetics were not affected by didanosine. In neither
study were there significant changes in the renal clearance
of either drug.
Zidovudine: At an oral dose of 1000 mg of CYTOVENE
every 8 hours, mean steady-state ganciclovir AUC0-8
decreased 17 ± 25% (range: -52% to 23%) in the presence
of zidovudine, 100 mg every 4 hours (n=12). Steady-state
zidovudine AUC0-4 increased 19 ± 27% (range:
-11% to 74%) in the presence of ganciclovir.
Since both zidovudine and ganciclovir have the potential
to cause neutropenia and anemia, some patients may not
tolerate concomitant therapy with these drugs at full
dosage.
Probenecid: At an oral dose of 1000 mg of CYTOVENE
every 8 hours (n=10), ganciclovir AUC0-8 increased
53 ± 91% (range: -14% to 299%) in the presence of probenecid,
500 mg every 6 hours. Renal clearance of ganciclovir decreased
22 ± 20% (range: -54% to -4%), which is consistent with
an interaction involving competition for renal tubular
secretion.
Imipenem-cilastatin: Generalized seizures have
been reported in patients who received ganciclovir and
imipenem-cilastatin. These drugs should not be used concomitantly
unless the potential benefits outweigh the risks.
Other Medications: It is possible that drugs
that inhibit replication of rapidly dividing cell populations
such as bone marrow, spermatogonia and germinal layers
of skin and gastrointestinal mucosa may have additive
toxicity when administered concomitantly with ganciclovir.
Therefore, drugs such as dapsone, pentamidine, flucytosine,
vincristine, vinblastine, adriamycin, amphotericin B,
trimethoprim/sulfamethoxazole combinations or other nucleoside
analogues, should be considered for concomitant use with
ganciclovir only if the potential benefits are judged
to outweigh the risks.
No formal drug interaction studies of CYTOVENE-IV or
CYTOVENE and drugs commonly used in transplant recipients
have been conducted. Increases in serum creatinine were
observed in patients treated with CYTOVENE-IV plus either
cyclosporine or amphotericin B, drugs with known potential
for nephrotoxicity (see ADVERSE EVENTS). In a retrospective
analysis of 93 liver allograft recipients receiving ganciclovir
(5 mg/kg infused over 1 hour every 12 hours) and oral
cyclosporine (at therapeutic doses), there was no evidence
of an effect on cyclosporine whole blood concentrations.
Carcinogenesis,
Mutagenesis##: Ganciclovir
was carcinogenic in the mouse at oral doses of 20 and
1000 mg/kg/day (approximately 0.1x and 1.4x, respectively,
the mean drug exposure in humans following the recommended
intravenous dose of 5 mg/kg, based on area under the plasma
concentration curve [AUC] comparisons). At the dose of
1000 mg/kg/day there was a significant increase in the
incidence of tumors of the preputial gland in males, forestomach
(nonglandular mucosa) in males and females, and reproductive
tissues (ovaries, uterus, mammary gland, clitoral gland
and vagina) and liver in females. At the dose of 20 mg/kg/day,
a slightly increased incidence of tumors was noted in
the preputial and harderian glands in males, forestomach
in males and females, and liver in females. No carcinogenic
effect was observed in mice administered ganciclovir at
1 mg/kg/day (estimated as 0.01x the human dose based on
AUC comparison). Except for histiocytic sarcoma of the
liver, ganciclovir-induced tumors were generally of epithelial
or vascular origin. Although the preputial and clitoral
glands, forestomach and harderian glands of mice do not
have human counterparts, ganciclovir should be considered
a potential carcinogen in humans.
Ganciclovir increased mutations in mouse lymphoma cells
and DNA damage in human lymphocytes in vitro at concentrations
between 50 to 500 and 250 to 2000 µg/mL, respectively.
In the mouse micronucleus assay, ganciclovir was clastogenic
at doses of 150 and 500 mg/kg (IV) (2.8 to 10x human exposure
based on AUC) but not 50 mg/kg (exposure approximately
comparable to the human based on AUC). Ganciclovir was
not mutagenic in the Ames Salmonella assay at concentrations
of 500 to 5000 µg/mL.
Impairment of
Fertility##: Ganciclovir
caused decreased mating behavior, decreased fertility,
and an increased incidence of embryolethality in female
mice following intravenous doses of 90 mg/kg/day (approximately
1.7x the mean drug exposure in humans following the dose
of 5 mg/kg, based on AUC comparisons). Ganciclovir caused
decreased fertility in male mice and hypospermatogenesis
in mice and dogs following daily oral or intravenous administration
of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure
(AUC) at the lowest dose showing toxicity in each species
ranged from 0.03 to 0.1x the AUC of the recommended human
intravenous dose.
Pregnancy: Category C##:
Ganciclovir has been shown to be embryotoxic in rabbits
and mice following intravenous administration and teratogenic
in rabbits. Fetal resorptions were present in at least
85% of rabbits and mice administered 60 mg/kg/day and
108 mg/kg/day (2x the human exposure based on AUC comparisons),
respectively. Effects observed in rabbits included: fetal
growth retardation, embryolethality, teratogenicity and/or
maternal toxicity. Teratogenic changes included cleft
palate, anophthalmia/microphthalmia, aplastic organs (kidney
and pancreas), hydrocephaly and brachygnathia. In mice,
effects observed were maternal/fetal toxicity and embryolethality.
Daily intravenous doses of 90 mg/kg administered to female
mice prior to mating, during gestation, and during lactation
caused hypoplasia of the testes and seminal vesicles in
the month-old male offspring, as well as pathologic changes
in the nonglandular region of the stomach (see Carcinogenesis,
Mutagenesis). The drug exposure in mice as estimated
by the AUC was approximately 1.7x the human AUC.
Ganciclovir may be teratogenic or embryotoxic at dose
levels recommended for human use. There are no adequate
and well-controlled studies in pregnant women. CYTOVENE-IV
or CYTOVENE should be used during pregnancy only if the
potential benefits justify the potential risk to the fetus.
##Footnote: All dose comparisons
presented in the Carcinogenesis, Mutagenesis, Impairment
of Fertility, and Pregnancy subsections are
based on the human AUC following administration of a single
5 mg/kg intravenous infusion of CYTOVENE-IV as used during
the maintenance phase of treatment. Compared with the
single 5 mg/kg intravenous infusion, human exposure is
doubled during the intravenous induction phase (5 mg/kg
bid) and approximately halved during maintenance treatment
with CYTOVENE capsules (1000 mg tid). The cross-species
dose comparisons should be divided by 2 for intravenous
induction treatment with CYTOVENE-IV and multiplied by
2 for CYTOVENE capsules.
Nursing Mothers: It is not known whether
ganciclovir is excreted in human milk. However, many drugs
are excreted in human milk and, because carcinogenic and
teratogenic effects occurred in animals treated with ganciclovir,
the possibility of serious adverse reactions from ganciclovir
in nursing infants is considered likely (see Pregnancy:
Category C). Mothers should be instructed to discontinue
nursing if they are receiving CYTOVENE-IV or CYTOVENE.
The minimum interval before nursing can safely be resumed
after the last dose of CYTOVENE-IV or CYTOVENE is unknown.
Pediatric Use: SAFETY AND EFFICACY OF CYTOVENE-IV
AND CYTOVENE IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED.
THE USE OF CYTOVENE-IV OR CYTOVENE IN THE PEDIATRIC POPULATION
WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY OF LONG-TERM
CARCINOGENICITY AND REPRODUCTIVE TOXICITY. ADMINISTRATION
TO PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN ONLY AFTER
CAREFUL EVALUATION AND ONLY IF THE POTENTIAL BENEFITS
OF TREATMENT OUTWEIGH THE RISKS.
The spectrum of adverse events reported in 120 immunocompromised
pediatric clinical trial participants with serious CMV
infections receiving CYTOVENE-IV solution were similar
to those reported in adults. Granulocytopenia (17%) and
thrombocytopenia (10%) were the most common adverse events
reported.
Sixteen pediatric patients (8 months to 15 years of age)
with life- or sight-threatening CMV infections were evaluated
in an open-label, CYTOVENE-IV solution, pharmacokinetics
study. Adverse events reported for more than one pediatric
patient were as follows: hypokalemia (4/16, 25%), abnormal
kidney function (3/16, 19%), sepsis (3/16, 19%), thrombocytopenia
(3/16, 19%), leukopenia (2/16, 13%), coagulation disorder
(2/16, 13%), hypertension (2/16, 13%), pneumonia (2/16,
13%) and immune system disorder (2/16, 13%).
There has been very limited clinical experience using
CYTOVENE-IV for the treatment of CMV retinitis in patients
under the age of 12 years. Two pediatric patients (ages
9 and 5 years) showed improvement or stabilization of
retinitis for 23 and 9 months, respectively. These pediatric
patients received induction treatment with 2.5 mg/kg tid
followed by maintenance therapy with 6 to 6.5 mg/kg once
per day, 5 to 7 days per week. When retinitis progressed
during once-daily maintenance therapy, both pediatric
patients were treated with the 5 mg/kg bid regimen. Two
other pediatric patients (ages 2.5 and 4 years) who received
similar induction regimens showed only partial or no response
to treatment. Another pediatric patient, a 6-year-old
with T-cell dysfunction, showed stabilization of retinitis
for 3 months while receiving continuous infusions of CYTOVENE-IV
at doses of 2 to 5 mg/kg/24 hours. Continuous infusion
treatment was discontinued due to granulocytopenia.
Eleven of the 72 patients in the placebo-controlled trial
in bone marrow transplant recipients were pediatric patients,
ranging in age from 3 to 10 years (5 treated with CYTOVENE-IV
and 6 with placebo). Five of the pediatric patients treated
with CYTOVENE-IV received 5 mg/kg intravenously bid for
up to 7 days; 4 patients went on to receive 5 mg/kg qd
up to day 100 posttransplant. Results were similar to
those observed in adult transplant recipients treated
with CYTOVENE-IV. Two of the 6 placebo-treated pediatric
patients developed CMV pneumonia vs none of the 5 patients
treated with CYTOVENE-IV. The spectrum of adverse events
in the pediatric group was similar to that observed in
the adult patients.
CYTOVENE capsules have not been studied in pediatric
patients under age 13.
Geriatric Use: The pharmacokinetic profiles
of CYTOVENE-IV and CYTOVENE in elderly patients have not
been established. Since elderly individuals frequently
have a reduced glomerular filtration rate, particular
attention should be paid to assessing renal function before
and during administration of CYTOVENE-IV or CYTOVENE (see
DOSAGE AND ADMINISTRATION).
Clinical studies of CYTOVENE-IV and CYTOVENE did not
include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger
subjects. In general, dose selection for an elderly patient
should be cautious, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy. CYTOVENE-IV
and CYTOVENE are known to be substantially excreted by
the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection.
In addition, renal function should be monitored and dosage
adjustments should be made accordingly (see Use in
Patients With Renal Impairment and DOSAGE AND ADMINISTRATION).
Use
in Patients With Renal Impairment: CYTOVENE-IV
and CYTOVENE should be used with caution in patients with
impaired renal function because the half-life and plasma/serum
concentrations of ganciclovir will be increased due to
reduced renal clearance (see DOSAGE AND ADMINISTRATION
and ADVERSE EVENTS: Renal Toxicity).
Hemodialysis has been shown to reduce plasma levels of
ganciclovir by approximately 50%.
|
|
