Approved Drug Label (PDF)
5
Warnings and Precautions
5.10 Risk of Infectious Diseases Due to Albumin (Human) Content
Epogen
(Subsection title has been
revised)
Procrit
(Subsection title has been
revised)
5.8 Severe Cutaneous Reactions
Epogen
(Newly added subsection)
Blistering and skin exfoliation
reactions including Erythema multiforme and Stevens-Johnson Syndrome
(SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated
with ESAs (including Epogen) in the postmarketing
setting. Discontinue Epogen therapy immediately if a severe cutaneous reaction,
such as SJS/TEN, is suspected.
Procrit
(Newly added subsection)
Blistering and skin exfoliation
reactions including Erythema multiforme and Stevens-Johnson Syndrome
(SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated
with ESAs (including PROCRIT) in the postmarketing setting. Discontinue PROCRIT
therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is
suspected.
6
Adverse Reactions
Epogen
(Additions and/or revisions are
underlined)
The following serious adverse
reactions are discussed in greater detail in other sections of the label:
Procrit
(Additions and/or revisions are
underlined)
The following serious adverse
reactions are discussed in greater detail in other sections of the label:
6.2 Postmarketing Experience
Epogen
(Additions and/or revisions are
underlined)
The following adverse reactions have
been identified during post-approval use of Epogen.
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.
Procrit
(Additions and/or revisions are
underlined)
The following adverse reactions
have been identified during post-approval use of PROCRIT.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Epogen
(Additions and/or revisions are
underlined)
What are the possible side effects of Epogen?
Epogen may cause serious side
effects, including:
Severe skin reactions. Signs
and symptoms of severe skin reactions with Epogen may include: skin rash with
itching,
blisters, skin sores, peeling, or areas of skin coming off. If you have
any signs or symptoms of a severe skin reaction, stop using Epogen and call
your healthcare provider or get medical help right away.
Common side effects of Epogen
include:
What are the ingredients in
Epogen?
Active ingredient: epoetin alfa
Inactive ingredients:
- Multiple-dose
vials contain benzyl alcohol.
- All
vials contain albumin (human), citric acid, sodium chloride, sodium citrate,
and Water for Injection.
Procrit
(Additions and/or revisions are underlined)
What are the possible side
effects of PROCRIT?
PROCRIT may cause serious side
effects, including:
Severe skin reactions. Signs
and symptoms of severe skin reactions with PROCRIT may include: skin rash with
itching, blisters, skin sores, peeling, or areas of skin coming off. If you
have any signs or symptoms of a severe skin reaction, stop using PROCRIT and
call your healthcare provider or get medical help right away.
Common side effects of PROCRIT
include:
- dizziness
- blood vessel blockage
- respiratory infection
- high blood sugar
- low white blood cells
- weight decrease
- low potassium levels in the blood
- trouble sleeping
- depression
- chills
- difficulty swallowing
- muscle spasm
What are the ingredients in PROCRIT?
Active ingredient: epoetin alfa
Inactive ingredients:
Multiple-dose vials contain benzyl alcohol.
All vials contain albumin (human), citric acid,
sodium chloride, sodium citrate and Water for Injection.
Approved Drug Label (PDF)
4
Contraindications
Epogen
(Additions and/or revisions are underlined)
Epogen from multiple-dose vials contains benzyl alcohol and is
contraindicated in:
Neonates, infants, pregnant women, and lactating women.
Procrit
(Additions and/or revisions are
underlined)
PROCRIT from multiple-dose vials
contains benzyl alcohol and is contraindicated in:
5
Warnings and Precautions
5.9 Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative
Epogen
(Newly added subsection)
Epogen from multiple-dose vials
contains benzyl alcohol and is contraindicated for use in neonates, infants,
pregnant women, and lactating women. In addition, do not mix Epogen with
bacteriostatic saline (which also contains benzyl alcohol) when administering
Epogen to these patient populations.
Serious and fatal reactions
including “gasping syndrome” can occur in neonates and infants treated with
benzyl alcohol-preserved drugs, including Epogen multiple-dose vials. The
“gasping syndrome” is characterized by central nervous system depression,
metabolic acidosis, and gasping respirations. There is a potential for similar
risks to fetuses and infants exposed to benzyl alcohol in utero or in
breast-fed milk, respectively. Epogen multiple-dose vials contain 11 mg of
benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious
adverse reactions may occur is not known.
Procrit
(Newly added subsection)
PROCRIT from multiple-dose vials
contains benzyl alcohol and is contraindicated for use in neonates, infants,
pregnant women, and lactating women. In addition, do not mix PROCRIT with
bacteriostatic saline (which also contains benzyl alcohol) when administering
PROCRIT to these patient populations.
Serious and fatal reactions
including “gasping syndrome” can occur in neonates and infants treated with
benzyl alcohol-preserved drugs, including PROCRIT multiple-dose vials. The
“gasping syndrome” is characterized by central nervous system depression,
metabolic acidosis, and gasping respirations. There is a potential for similar
risks to fetuses and infants exposed to benzyl alcohol in utero or in
breast-fed milk, respectively. PROCRIT multiple-dose vials contain 11 mg of
benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious
adverse reactions may occur is not known.
8
Use in Specific Populations
8.1 Pregnancy
Epogen
(Pregnancy and Lactation
Labeling Rule (PLLR) Conversion; additions
and/or revisions are underlined)
Risk Summary
Epogen from multiple-dose vials
contains benzyl alcohol and is contraindicated in pregnant women.
When therapy with Epogen is needed during pregnancy, use a benzyl alcohol-free
formulation (i.e., single-dose vial). Do not mix Epogen with bacteriostatic
saline when administering to pregnant women because it contains benzyl alcohol.
The limited available
data on Epogen use in pregnant women are insufficient to determine a
drug-associated risk of adverse developmental outcomes. In animal reproductive and developmental
toxicity studies, adverse fetal effects including embryo-fetal death,
skeletal anomalies, and growth defects occurred when pregnant rats received
epoetin alfa at doses approximating the clinical recommended starting doses. Consider
the benefits and risks of Epogen single-dose vials for the mother
and possible risks to the fetus when prescribing Epogen to a pregnant
woman.
The estimated background risk
of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risks of
major birth defects and miscarriage in clinically recognized pregnancies is
2-4% and 15- 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
The multiple-dose vials of
Epogen contain benzyl alcohol. The preservative benzyl alcohol has been
associated with serious adverse reactions and death when administered
intravenously to neonates and infants. There
is a potential for similar risks to fetuses exposed to benzyl alcohol in utero.
Data
Human Data
…Due to the limited number of
exposed pregnancies and multiple confounding factors (such as underlying
maternal conditions, other maternal medications, and gestational timing of
exposure), these published case reports and studies do not reliably estimate
the frequency, presence or absence of adverse outcomes.
Animal Data
When rats received Epogen at doses
greater than or equal to 100 Units/kg/day during mating and through
early pregnancy (dosing stopped prior to organogenesis), there were slight
increases in the incidences of pre-and post- implantation loss, and a decrease
in live fetuses in the presence of maternal toxicity (red limbs/pinna, focal
splenic capsular toxicity, increased organ weights)… When pregnant rats and rabbits received
intravenous doses of up to 500 mg/kg/day of Epogen only during organogenesis (gestational
days 7 to 17 in rats and gestational days 6 to 18 in rabbits), no
teratogenic effects were observed in the offspring. The offspring (F1
generation) of the treated rats were observed postnatally; rats from the F1
generation reached maturity and were mated; no Epogen-related effects were
apparent for their offspring (F2 generation fetuses).
When pregnant rats received Epogen
at doses of 500 Units/kg/day late in pregnancy (after the period of
organogenesis from day 17 of gestation through day 21 of lactation), pups
exhibited decreased number of caudal vertebrae, decreased body weight gain, and
delayed appearance of abdominal hair, eyelid opening, and ossification in the
presence of maternal toxicity (red limbs/pinna, increased organ weights). This
animal dose level of 500 U/kg/day is approximately five times the clinical
recommended starting dose depending on the patient’s treatment indication.
Procrit
(Pregnancy and Lactation
Labeling Rule (PLLR) Conversion; additions
and/or revisions are underlined)
Risk Summary
PROCRIT from multiple-dose vials contains
benzyl alcohol and is contraindicated in pregnant women. When therapy
with PROCRIT is needed during pregnancy, use a benzyl alcohol-free formulation (i.e.,
single-dose vial). Do not mix PROCRIT with bacteriostatic saline when
administering to pregnant women because it contains benzyl alcohol.
The limited available data
on PROCRIT use in pregnant women are insufficient to determine a
drug-associated risk of adverse developmental outcomes. In animal
reproductive and developmental toxicity studies, adverse fetal effects including
embryo-fetal death, skeletal anomalies, and growth defects occurred when
pregnant rats received epoetin alfa at doses approximating the clinical
recommended starting doses. Consider the benefits and risks of PROCRIT
single-dose vials for the mother and possible risks to the fetus when
prescribing PROCRIT to a pregnant woman.
The estimated background risk
of major birth defects and miscarriage for the indicated population is unknown.
. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risks of
major birth defects and miscarriage in clinically recognized pregnancies is
2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
The multiple-dose vials of
PROCRIT contain benzyl alcohol. The preservative benzyl alcohol has been
associated with serious adverse reactions and death when administered
intravenously to neonates and infants. There
is a potential for similar risks to fetuses exposed to benzyl alcohol in utero.
Data
Human Data
…Due to the limited number of
exposed pregnancies and multiple confounding factors (such as underlying
maternal conditions, other maternal medications, and gestational timing of
exposure), these published case reports and studies do not reliably estimate
the frequency, presence or absence of adverse outcomes.
Animal Data
When rats received PROCRIT at
doses greater than or equal to 100 Units/kg/day during mating and
through early pregnancy (dosing stopped prior to organogenesis), there were
slight increases in the incidences of pre- and post- implantation loss, and a
decrease in live fetuses in the presence of maternal toxicity (red
limbs/pinna, focal splenic capsular toxicity, increased organ weights)…When
pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of
PROCRIT only during organogenesis (gestational days 7 to 17 in rats and
gestational days 6 to 18 in rabbits), no teratogenic effects were observed
in the offspring. The offspring (F1 generation) of the treated rats were
observed postnatally; rats from the F1 generation reached maturity and were
mated; no PROCRIT-related effects were apparent for their offspring (F2
generation fetuses).
When pregnant rats received
PROCRIT at doses of 500 Units/kg/day late in pregnancy (after the period of
organogenesis from day 17 of gestation through day 21 of lactation), pups
exhibited decreased number of caudal vertebrae, decreased body weight gain, and
delayed appearance of abdominal hair, eyelid opening, and ossification in the
presence of maternal toxicity (red limbs/pinna, increased organ weights). This
animal dose level of 500 U/kg/day is approximately five times the clinical
recommended starting dose depending on the patient’s treatment indication.
8.2 Lactation
Epogen
(Pregnancy and Lactation
Labeling Rule (PLLR) Conversion; additions
and/or revisions are underlined)
Risk Summary
Epogen from multiple-dose
vials contains benzyl alcohol and is contraindicated in lactating
women. Advise a lactating woman not to breastfeed for at least 2 weeks after
the last dose.The preservative benzyl alcohol has been associated with serious
adverse reactions and death when administered intravenously to neonates and
infants. There is a potential for similar
risks to infants exposed to benzyl alcohol through human milk.
Do not mix Epogen with
bacteriostatic saline containing benzyl alcohol, if administering Epogen
to a lactating woman.
There is no information
regarding the presence of Epogen in human milk, the effects on the
breastfed infant, or the effects on milk production. However, endogenous
erythropoietin is present in human milk. Because many drugs are present
in human milk, caution should be exercised when Epogen from single-dose vials
is administered to a lactating woman.
Procrit
(Pregnancy and Lactation
Labeling Rule (PLLR) Conversion; additions
and/or revisions are underlined)
Risk Summary
PROCRIT from multiple-dose
vials contains benzyl alcohol and is contraindicated in lactating
women. Advise a lactating woman not to breastfeed for at least 2 weeks after
the last dose. The preservative benzyl alcohol has been associated with serious
adverse reactions and death when administered intravenously to neonates and
infants. There is a potential for
similar risks to infants exposed to benzyl alcohol through human milk.
Do not mix PROCRIT with
bacteriostatic saline containing benzyl alcohol, if administering PROCRIT to
a lactating woman.
There is no information
regarding the presence of PROCRIT in human milk, the effects on the
breastfed infant, or the effects on milk
production. However, endogenous erythropoietin is present in human milk.
Because many drugs are present in human milk, caution should be
exercised when PROCRIT from single-dose vials is administered to a lactating
woman.
8.4 Pediatric Use
Epogen
(Additions and/or revisions are
underlined)
The multiple-dose vials are
formulated with benzyl alcohol and are contraindicated for use in neonates
and infants. When therapy with Epogen is needed in neonates and infants, use
the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix
the single-dose vials with bacteriostatic saline when administering
Epogen to neonates or infants because it contains benzyl alcohol.
Serious adverse reactions
including fatal reactions and the “gasping syndrome” occurred in premature
neonates and infants in the neonatal intensive care unit who received drugs
containing benzyl alcohol as a preservative. In
these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high
levels of benzyl alcohol and its metabolites in the blood and urine (blood
levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse
reactions included gradual neurological deterioration, seizures,
intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and
renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm,
low birth weight infants may be more likely to develop these reactions because
they may be less able to metabolize benzyl alcohol. The minimum amount of
benzyl alcohol at which serious adverse reactions may occur is not known.
Pediatric Patients with CKD
Use of Epogen in pediatric
patients with CKD not requiring dialysis is supported by efficacy in pediatric
patients requiring dialysis. The mechanism of action of Epogen is the same for
these two populations. Published literature also has reported the use of Epogen
in pediatric patients with CKD not requiring dialysis. Dose-dependent increases
in hemoglobin and hematocrit were observed with reductions in transfusion
requirements.
The safety data from the
pediatric studies and postmarketing reports are similar to those
obtained from the studies of Epogen in adult patients with CKD. Postmarketing reports do not
indicate a difference in safety profiles in pediatric patients with CKD
requiring dialysis and not requiring dialysis.
Procrit
(Additions and/or revisions are
underlined)
The multiple-dose vials are
formulated with benzyl alcohol and
are contraindicated for use in neonates and infants. When therapy with PROCRIT is needed in neonates and infants,
use the single-dose vial, which is a benzyl alcohol-free formulation. Do
not mix the single-dose vials with bacteriostatic saline when administering
PROCRIT to neonates or infants because it contains benzyl alcohol.
Serious adverse reactions
including fatal reactions and the “gasping syndrome” occurred in
premature neonates and infants in the neonatal intensive care unit who received
drugs containing benzyl alcohol as a preservative. In these cases, benzyl
alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl
alcohol and its metabolites in the blood and urine (blood levels of
benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse
reactions included gradual neurological deterioration, seizures,
intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and
renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm,
low birth weight infants may be more likely to develop these reactions because
they may be less able to metabolize benzyl alcohol. The minimum amount of
benzyl alcohol at which serious adverse reactions may occur is not known.
Pediatric Patients with CKD
Use of PROCRIT in pediatric
patients with CKD not requiring dialysis is supported by efficacy in pediatric
patients requiring dialysis. The mechanism of action of PROCRIT is the same for
these two populations. Published literature also has reported the use of
PROCRIT in pediatric patients with CKD not requiring dialysis. Dose-dependent
increases in hemoglobin and hematocrit were observed with reductions in
transfusion requirements.
The safety data from the
pediatric studies and postmarketing reports are similar to those
obtained from the studies of PROCRIT in adult patients with CKD.
Postmarketing reports do not
indicate a difference in safety profiles in pediatric patients with CKD
requiring dialysis and not requiring dialysis.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
Epogen
(Additions and/or revisions are
underlined)
Advise the patient to read the
FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients:
Procrit
(Additions and/or revisions are
underlined)
Advise the patient to read the
FDA-approved patient labeling (Medication Guide and Instructions for Use).
Inform patients:
MEDICATION GUIDE
Procrit
(Additions and/or revisions are
underlined)
What is PROCRIT?
It is not known if PROCRIT is
safe and effective in treating anemia in children less than 1 month old who
have chronic kidney disease and in children less than 5 years old who have
anemia caused by chemotherapy.
Before taking PROCRIT, tell your healthcare provider about all of your
medical conditions, including if you:
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer
(Additions and/or revisions
are underlined)
ESAs resulted in decreased locoregional
control/progression-free survival (PFS) and/or overall survival (OS)
(see Table 2). Adverse effects on PFS and/or OS were observed in studies
of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid
malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced
head![]()
and neck cancer receiving radiation
therapy (Studies 6 and 7); and in patients with non-small cell lung cancer
or various malignancies who were not receiving chemotherapy or radiotherapy (Studies
8 and 9).
Table 2. Randomized, Controlled
Studies With Decreased Survival and/or Decreased Locoregional Control
This study did not include
a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest
hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.
Decreased Progression-free
Survival and Overall Survival
Study 1 was a randomized, open-label, multicenter study
in 2,098 anemic women with metastatic breast cancer, who received first line or
second line chemotherapy. This was a non- inferiority study designed to rule out
a 15% risk increase in tumor progression or death of epoetin alfa plus standard
of care (SOC) as compared with SOC alone. The median progression free survival
(PFS) per investigator assessment of disease progression was 7.4 months in each
arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. At
the time of clinical data cutoff, 1337 deaths were reported. Median overall survival
in the epoetin alfa plus SOC group was 17.2 months compared with 17.4 months in
the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). There were more deaths from disease
progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular
events in the epoetin alfa plus SOC arm (3% vs. 1%).
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions
are underlined)
The following adverse reactions have been identified during post-approval
use of Epogen. 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
are underlined)
Advise the patient to read
the FDA-approved patient labeling (Medication
Guide). Prior to treatment, inform patients of the risks and benefits of Epogen.
MEDICATION GUIDE Epogen® (Ee-po-jen) (epoetin alfa)
(Additions and/or revisions
are underlined)
Epogen should not be used for
treatment of anemia:
• If your anemia caused by chemotherapy treatment can be managed
by RBC transfusion.
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