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CLL Complications
Neumega: Treatment of Thrombocytopenia10/16/03 by Chaya Venkat We are all familiar with growth factors such as Epogen, Neupogen, Neulasta and Leukine for improved production of red blood cells, neutrophils and macrophages. However, this is the first time I have come across a growth factor for platelets. For whatever reason, a significant portion of CLL patients seem to have specific problems with platelet production. A decreasing platelet count is often the "canary in the mine" giving early warning of bone marrow insufficiency. Even when the bone marrow is functioning quite well, low platelet counts can be due to ITP, an autoimmune disease where platelets are destroyed prematurely by antibodies created to attack them. This is a part of the collapse of the ability to discriminate between "self" and "non-self", a crucial distinction that is made routinely by healthy people but this capability gets corrupted in CLL patients as the cancer load increases. Yet another reason for reduced platelets could be compromised spleen function whereby platelets and red blood cells get chewed up well ahead of their time. As we discussed in a recent article on Rai and Binet staging, it is important to know whether your platelet and red blood cell counts are below normal ranges, but it is also important to know why they are low. If the low counts are due to autoimmune disease or spleen involvement, there are ways of handling that. A more serious problem would be dead or dying bone marrow function. Growth factors such as Epogen and Neulasta work by encouraging the bone marrow to produce more of the required cell lines. The information below comes from the FDA website, and it discusses a similar growth factor for platelets. Neumega (generic name oprelvekin) has been approved by the FDA in 1997, I am surprised we do not hear more about it. Several of our readers have low platelet counts, many are dependent on frequent transfusions to maintain these counts above certain "danger" threshold values. Extremely low platelet counts put patients at risk of uncontrolled bleeding, stroke, or internal bleeding that may not be detected until it shows up as anemia. If you are presently dependent on transfusions to keep your platelet counts up, talk to your doctors about this growth factor. Here's a link you might want to visit to get additional information: http://www.centerwatch.com/patient/drugs/dru346.html. The manufacturer, a wholly-owned subsidiary of American Home Products, has a website that provides additional information on Neumega: http://www.neumega.com/home.html. The following is a quote from the Neumega website: NEUMEGA is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. Below
is the FDA's approval literature on the drug. The entire document may be
viewed at:
FDA Reference Supplement Number:
Boxed Warning Allergic Reactions Including Anaphylaxis Neumega has caused allergic
or hypersensitivity reactions, including anaphylaxis. Administration
of Neumega should be permanently discontinued in any patient who
develops an allergic or hypersensitivity reaction (see WARNINGS,
CONTRAINDICATIONS, ADVERSE REACTIONS and ADVERSE REACTIONS,
Immunogenicity). Complete Label NEUMEGA Description Mechanism Interleukin eleven (IL-11) is a thrombopoietic growth factor that
directly stimulates the proliferation of hematopoietic stem cells and
megakaryocyte progenitor cells and induces megakaryocyte maturation
resulting in increased platelet production. IL-11 is a member of a
family of human growth factors which includes human growth hormone,
granulocyte colony- stimulating factor (G-CSF), and other growth
factors. Oprelvekin, the active ingredient in Neumega, is produced in
Escherichia coli (E. coli) by recombinant DNA technology. The protein
has a molecular mass of approximately 19,000 daltons, and is non-glycosylated.
The polypeptide is 177 amino acids in length and differs from the 178
amino acid length of native IL-11 only in lacking the amino-terminal
proline residue. This alteration has not resulted in measurable
differences in bioactivity either in vitro or in vivo. Neumega is
formulated in single-use vials containing 5 mg of oprelvekin (specific
activity approximately 8 x 106 Units/mg) as a sterile, lyophilized
powder with 23 mg Glycine, USP, 1.6 mg Dibasic Sodium Phosphate
Heptahydrate, USP, and 0.55 mg Monobasic Sodium Phosphate Monohydrate,
USP. When reconstituted with 1 mL of Sterile Water for Injection, USP,
the resulting solution has a pH of 7.0 and a concentration of 5 mg/mL. Generic Drug Name oprelvekin Manufacturer Genetics Institute, Inc. Cambridge, MA 02140-2387, USA US License
Number 1163
Clinical Pharmacology The primary hematopoietic activity of Neumega is stimulation of
megakaryocytopoiesis and thrombopoiesis. Neumega has shown potent
thrombopoietic activity in animal models of compromised hematopoiesis,
including moderately to severely myelosuppressed mice and nonhuman
primates. In these models, Neumega improved platelet nadirs and
accelerated platelet recoveries compared to controls. Preclinical
trials have shown that mature megakaryocytes which develop during in
vivo treatment with Neumega are ultrastructurally normal. Platelets
produced in response to Neumega were morphologically and functionally
normal and possessed a normal life span. IL-11 has also been shown to
have non-hematopoietic activities in animals including the regulation
of intestinal epithelium growth (enhanced healing of gastrointestinal
lesions), the inhibition of adipogenesis, the induction of acute phase
protein synthesis, inhibition of pro- inflammatory cytokine production
by macrophages, and the stimulation of osteoclastogenesis and
neurogenesis. Non-hematopoietic pathologic changes observed in animals
include fibrosis of tendons and joint capsules, periosteal thickening,
papilledema, and embryotoxicity (see PRECAUTIONS, Pediatric Use and
PRECAUTIONS, Pregnancy Category C). IL-11 is produced by bone marrow
stromal cells and is part of the cytokine family that shares the gp130
signal transducer. Primary osteoblasts and mature osteoclasts express
mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Both
bone-forming and bone-resorbing cells are potential targets of IL-11.
(1) Pharmacokinetics The pharmacokinetics of Neumega have been
evaluated in studies of healthy, adult subjects and cancer patients
receiving chemotherapy. In a study in which a single 50 µg/kg
subcutaneous dose was administered to eighteen healthy men, the peak
serum concentration (Cmax) of 17.4 ± 5.4 ng/mL (mean ± S.D.) was
reached at 3.2 ± 2.4 hrs (Tmax) following dosing. The terminal
half-life was 6.9 ± 1.7 hrs. In a second study in which single 75 µg/kg
subcutaneous and intravenous doses were administered to twenty-four
healthy subjects, the pharmacokinetic profiles were similar between
men and women. The absolute bioavailability of Neumega was >80%. In
a study in which multiple, subcutaneous doses of both 25 and 50 µg/kg
were administered to cancer patients receiving chemotherapy, Neumega
did not accumulate and clearance of Neumega was not impaired following
multiple doses. In a dose escalation Phase 1 study, Neumega was also
administered to 43 pediatric (ages 8 months to 18 years) and 1 adult
patient receiving ICE (ifosfamide, carboplatin, etoposide)
chemotherapy. Administered doses ranged from 25 to 125 ?g/kg. Analysis
of data from 40 pediatric patients showed that Cmax and Tmax, and
terminal half-life were comparable to that in adults. The mean area
under the concentration-time curve (AUC) for pediatric patients (8
months to 12 years), receiving 50 µg/kg was approximately half that
achieved in healthy adults receiving 50 µg/kg. Available data suggest
that clearance of IL-11 decreases with increasing age. In preclinical
trials in rats, radiolabeled Neumega was rapidly cleared from the
serum and distributed to highly perfused organs. The kidney was the
primary route of elimination. The amount of intact Neumega in urine
was low, indicating that the molecule was metabolized before
excretion. In a clinical study, a single dose of Neumega was
administered to subjects with severely impaired renal function
(creatinine clearance <15 mL/min). The mean ± S.D. values for Cmax
and AUC were 30.8 ± 8.6 ng/mL and 373 ± 106 ng*hr/mL, respectively.
When compared with control subjects in this study with normal renal
function, the mean Cmax was 2.2 fold higher and the mean AUC was 2.6
fold (95% confidence interval, 1.7%-3.8%) higher in the subjects with
severe renal impairment. In the subjects with severe renal impairment,
clearance was approximately 40% of the value seen in subjects with
normal renal function. The average terminal half-life was similar in
subjects with severe renal impairment and those with normal renal
function. Pharmacodynamics In a study in which Neumega was
administered to non-myelosuppressed cancer patients, daily
subcutaneous dosing for 14 days with Neumega increased the platelet
count in a dose- dependent manner. Platelet counts began to increase
relative to baseline between 5 and 9 days after the start of dosing
with Neumega. After cessation of treatment, platelet counts continued
to increase for up to 7 days then returned toward baseline within 14
days. No change in platelet reactivity as measured by platelet
activation in response to ADP, and platelet aggregation in response to
ADP, epinephrine, collagen, ristocetin and arachidonic acid has been
observed in association with Neumega treatment. In a randomized,
double-blind, placebo-controlled study in normal volunteers, subjects
receiving Neumega had a mean increase in plasma volume of >20%, and
all subjects receiving Neumega had at least a 10% increase in plasma
volume. Red blood cell volume decreased similarly (due to repeated
phlebotomy) in the Neumega and placebo groups. As a result, whole
blood volume increased approximately 10% and hemoglobin concentration
decreased approximately 10% in subjects receiving Neumega compared
with subjects receiving placebo. Mean 24 hour sodium excretion
decreased, and potassium excretion did not increase, in subjects
receiving Neumega compared with subjects receiving placebo. Clinical Studies CLINICAL STUDIES Two randomized, double-blind, placebo-controlled
trials in adults studied Neumega for the prevention of severe
thrombocytopenia following single or repeated sequential cycles of
various myelosuppressive chemotherapy regimens. One study evaluated
the effectiveness of Neumega in eliminating the need for platelet
transfusions in patients who had recovered from an episode of severe
chemotherapy-induced thrombocytopenia (defined as a platelet count
=20,000/µL), and were to receive one additional cycle of the same
chemotherapy without dose reduction. Patients had various underlying
non- myeloid malignancies, and were undergoing dose-intensive
chemotherapy with a variety of regimens. Patients were randomized to
receive Neumega at a dose of 25 µg/kg or 50 µg/kg, or placebo. The
primary endpoint was whether the patient required one or more platelet
transfusions in the subsequent chemotherapy cycle. Ninety-three
patients were randomized. Five patients withdrew from the study prior
to receiving study drug. As a result, eighty-eight patients were
included in a modified intent-to-treat analysis. The results for the
Neumega 50 µg/kg and placebo groups are summarized in Table 1. The
placebo group includes one patient who underwent chemotherapy dose
reduction and who avoided platelet transfusions. (see table 1) In the
primary efficacy analysis, more patients avoided platelet transfusion
in the Neumega 50 µg/kg arm than in the placebo arm (p = 0.04,
Fisher’s Exact test, 2-tailed). The difference in the proportion of
patients avoiding platelet transfusions in the Neumega 50 µg/kg and
placebo groups was 21% (95% confidence interval, 2%-40%). The results
observed in patients receiving 25 µg/kg of Neumega were intermediate
between those of the placebo and the 50 µg/kg groups. A second study
evaluated the effectiveness of Neumega in eliminating platelet
transfusions over two dose-intensive chemotherapy cycles in breast
cancer patients who had not previously experienced severe
chemotherapy-induced thrombocytopenia. All patients received the same
chemotherapy regimen (cyclophosphamide 3,200 mg/m2 and doxorubicin 75
mg/m2). All patients received concomitant filgrastim (G-CSF) in all
cycles. The patients were stratified by whether or not they had
received prior chemotherapy, and randomized to receive Neumega 50 µg/kg
or placebo. The primary endpoint was whether or not a patient required
one or more platelet transfusions in the two study cycles.
Seventy-seven patients were randomized. Thirteen patients failed to
complete both study cycles—eight of these had insufficient data to
be evaluated for the primary endpoint. The results of this trial are
summarized in Table 2. (see table 2) This study showed a trend in
favor of Neumega, particularly in the subgroup of patients with prior
chemotherapy. Open-label treatment with Neumega has been continued for
up to four consecutive chemotherapy cycles without evidence of any
adverse effect on the rate of neutrophil recovery or red blood cell
transfusion requirements. Some patients continued to maintain platelet
nadirs >20,000/µL for at least four sequential cycles of
chemotherapy without the need for transfusions, chemotherapy dose
reduction, or changes in treatment schedules. Platelet activation
trials done on a limited number of patients showed no evidence of
abnormal spontaneous platelet activation, or an abnormal response to
ADP. In an unblinded, retrospective analysis of the two
placebo-controlled studies, 19 of 69 patients (28%) receiving Neumega
50 µg/kg and 34 of 67 patients (51%) receiving placebo reported at
least one hemorrhagic adverse event which involved bleeding. In a
randomized, double-blind, placebo-controlled, Phase 2 study conducted
in patients who received autologous bone marrow transplantation
following myeloablative chemotherapy, the incidence of platelet
transfusions and time to neutrophil and platelet engraftment were
similar in the Neumega and placebo-treated arms. In long term
follow-up of patients, the distribution of survival and
progression-free survival times was similar between patients
randomized to Neumega therapy and those randomized to receive placebo. Indications Neumega is indicated for the prevention of severe thrombocytopenia
and the reduction of the need for platelet transfusions following
myelosuppressive chemotherapy in adult patients with nonmyeloid
malignancies who are at high risk of severe thrombocytopenia. Efficacy
was mdemonstrated in patients who had experienced severe
thrombocytopenia following the previous chemotherapy cycle. Neumega is
not indicated following myeloablative chemotherapy. The safety and
effectiveness of Neumega have not been established in pediatric
patients. Contra- Neumega is contraindicated in patients with a history of
hypersensitivity to Neumega or any component of the product (see
WARNINGS, Allergic Reactions Including Anaphylaxis). Warnings Allergic Reactions Including Anaphylaxis In the post-marketing
setting, Neumega has caused allergic or hypersensitivity reactions,
including anaphylaxis. The administration of Neumega should be
attended by appropriate precautions in case allergic reactions occur.
In addition, patients should be counseled about the symptoms for which
they should seek medical attention. (see PRECAUTIONS, Information for
Patients). Signs and symptoms reported included fever, rash, urticaria,
shortness of breath, hypotension, flushing, facial edema, edema of the
tongue, laryngeal edema, and mental status changes. Reactions occurred
after the first dose or subsequent doses of Neumega. Administration of
Neumega should be permanently discontinued in any patient who develops
an allergic or hypersensitivity reaction (see BOXED WARNING,
CONTRAINDICATIONS, ADVERSE REACTIONS, and ADVERSE REACTIONS,
Immunogenicity). Fluid Retention Neumega is known to cause serious
fluid retention that can result in peripheral edema, dyspnea on
exertion, pulmonary edema, capillary leak syndrome, atrial
arrhythmias, and exacerbation of pre-existing pleural effusions. (see
CLINICAL PHARMACOLOGY; Pharmacodynamics, WARNINGS, Cardiovascular
Events; and WARNINGS, Dilutional Anemia). It should be used with
caution in patients with clinically evident congestive heart failure,
patients who may be susceptible to developing congestive heart
failure, patients receiving aggressive hydration, patients with a
history of heart failure who are well-compensated and receiving
appropriate medical therapy, and patients who may develop fluid
retention as a result of associated medical conditions or whose
medical condition may be exacerbated by fluid retention. Fluid
retention is reversible within several days following discontinuation
of Neumega. During dosing with Neumega, fluid balance should be
monitored and appropriate medical management is advised. Close
monitoring of fluid and electrolyte status should be performed in
patients receiving chronic diuretic therapy. Sudden deaths have
occurred in oprelvekin-treated patients receiving chronic diuretic
therapy and ifosfamide who developed severe hypokalemia (see ADVERSE
REACTIONS). Pre-existing fluid collections, including pericardial
effusions or ascites, should be monitored. Drainage should be
considered if medically indicated. Dilutional Anemia Moderate
decreases in hemoglobin concentration, hematocrit, and red blood cell
count (~10% to 15%) without a decrease in red blood cell mass have
been observed. These changes are predominantly due to an increase in
plasma volume (dilutional anemia) that is primarily related to renal
sodium and water retention. The decrease in hemoglobin concentration
typically begins within 3 to 5 days of the initiation of Neumega, and
is reversible over approximately a week following discontinuation of
Neumega (see WARNINGS, Fluid Retention). Cardiovascular Events Neumega
use is associated with cardiovascular events including arrhythmias and
pulmonary edema. Cardiac arrest has been reported, but the causal
relationship to Neumega is uncertain. Use with caution in patients
with a history of atrial arrhythmias, and only after consideration of
the potential risks in relation to anticipated benefit. In clinical
trials, cardiac events including atrial arrhythmias (atrial
fibrillation or atrial flutter) occurred in 15% (23/157) of patients
treated with Neumega at doses of 50 µg/kg. Arrhythmias were usually
brief in duration; conversion to sinus rhythm typically occurred
spontaneously or after rate-control drug therapy. Approximately one-
half (11/24) of the patients who were rechallenged had recurrent
atrial arrhythmias. Clinical sequelae, including stroke, have been
reported in patients who experienced atrial arrhythmias while
receiving Neumega. The mechanism for induction of arrhythmias is not
known. Neumega was not directly arrhythmogenic in animal models. In
some patients, development of atrial arrhythmias may be due to
increased plasma volume associated with fluid retention (see WARNINGS,
Fluid Retention). Nervous System Events Stroke has been reported in
the setting of patients who develop atrial fibrillation/flutter while
receiving Neumega (see WARNINGS, Cardiovascular Events). Patients with
a history of stroke or transient ischemic attack may also be at
increased risk for these events. Papilledema Papilledema has been
reported in 2% (10/405) of patients receiving Neumega in clinical
trials following repeated cycles of exposure. The incidence was higher
16% (7/43) in children than in adults, 1% (3/362). Nonhuman primates
treated with Neumega at a dose of 1,000 µg/kg SC once daily for 4 to
13 weeks developed papilledema that was not associated with
inflammation or any other histologic abnormality and was reversible
after dosing was discontinued. Neumega should be used with caution in
patients with pre-existing papilledema, or with tumors involving the
central nervous system since it is possible that papilledema could
worsen or develop during treatment (see ADVERSE REACTIONS). Precautions General Dosing with Neumega should begin 6 to 24 hours following the
completion of chemotherapy dosing. The safety and efficacy of Neumega
given immediately prior to or concurrently with cytotoxic chemotherapy
or initiated at the time of expected nadir have not been established
(see DOSAGE AND ADMINISTRATION). The effectiveness of Neumega has not
been evaluated in patients receiving chemotherapy regimens of greater
than 5 days duration or regimens associated with delayed
myelosuppression (eg, nitrosoureas, mitomycin-C). Chronic
Administration Neumega has been administered safely using the
recommended dosage schedule (see DOSAGE AND ADMINISTRATION) for up to
6 cycles following chemotherapy. The safety and efficacy of chronic
administration of Neumega have not been established. Continuous dosage
(2 to 13 weeks) in nonhuman primates produced joint capsule and tendon
fibrosis and periosteal hyperostosis (see PRECAUTIONS, Pediatric Use).
The relevance of these findings to humans is unclear. Information for
Patients In situations when the physician determines that Neumega may
be used outside of the hospital or office setting, persons who will be
administering Neumega should be instructed as to the proper dose, and
the method for reconstituting and administering Neumega (see DOSAGE
AND ADMINISTRATION). If home use is prescribed, patients should be
instructed in the importance of proper disposal and cautioned against
the reuse of needles, syringes, drug product, and diluent. A puncture
resistant container should be used by the patient for the disposal of
used needles. Patients should be informed of the most common adverse
reactions associated with Neumega administration, including those
symptoms related to fluid retention (see ADVERSE REACTIONS and
WARNINGS). Mild to moderate peripheral edema and shortness of breath
on exertion can occur within the first week of treatment and may
continue for the duration of administration of Neumega. Patients who
have preexisting pleural or other effusions or a history of congestive
heart failure should be advised to contact their physician for
worsening of dyspnea. Most patients who receive Neumega develop
anemia. Patients should be advised to contact their physician if
symptoms attributable to atrial arrhythmia develop. Female patients of
childbearing potential should be advised of the possible risks to the
fetus of Neumega (see PRECAUTIONS, Pregnancy Category C). Laboratory
Monitoring A complete blood count should be obtained prior to
chemotherapy and at regular intervals during Neumega therapy (see
DOSAGE AND ADMINISTRATION). Platelet counts should be monitored during
the time of the expected nadir and until adequate recovery has
occurred (post-nadir counts =50,000/?L). Drug Interactions Most
patients in trials evaluating Neumega were treated concomitantly with
filgrastim (G-CSF) with no adverse effect of Neumega on the activity
of G-CSF. No information is available on the clinical use of
sargramostim (GM-CSF) with Neumega in human subjects. However, in a
study in nonhuman primates in which Neumega and GM-CSF were
coadministered, there were no adverse interactions between Neumega and
GM-CSF and no apparent difference in the pharmacokinetic profile of
Neumega. Drug interactions between Neumega and other drugs have not
been fully evaluated. Based on in vitro and nonclinical in vivo
evaluations of Neumega, drug-drug interactions with known substrates
of P450 enzymes would not be predicted. Carcinogenesis, Mutagenesis,
Impairment of Fertility No trials have been performed to assess the
carcinogenic potential of Neumega. In vitro, Neumega did not stimulate
the growth of tumor colony-forming cells harvested from patients with
a variety of human malignancies. Neumega has been shown to be non-genotoxic
in in vitro trials. These data suggest that Neumega is not mutagenic.
Although prolonged estrus cycles have been noted at 2 to 20 times the
human dose, no effects on fertility have been observed in rats treated
with Neumega at doses up to 1000 µg/kg/day. Pregnancy Category C
Neumega has been shown to have embryocidal effects in pregnant rats
and rabbits when given in doses of 0.2 to 20 times the human dose.
There are no adequate and well-controlled studies of Neumega in
pregnant women. Neumega should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Neumega
has been tested in studies of fertility, early embryonic development,
and pre and postnatal development in rats and in studies of
organogenesis (teratogenicity) in rats and rabbits. Parental toxicity
has been observed when Neumega is given at doses of 2 to 20 times the
human dose (=100 µg/kg/day) in the rat and at 0.02 to 2.0 times the
human dose (=1 µg/kg/day) in the rabbit. Findings in pregnant rats
consisted of transient hypoactivity and dyspnea after administration
(maternal toxicity), as well as prolonged estrus cycle, increased
early embryonic deaths and decreased numbers of live fetuses. In
addition, low fetal body weights and a reduced number of ossified
sacral and caudal vertebrae (ie, retarded fetal development) occurred
in rats at 20 times the human dose. Findings in pregnant rabbits
consisted of decreased fecal/urine eliminations (the only toxicity
noted at 1 µg/kg/day in dams) as well as decreased food consumption,
body weight loss, abortion, increased embryonic and fetal deaths, and
decreased numbers of live fetuses. No teratogenic effects of Neumega
were observed in rabbits at doses up to 0.6 times the human dose (30
µg/kg/day). Adverse effects in the first generation offspring of rats
given Neumega at maternally toxic doses =2 times the human dose (=100
µg/kg/day) during both gestation and lactation included increased
newborn mortality, decreased viability index on day 4 of lactation,
and decreased body weights during lactation. In rats given 20 times
the human dose (1000 µg/kg/day) during both gestation and lactation,
maternal toxicity and growth retardation of the first generation
offspring resulted in an increased rate of fetal death of the second
generation offspring. Nursing Mothers It is not known if Neumega is
excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing
infants from Neumega, 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. Pediatric Use A safe and effective dose of
Neumega has not been established in children. In a Phase 1, single
arm, dose-escalation study, 43 pediatric patients were treated with
Neumega at doses ranging from 25 to 125 ?g/kg/day following ICE
chemotherapy. All patients required platelet transfusions and the lack
of a comparator arm made the study design inadequate to assess
efficacy. The projected effective dose (based on comparable AUC
observed for the effective dose in healthy adults) in children appears
to exceed the maximum tolerated pediatric dose of 50 ?g/kg/day (see
CLINICAL PHARMACOLOGY, Pharmacokinetics). Papilledema was
dose-limiting and occurred in 16% of children (see WARNINGS,
Papilledema). The most common adverse events seen in pediatric studies
included tachycardia (84%), conjunctival injection (58%), radiographic
and echocardiographic evidence of cardiomegaly (21%) and periosteal
changes (11%). These events occurred at a higher frequency in children
than adults. The incidence of other adverse events were generally
similar to those observed using Neumega at a dose of 50 µg/kg in the
randomized studies in adults receiving chemotherapy (see ADVERSE
REACTIONS). Studies in animals were predictive of the effect of
Neumega on developing bone in children. In growing rodents treated
with 100, 300, or 1000 µg/kg/day for a minimum of 28 days, thickening
of femoral and tibial growth plates was noted, which did not
completely resolve after a 28-day non-treatment period. In a nonhuman
primate toxicology study of Neumega, animals treated for 2 to 13 weeks
at doses of 10 to 1000 µg/kg showed partially reversible joint
capsule and tendon fibrosis and periosteal hyperostosis. An
asymptomatic, laminated periosteal reaction in the diaphyses of the
femur, tibia, and fibula has been observed in one patient during
pediatric studies involving multiple courses of Neumega treatment. The
relationship of these findings to treatment with Neumega is unclear.
No studies have been performed to assess the long- term effects of
Neumega on growth and development. Use in Patients with Renal
Impairment Neumega is eliminated primarily by the kidneys. The
pharmacokinetics of Neumega have not been studied in patients with
mild or moderate renal impairment (creatinine clearance =15 mL/min).
Fluid retention associated with Neumega treatment has not been studied
in patients with renal impairment, but fluid balance should be
carefully monitored in these patients (see WARNINGS, Fluid Retention). Adverse Reactions Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies of
a drug cannot be directly compared to rates in the clinical studies of
another drug and may not reflect the rates observed in practice. The
adverse reaction information from clinical trials does, however,
provide a basis for identifying the adverse events that appear to be
related to drug use and for approximating rates. Three hundred
twenty-four subjects, with ages ranging from 8 months to 75 years,
have been exposed to Neumega treatment in clinical studies. Subjects
have received up to six (eight in pediatric patients) sequential
courses of Neumega treatment, with each course lasting from 1 to 28
days. Apart from the sequelae of the underlying malignancy or
cytotoxic chemotherapy, most adverse events were mild or moderate in
severity and reversible after discontinuation of Neumega dosing. In
general, the incidence and type of adverse events were similar between
Neumega 50 µg/kg and placebo groups. The most frequently reported
serious adverse events were neutropenic fever, syncope, atrial
fibrillation, fever and pneumonia. The most commonly reported adverse
events were edema, dyspnea, tachycardia, conjunctival injection,
palpitations, atrial arrhythmias, and pleural effusions. The most
commonly reported adverse reactions resulting in clinical intervention
(eg, discontinuation of Neumega, adjustment in dosage, or the need for
concomitant medication to treat an adverse reaction symptom) were
atrial arrhythmias, syncope, dyspnea, congestive heart failure, and
pulmonary edema. Selected adverse events that occurred in =10% of
Neumega-treated patients are listed in Table 3. (Table 3) The
following adverse events also occurred more frequently in cancer
patients receiving Neumega than in those receiving placebo: amblyopia,
paresthesia, dehydration, skin discoloration, exfoliative dermatitis,
and eye hemorrhage; a statistically significant association of Neumega
to these events has not been established. Other than a higher
incidence of severe asthenia in Neumega treated patients (10 [14%] in
Neumega patients versus 2 [3%] in placebo patients), the incidence of
severe or life-threatening adverse events was comparable in the
Neumega and placebo treatment groups. Two patients with cancer treated
with Neumega experienced sudden death which the investigator
considered possibly or probably related to Neumega. Both deaths
occurred in patients with severe hypokalemia (<3.0 mEq/L) who had
received high doses of ifosfamide and were receiving daily doses of a
diuretic (see WARNINGS, Cardiovascular Events). Other serious events
associated with Neumega were cardiovascular events including atrial
arrhythmias, stroke and papilledema. In addition, cardiomegaly was
reported in children. The following adverse events, occurring in =10%
of patients, were observed at equal or greater frequency in
placebo-treated patients: asthenia, pain, chills, abdominal pain,
infection, anorexia, constipation, dyspepsia, ecchymosis, myalgia,
bone pain, nervousness, and alopecia. The incidence of fever,
neutropenic fever, flu-like symptoms, thrombocytosis, thrombotic
events, average number of units of red blood cells transfused per
patient, and the duration of neutropenia <500 cells/µL were
similar in the Neumega 50 µg/kg and placebo groups. Immunogenicity In
clinical studies that evaluated the immunogenicity of Neumega, two of
181 patients (1%) developed antibodies to Neumega. In one of these two
patients, neutralizing antibodies to Neumega were detected in an
unvalidated assay. The clinical relevance of the presence of these
antibodies is unknown. In the post-marketing setting, cases of
allergic reactions, including anaphylaxis have been reported (see
WARNINGS, Allergic Reactions Including Anaphylaxis). The presence of
antibodies to Neumega was not assessed in these patients. The data
reflect the percentage of patients whose test results were considered
positive for antibodies to Neumega and are highly dependent on the
sensitivity and specificity of the assay. Additionally the observed
incidence of antibody positivity in an assay may be influenced by
several factors including sample handling, concomitant medications,
and underlying disease. these reasons, comparisons of the incidence of
antibodies to Neumega with incidence of antibodies to other products
may be misleading. Abnormal Laboratory Values The most common
laboratory abnormality reported in patients in clinical trials was a
decrease hemoglobin concentration predominantly as a result of
expansion of the plasma volume (see WARNINGS, Fluid Retention). The
increase in plasma volume is also associated with a decrease in the
serum concentration of albumin and several other proteins (eg,
transferrin and gamma globulins). A parallel decrease in calcium
without clinical effects has been documented. After daily SC
injections, treatment with Neumega resulted in a two-fold increase in
plasma fibrinogen. Other acute-phase proteins also increased. These
protein levels returned to normal after dosing with Neumega was
discontinued. Von Willebrand factor (vWF) concentrations increased
with a normal multimer pattern in healthy subjects receiving Neumega.
Postmarketing Reports The following adverse reactions have been
reported during the post-approval use of Neumega: allergic reactions,
anaphylaxis (see BOXED WARNING, WARNINGS, Allergic Reactions including
Anaphylaxis and CONTRAINDICATIONS). 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. Decisions to include these
reactions in labeling are typically based on one or more of the
following factors: (1) seriousness of the reactions, (2) frequency of
reporting, or (3) strength of causal connection to Neumega. Overdosage Doses of Neumega above 125 µg/kg have not been administered to
humans. While clinical experience is limited, doses of Neumega greater
than 50 µg/kg may be associated with an increased incidence of
cardiovascular events in adult patients (see WARNINGS, Fluid Retention
and Cardiovascular Events). If an overdose of Neumega is administered,
Neumega should be discontinued, and the patient should be closely
observed for signs of toxicity (see WARNINGS and ADVERSE REACTIONS).
Reinstitution of Neumega therapy should be based upon individual
patient factors (eg, evidence of toxicity, continued need for
therapy). Dosage and Administration The recommended dose of Neumega in adults is 50 µg/kg given once
daily. Neumega should be administered subcutaneously as a single
injection in either the abdomen, thigh, or hip (or upper arm if not
self-injecting). A safe and effective dose has not been established in
children (see PRECAUTIONS, Pediatric Use). Dosing should be initiated
6 to 24 hours after the completion of chemotherapy. Platelet counts
should be monitored periodically to assess the optimal duration of
therapy. Dosing should be continued until the post-nadir platelet
count is =50,000/µL. In controlled clinical trials, doses were
administered in courses of 10 to 21 days. Dosing beyond 21 days per
treatment course is not recommended. Treatment with Neumega should be
discontinued at least 2 days before starting the next planned cycle of
chemotherapy. Preparation of Neumega 1. Neumega is a sterile, white,
preservative-free, lyophilized powder for subcutaneous injection upon
reconstitution. Neumega (5 mg vials) should be reconstituted
aseptically with 1.0 mL of Sterile Water for Injection, USP (without
preservative). The reconstituted Neumega solution is clear, colorless,
isotonic, with a pH of 7.0, and contains 5 mg/mL of Neumega. The
single- use vial should not be re-entered or reused. Any unused
portion of either reconstituted Neumega solution or Sterile Water for
Injection, USP should be discarded. 2. During reconstitution, the
Sterile Water for Injection, USP should be directed at the side of the
vial and the contents gently swirled. EXCESSIVE OR VIGOROUS AGITATION
SHOULD BE AVOIDED. 3. Parenteral drug products should be inspected
visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. If particulate
matter is present or the solution is discolored, the vial should not
be used. 4. Because neither Neumega powder for injection nor its
accompanying diluent, Sterile Water for Injection, USP contains a
preservative, Neumega should be used within 3 hours following
reconstitution. Reconstituted Neumega may be refrigerated [2°C to 8°C
(36°F to 46°F)] or at room temperature [up to 25°C (77°F)]. DO NOT
FREEZE OR SHAKE THE RECONSTITUTED SOLUTION. How Supplied Neumega is supplied as a sterile, white, preservative-free,
lyophilized powder in vials containing 5 mg Oprelvekin. Neumega is
available in boxes containing one single-dose Neumega vial and one
1-mL vial of diluent for Neumega (Sterile Water for Injection, USP) -
NDC 58394-004- 01, and boxes containing seven single-dose Neumega
vials and seven 1-mL vials of diluent for Neumega (Sterile Water for
Injection, USP) - NDC 58394-004-02. Storage Lyophilized Neumega and
diluent should be stored in a refrigerator at 2°C to 8°C (36°F to
46°F). Protect from light. DO NOT FREEZE. Reconstituted Neumega must
be used within 3 hours of reconstitution and can be stored in the vial
either at 2°C to 8°C (36°F to 46°F) or at room temperature up to
25°C (77°F). NDC 58394-004-01 58394-004-02 Contact Telephone: 1-800-934-5556 References (1) Du, X. and Williams, D., Interleukin 11: review of molecular,
cell biology and clinical use. Blood. 1997;89(11):3897-3908. Date April 2024 |
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