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
Xigris Side Effects, and Drug Interactions - Drotrecogin alfa
Xigris Side Effects, and Drug Interactions - Drotrecogin alfa
SIDE EFFECTS
Bleeding
Bleeding is the most common adverse reaction associated with
Xigris.
In the phase 3 study, serious bleeding events were observed
during the 28-day study period in 3.5% of Xigris treated and 2.0% of placebo
treated patients, respectively. The difference in serious bleeding between Xigris
and placebo occurred primarily during the infusion period and is shown in Table
2.1 Serious bleeding events were defined as any intracranial hemorrhage,
any life-threatening bleed, any bleeding event requiring the administration
of ³3 units of packed red blood cells per day for
2 consecutive days, or any bleeding event assessed as a serious adverse event.
Table 2: Number of Patients Experiencing a Serious Bleeding
Event by Site of Hemorrhage During the Study Drug Infusion Perioda
in PROWESS1
| |
Xigris N=850
|
Placebo N=840
|
|
Total
|
20 (2.4%)
|
8 (1.0%)
|
|
Site of Hemorrhage
|
|
|
|
Gastrointestinal
|
5
|
4
|
|
Intra-abdominal
|
2
|
3
|
|
Intra-thoracic
|
4
|
0
|
|
Retroperitoneal
|
3
|
0
|
|
Intracranial
|
2
|
0
|
|
Genitourinary
|
2
|
0
|
|
Skin/soft tissue
|
1
|
0
|
|
Otherb
|
1
|
1
|
aStudy drug infusion period is defined as the date
of initiation of study drug to the date of study drug discontinuation plus the
next calendar day.
bPatients requiring the administration of ³3
units of packed red blood cells per day for 2 consecutive days without an identified
site of bleeding.
In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred
during the infusion period for Xigris treated patients and no cases were reported
in the placebo patients. The incidence of ICH during the 28-day study period
was 0.2% for Xigris treated patients and 0.1% for placebo treated patients.
ICH has been reported in patients receiving Xigris in non–placebo controlled
trials with an incidence of approximately 1% during the infusion period. The
risk of ICH may be increased in patients with risk factors for bleeding such
as severe coagulopathy and severe thrombocytopenia (see WARNINGS).
In PROWESS, 25% of the Xigris-treated patients and 18% of the
placebo-treated patients experienced at least one bleeding event during the
28-day study period. In both treatment groups, the majority of bleeding events
were ecchymoses or gastrointestinal tract bleeding.
Other Adverse Reactions
Patients administered Xigris as treatment for severe sepsis
experience many events which are potential sequelae of severe sepsis and may
or may not be attributable to Xigris therapy. In clinical trials, there were
no types of non-bleeding adverse events suggesting a causal association with
Xigris.
DRUG INTERACTIONS
Drug interactions with Xigris have not been studied in patients
with severe sepsis. Caution should be employed when Xigris is used with
other drugs that affect hemostasis (see CLINICAL
PHARMACOLOGY, WARNINGS).
Approximately 2/3 of the patients in the phase 3 study received prophylactic
low dose heparin. Concomitant use of prophylactic low dose heparin did not appear
to affect safety. Its effect on the efficacy of Xigris has not been evaluated
in a randomized controlled clinical trial.
Drug/Laboratory Test Interaction
Because Xigris may affect the APTT assay, Xigris present in
plasma samples may interfere with one-stage coagulation assays based on the
APTT (such as factor VIII, IX, and XI assays). This interference may result
in an apparent factor concentration that is lower than the true concentration.
Xigris present in plasma samples does not interfere with one-stage factor assays
based on the PT (such as factor II, V, VII, and X assays).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate potential carcinogenicity
of Xigris have not been performed.
Xigris was not mutagenic in an in vivo micronucleus study in
mice or in an in vitro chromosomal aberration study in human peripheral blood
lymphocytes with or without rat liver metabolic activation.
The potential of Xigris to impair fertility has not been evaluated
in male or female animals.
Pregnancy Category C
Animal reproductive studies have not been conducted with Xigris.
It is not known whether Xigris can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Xigris should be given to pregnant
women only if clearly needed.
Nursing Mothers
It is not known whether Xigris is excreted in human milk or
absorbed systemically after ingestion. Because many drugs are excreted in human
milk, and because of the potential for adverse effects on the nursing infant,
a decision should be made whether to discontinue nursing or discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of Xigris have not been established
in the age group newborn (38 weeks gestational age) to 18 years. The efficacy
of Xigris in adult patients with severe sepsis and high risk of death cannot
be extrapolated to pediatric patients with severe sepsis.
Geriatric Use
In clinical studies evaluating 1821 patients with severe sepsis,
approximately 50% of the patients were 65 years or older. No overall differences
in safety or effectiveness were observed between these patients and younger
patients.
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