A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Procrit Side Effects, and Drug Interactions - Erythropoietin
Procrit Side Effects, and Drug Interactions - Erythropoietin
SIDE EFFECTS
Immunogenicity
As with all therapeutic proteins, there is the potential for
immunogenicity. The observed incidence of antibody positivity
in an assay may be influenced by several factors including
assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies
to PROCRIT® with the incidence of antibodies to other
products may be misleading.
A few cases of PRCA associated with antibodies with
neutralizing activity have been reported in patients receiving
PROCRIT® (see WARNINGS: PURE RED CELL APLASIA).
These cases were observed in patients treated by either SC
or IV routes of administration and occurred predominantly in
CRF patients.
Chronic Renal Failure Patients
Studies analyzed to date indicate that PROCRIT is generally well-tolerated.
The adverse events reported are frequent sequelae of CRF
and are not necessarily attributable to PROCRIT therapy. In
double-blind, placebo-controlled studies involving over 300 patients
with CRF, the events reported in greater than 5% of patients treated
with PROCRIT during the blinded phase
were:
|
PERCENT OF PATIENTS REPORTING EVENT
|
|
Event
|
Patients Treated
With Epoetin Alfa
(N= 200)
|
PLACEBO- Treated
Patients
(N= 135)
|
| Hypertension |
24%
|
19%
|
| Headache |
16%
|
12%
|
| Arthralgias |
11%
|
6%
|
| Nausea |
11%
|
9%
|
| Edema |
9%
|
10%
|
| Fatigue |
9%
|
14%
|
| Diarrhea |
9%
|
6%
|
| Vomiting |
8%
|
5%
|
| Chest Pain |
7%
|
9%
|
| Skin Reaction (Administration
Site) |
7%
|
12%
|
| Asthenia |
7%
|
12%
|
| Dizziness |
7%
|
13%
|
| Clotted Access |
7%
|
2%
|
Significant adverse events of concern in patients with CRF
treated in double-blinded, placebo-controlled trials occurred in
the following percent of patients during the blinded phase
of the studies:
| Seizure |
1.1%
|
1.1%
|
| CVA/ TIA
|
0.4%
|
0.6%
|
| MI |
0.4%
|
1.1%
|
| Death |
0
|
1.7%
|
In the U.S. PROCRIT studies in patients on dialysis
(over 567 patients), the incidence
(number of events per patient-year)
of the most frequently reported adverse events were: hypertension
(0.75), headache (0.40),
tachycardia (0.31), nausea/vomiting (0.26), clotted vascular
access (0.25), shortness of breath
(0.14), hyperkalemia
(0.11), and diarrhea
(0.11). Other reported events occurred at a rate
of less than 0.10 events per
patient per
year.
Events reported to have occurred within several hours of administration
of PROCRIT were rare, mild, and transient, and included injection
site stinging in dialysis
patients and flu-like symptoms such
as arthralgias and myalgias.
In all studies analyzed to date, PROCRIT administration
was generally well-tolerated, irrespective of the route of administration.
Pediatric CRF Patients: In pediatric patients with CRF on
dialysis, the pattern of most adverse events was similar to
that found in adults. Additional adverse events reported
during the double-blind phase in > 10% of pediatric patients
in either treatment group were: abdominal pain, dialysis
access complications including access infections and
peritonitis in those receiving peritoneal dialysis, fever, upper
respiratory infection, cough, pharyngitis, and constipation.
The rates are similar between the treatment groups for
each event.
Hypertension: Increases in blood
pressure have been
reported in clinical
trials, often during the first 90 days of therapy. On occasion,
hypertensive encephalopathy
and seizures have been observed in patients with CRF
treated with PROCRIT. When data from all patients in the U.S. Phase
III multicenter trial were analyzed, there was an apparent
trend of more reports of hypertensive
adverse events in patients on dialysis with a faster rate
of rise of hematocrit
(greater than 4 hematocrit
points in any two-week period). However, in a double-blind, placebo-controlled
trial, hypertensive
adverse events were not reported at an increased rate in the group
treated with PROCRIT (150 Units/kg T.I.W.) relative to the placebo
group.
Seizures: There have been 47 seizures in 1,010 patients
on dialysis treated
with PROCRIT in clinical
trials, with an exposure
of 986 patient-years for a rate
of approximately 0.048 events per
patient-year. However, there appeared to be a higher rate
of seizures during the first 90 days of therapy
(occurring in approximately 2.5% of patients) when compared to subsequent
90-day periods. The baseline
incidence of seizures
in the untreated dialysis
population is difficult
to determine; it appears to be in the range
of 5-10% per patient-year.26-28
Thrombotic Events: In
clinical trials where
the maintenance hematocrit was 35 ± 3% on PROCRIT, clotting
of the vascular access
(A-V shunt) has occurred at an annualized rate
of about 0.25 events per patient-year, and other thrombotic
events (myocardial infarction, cerebrovascular accident, transient
ischemic attack, and pulmonary
embolism) occurred at a rate
of 0.04 events per patient-year.
In a separate study of 1,111
untreated dialysis patients, clotting
of the vascular access
occurred at a rate of 0.5
events per patient-year.
However, in chronic
renal failure
patients on hemodialysis
who also had clinically evident ischemic heart
disease or congestive heart
failure, the risk of A-V
shunt thrombosis
was higher (39% vs 29%, p<0.001), and myocardial
infarction, vascular
ischemic events, and venous
thrombosis were increased
in patients targeted to a hematocrit of 42 ± 3% compared
to those maintained at 30 ± 3%. (see WARNINGS)
In patients treated with commercial PROCRIT, there have been rare
reports of serious or unusual thromboembolic events including migratory
thrombophlebitis, microvascular thrombosis,
pulmonary embolus,
and thrombosis of
the retinal artery, and temporal
and renal veins. A causal
relationship has not been established.
Allergic Reactions: There have been no reports of serious
allergic reactions or anaphylaxis associated with PROCRIT®
administration during clinical trials. Skin rashes and urticaria
have been observed rarely and when reported have generally
been mild and transient in nature.There have been rare
reports of potentially serious allergic reactions including
urticaria with associated respiratory symptoms or circumoral
edema, or urticaria alone. Most reactions occurred in situations
where a causal relationship could not be established.
Symptoms recurred with rechallenge in a few instances,
suggesting that allergic reactivity may occasionally be associated
with PROCRIT® therapy. If an anaphylactoid reaction
occurs, PROCRIT® should be immediately discontinued and
appropriate therapy initiated.
Zidovudine-Treated HIV-Infected Patients
Adverse events reported in clinical
trials with PROCRIT in zidovudine-treated HIV-infected patients
were consistent with the progression
of HIV infection. In double-blind,
placebo-controlled studies of three-months duration
involving approximately 300 zidovudine-treated HIV-infected patients,
adverse events with an incidence
of ≥10% in either patients treated with PROCRIT or placebo-treated
patients were:
|
Percent of Patients Reporting Event
|
|
Event
|
Patients Treated with PROCRIT
(N= 144)
|
PLACEBO-Treated
Patients
(N= 153)
|
| Pyrexia |
38%
|
29%
|
| Fatigue |
25%
|
31%
|
| Headache |
19%
|
14%
|
| Cough |
18%
|
14%
|
| Diarrhea |
16%
|
18%
|
| Rash |
16%
|
8%
|
| Congestion, Respiratory |
15%
|
10%
|
| Nausea |
15%
|
12%
|
| Shortness of Breath
|
14%
|
13%
|
| Asthenia |
11%
|
14%
|
| Skin Reaction, (Administration
Site) |
10%
|
7%
|
| Dizziness |
9%
|
10%
|
In the 297 patients studied, PROCRIT was not associated with significant
increases in opportunistic infections or mortality.22
In 71 patients from this
group treated with PROCRIT
at 150 Units/kg (T.I.W.), serum p24 antigen
levels did not appear to increase.23 Preliminary data
showed no enhancement
of HIV replication
in infected cell lines
in vitro.22
Peripheral white blood
cell and platelet
counts are unchanged following PROCRIT therapy.
Allergic Reactions: Two zidovudine-treated HIV-infected
patients had urticarial
reactions within 48 hours of their first exposure to study medication.
One patient was treated
with PROCRIT and one was treated with placebo
(PROCRIT vehicle alone).
Both patients had positive
immediate skin tests against their study medication
with a negative saline
control. The basis for
this apparent pre-existing
hypersensitivity
to components of the PROCRIT formulation is unknown, but may be
related to HIV-induced immunosuppression or prior exposure
to blood products.
Seizures: In
double-blind and open-label trials of PROCRIT in zidovudine-treated
HIV-infected patients, ten patients have experienced seizures.22
In general, these seizures
appear to be related to underlying pathology
such as meningitis
or cerebral neoplasms, not PROCRIT therapy.
Cancer Patients on Chemotherapy
Adverse experiences reported in clinical
trials with PROCRIT in cancer patients were consistent with the
underlying disease state.
In double-blind, placebo-controlled
studies of up to 3-months duration
involving 131 cancer patients, adverse events with an incidence
> 10% in either patients treated with PROCRIT or placebo-treated
patients were as indicated below.
|
Percent of Patients Reporting Event
|
|
Event
|
Patients Treated with PROCRIT
(N= 63)
|
PLACEBO-Treated
Patients
(N= 68)
|
| Pyrexia |
29%
|
19%
|
| Diarrhea |
21% *
|
7%
|
| Nausea |
17% *
|
32%
|
| Vomiting |
17%
|
15%
|
| Edema |
17% *
|
1%
|
| Asthenia |
13%
|
16%
|
| Fatigue |
13%
|
15%
|
| Shortness of Breath
|
13%
|
9%
|
| Paresthesia |
11%
|
6%
|
| Upper Respiratory
Infection |
11%
|
4%
|
| Dizziness |
5%
|
12%
|
| Trunk Pain |
3% *
|
16%
|
* Statistically significant
Although some statistically significant
differences between patients treated with PROCRIT and placebo-treated
patients were noted, the overall safety profile
of PROCRIT appeared to be consistent with the disease
process of advanced cancer. During double-blind and subsequent open-label
therapy in which patients (N=72 for total exposure
to PROCRIT) were treated for up to 32 weeks with doses as high as
927 Units/kg, the adverse experience profile of PROCRIT was consistent
with the progression
of advanced cancer.
Three hundred thirty-three (333) cancer patients enrolled in
a placebo-controlled, double-blind trial utilizing Weekly
dosing with PROCRIT® for up to 4 months were evaluable for
adverse events. The incidence of adverse events was similar
in both treatment and placebo arms.
Surgery Patients
Adverse events with an incidence
of >10% are shown in the following table:
|
Percent of Patients Reporting Event
|
|
Event
|
Patients Treated with PROCRIT
300 U/ kg
(N= 112) a
|
Patients Treated with PROCRIT
100 U/ kg
(N= 101) a
|
PLACEBO Treated
Patients
(N= 103) a
|
PROCRIT
600 U/ kg
(N= 73) b
|
PROCRIT
300 U/ kg
(N= 72) b
|
| Pyrexia |
51%
|
50%
|
60%
|
47%
|
42%
|
| Nausea |
48%
|
43%
|
45%
|
45%
|
58%
|
| Constipation |
43%
|
42%
|
43%
|
51%
|
53%
|
| Skin Reaction, (Administration
Site) |
25%
|
19%
|
22%
|
26%
|
29%
|
| Vomiting |
22%
|
12%
|
14%
|
21%
|
29%
|
| Skin Pain |
18%
|
18%
|
17%
|
5%
|
4%
|
| Pruritus |
16%
|
16%
|
14%
|
14%
|
22%
|
| Insomnia |
13%
|
16%
|
13%
|
21%
|
18%
|
| Headache |
13%
|
11%
|
9%
|
10%
|
19%
|
| Dizziness |
12%
|
9%
|
12%
|
11%
|
21%
|
| Urinary Tract Infection |
12%
|
3%
|
11%
|
11%
|
8%
|
| Hypertension |
10%
|
11%
|
10%
|
5%
|
10%
|
| Diarrhea |
10%
|
7%
|
12%
|
10%
|
6%
|
| Deep Venous Thrombosis |
10%
|
3%
|
5%
|
0% c
|
0% c
|
| Dyspepsia |
9%
|
11%
|
6%
|
7%
|
8%
|
| Anxiety |
7%
|
2%
|
11%
|
11%
|
4%
|
| Edema |
6%
|
11%
|
8%
|
11%
|
7%
|
a Study including patients undergoing orthopedic
surgery treated with PROCRIT or placebo
for 15 days
bStudy including patients undergoing orthopedic
surgery treated with
PROCRIT 600 U/kg weekly x 4 or 300 U/kg daily x 15
cDetermined by clinical
symptoms
Thrombotic/vascular events: In
three double-blind, placebo-controlled orthopedic surgery
studies, the rate of deep
venous thrombosis
(DVT) was similar among Epoetin alfa and placebo-treated patients
in the recommended population of patients with a pretreatment
hemoglobin of >10
to < 13 g/dL. 14, 16, 24 However, in 2 of 3 orthopedic
surgery studies the
overall rate (all pretreatment
hemoglobin groups
combined) of DVTs detected by postoperative ultrasonography
and/or surveillance
venography was higher in the Epoetin alfa-treated group
than in the placebo-treated group (11% vs. 6%). This finding was
attributable to the difference in DVT rates observed in the subgroup
of patients with pretreatment
hemoglobin >13 g/dL. However, the incidence
of DVTs was within the range
of that reported in the literature for orthopedic
surgery patients.
In the orthopedic
surgery study of patients
with pretreatment
hemoglobin of >10 to <13 g/dLwhich compared two dosing regimens
(600 U/kg weekly x 4 and 300 U/kg daily x 15), four subjects in
the 600 U/kg weekly PROCRIT group (5%) and no
subjects in the 300 U/kg daily group
had a thrombotic vascular event during the study period.15
In a study examining the use of Epoetin alfa in 182 patients scheduled
for coronary artery
bypass graft
surgery, 23% of patients
treated with Epoetin alfa and 29% treated with placebo
experienced thrombotic/vascular events. There were 4 deaths among
the Epoetin alfa-treated patients that were associated with a thrombotic/
vascular event. A causative
role of Epoetin alfa cannot
be excluded. (See WARNINGS)
DRUG INTERACTIONS
No evidence of interaction
of PROCRIT with other drugs was observed in the course of clinical
trials.
top
