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n
h
010270-05
Rx only
Rx only
Rx only
Rx only
nasal spray
500
mcg/spray
010270-05
0.125 mL
(Cyanocobalamin, USP)
nasal spray
500 mcg/spray
0.125 mL
nasal spray
500
mcg/spray
010270-05
0.125 mL
nasal spray
500 mcg/spray
010270-05
0.125 mL
(Cyanocobalamin, USP)
Mean Serum Vitamin B 12 Trough Level ± SEM (pg/mL)
Rx only
Mean Serum Vitamin B 12 Trough Level ± SEM (pg/mL)
(Cyanocobalamin, USP)
n
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(Cyanocobalamin, USP)
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500 mcg/spray 0.125 mL
Mean Serum Vitamin B 12 Trough Level ± SEM (pg/mL)
s
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n
(Cy
Mean S
010270
500 mcg/spray
0.125 mL
l
r
e
maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme
megaloblastic anemia, indiscriminate use of vitamin B12 could mask the true diagnosis.
that seen one month after 100 mcg intramuscular dose (Figure).
supplementation.
systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic to normal
Distribution
and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and
testpotassium
(Schilling Test).
Nascobal
Nasal Spraywith
is not
suitable
vitamin Therefore,
B12 absorption
serum
levels and the platelet count
erythropoiesis
vitamin
B12fortherapy.
In the blood, B 12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is
neurologic damage that begins with an inability to produce myelin and is followed by gradual
should be monitored carefully during therapy.
CONTRAINDICATIONS
distributed and stored primarily in the liver and bone marrow.
degeneration of the axon and nerve head.
B
or
any
component
of
the
medication
is
a
contraindication.
Sensitivity
to
cobalt
and/or
vitamin
12
Elimination
Vitamin B12 deficiency may suppress the signs of polycythemia vera. Treatment
with vitamin B12
Cyanocobalamin is the most stable and widely used form of vitamin B12, and has hematopoietic
may unmask this condition.
activity apparently identical to that of the antianemia factor in purified liver extract. The information
WARNINGS
About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; in normal subjects with sufficient
PatientsIf with
early
Leber’s
disease
(hereditary
optic
nerve
atrophy)
who
were
treated
with
below, describing the clinical pharmacology of cyanocobalamin, has been derived from studies with
intrinsic factor, all but about 1 mcg is re-absorbed. When B12 is administered in doses which
®
a patient is not properly maintained with Nascobal Nasal Spray, intramuscular vitamin
vitamin B12 is
Figure.
Vitaminproteins
B 12 Serum
Levels
After Intramuscular
severe
swift optic
atrophy.
B12 suffered
injectable vitamin B12.
saturate the binding capacity
of plasma
and Trough
the liver,
the unbound
B12 is rapidly eliminated
necessary
forand
adequate
treatment
of the patient. No single regimen fits all cases, and the status of
Solution
(IM)
of
100
mcg
and
Nasal
Gel
(IN)
Administration
of
in
the
urine.
Retention
of
B
in
the
body
is
dose-dependent.
About
80-90%
of
an
intramuscular
Hypokalemia
andobserved
sudden death
may is
occur
in severe
anemia
which is treated
Vitamin B12 is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of
12
the patient
in follow-up
the final
criterionmegaloblastic
for adequacy of
therapy.
500 mcg
Cyanocobalamin
After Weekly
dose up to 50 mcg is retained
in the
body; this percentage
dropsDoses.
to 55% for a 100 mcg dose, and
intensely
with
vitamin B12of
. Folic
acid is
not aSpray
substitute
for vitamin
B12 although
it may
improve
injection. It is bound to plasma proteins and stored in the liver. Vitamin B12 is excreted in the bile
effectiveness
Nascobal
Nasal
in patients
with nasal
congestion,
allergic
rhinitis and
The
decreases to 15% when a 1000 mcg dose is given.
B12-deficient
megaloblastic
anemia.
Exclusive
use ofTherefore,
folic acid treatment
in treatingwith
vitamin
B12- Nasal
vitaminupper
and undergoes some enterohepatic recycling. Absorbed vitamin B12 is transported via specific B12
respiratory
infections has
not been
determined.
Nascobal
deficient
megaloblastic
anemia
could
result
in
progressive
and
irreversible
neurologic
damage.
binding proteins, transcobalamin I and II, to the various tissues. The liver is the main organ for
Spray should be deferred until symptoms have subsided.
vitamin B12occurs
storage.
Anaphylactic shock and death have been reported after parenteral vitamin B12 administration. No
Cyanocobalamin
as dark red crystals or orthorhombic needles or crystalline red powder. It is
2. LABORATORY
TESTS
Pernicious
anemia
associated
with antrials
increased
incidenceNasal
of carcinoma
the stomach,
such reactions
have
beenis
reported
in clinical
with Nascobal
Spray orofNascobal
Nasalbut this
reverses
megaloblastic
Parenteral in
(intramuscular)
of vitamin
B12 completely
very
the anhydrousadministration
form, and sparingly
to moderately
soluble
in waterthe
(1:80).
Its
Rx
onlyhygroscopic
INDICATIONS AND USAGE
and
levels should
be obtained
Hematocrit,
vitamin pathology
B12, folateand
is
believed to reticulocyte
be related tocount,
the underlying
notiron
to treatment
with vitamin
B12. prior to
Gel.
anemia
and
GI
symptoms
of
vitamin
B
deficiency;
the
degree
of
improvement
in
neurologic
pharmacologic activity is destroyed by heavy metals
(iron) and strong oxidizing or reducing agents
12
Nascobal Nasal Spray is indicated for the maintenance of normal hematologic status in pernicious
treatment.
If
folate
levels
are
low,
folic
acid
should
also
be
administered.
All
hematologic
depends
on the duration
severity
of the
lesions,
although
progression
of the lesions
as infection,
Blunted5.orPREGNANCY
impeded therapeutic response to vitamin B12 may be due to such conditions
(vitaminsymptoms
C), but not
by autoclaving
for shortand
periods
of time
(15-20
minutes)
at 121°C.
The vitamin
anemia patients who are in remission following intramuscular vitamin B12 therapy and who have no
® Nasal Spray.
parameters
should
beC:normal
beginning
treatment
Nascobal
Pregnancy
Category
Animalwhen
reproduction
studies
havewith
not
been
with vitamin
B12. It is
is immediately
arrested.
uremia,
drugs having
bone
marrow
suppressant
properties
such
asconducted
chloramphenicol,
and
are very
unstable in light.
B12 coenzymes
nervous system involvement.
Vitamin
B
blood
levels
and
peripheral
blood
counts
must
be
monitored
initially
atpregnant
one month
after
also
not
known
whether
vitamin
B
can
cause
fetal
harm
when
administered
to
a
woman
concurrent
iron
or
folic
acid
deficiency.
12
on the
presence
sufficient
intrinsicasfactor
Gastrointestinal
of vitamin
B12 depends USP
® Nasal Sprayabsorption
is a solution
of Cyanocobalamin,
(vitamin
B12)offor
administration
a and
Nascobal
DESCRIPTION
PHARMACOKINETICS
intestinal
parasites
or bacteria.
The
fish
tapeworm
IV.or
Competition
for vitamin
B 12 by12 ®
Nascobal Nasal Spray is also indicated as a supplement for other vitamin B12 deficiencies,
the
startaffect
of treatment
with Nascobal
Nasal Spray,
then
at intervals
of 3have
to
6 months.
can
reproduction
capacity.
Adequate
andand
well-controlled
studies
not
been done in
calcium
ions.
Intrinsic
factor
deficiency
causes
pernicious
anemia,
which
may
be
associated
with
spray
to
the
nasal
mucosa.
Each
unit
dose
device
of
Nascobal
Nasal
Spray
contains
0.125
mL
of
a
infested
patients
often
(Diphyllobothrium
latum) absorbs
huge
quantities
of vitamin
B12 and
Cyanocobalamin is a synthetic form of vitamin B12 with equivalent vitamin B12 activity. The chemical
Absorption
PRECAUTIONS
including:
pregnant
women.
However,
vitamin
B
is
an
essential
vitamin
and
requirements
are
increased
Ahave
decline
in the serum
levels
of B12The
after
oneloop
month
of treatment
B12 nasal
sprayofmay
12blind
of the spinal
cord.
Prompt
parenteral
administration
of vitamin
500 mcg/0.1
mLcombined
solution degeneration
of cyanocobalamin
withThe
sodium
citrate,
citric
acid,
glycerin
and
associated
gastric
atrophy.
syndrome
may with
produce
deficiency
vita-indicate
name
issubacute
5,6-dimethyl-benzimidazolyl
cyanocobamide.
cobalt
content
is 4.35%.
The
molecular
1. GENERAL
during
Amounts
ofadjusted
vitamin Bupward.
that are
recommended
the one
Food
and Nutrition
Board,
A three way crossover study in 25 fasting healthy subjects was conducted to compare the
that
dose
may of
need
to be
Patients
should
beby
seen
month
each
progression
ofwater.
neurologic
damage.
B12
benzalkonium
in
purified
The spray
solution
has a pHweight
between
and 5.5.
or folate.
minthe
Bpregnancy.
recommended
before
Nascobal
Nasal after
Spray
is dose
An intradermal
dose
parenteral
vitamin
B1212 isResearch
H88CoN
corresponds
to a molecular
of 4.5
1355.38
andEach
the
formula
is prevents
C 63chloride
12test
14O
14P, which
Academy
of
Science
-of
Council
for
should
be
bioavailabilityI. ofDietary
the B12deficiency
nasal spray
the B12
gel and
evaluate
the relative
bioavailability
adjustment;
continued
low
levels
serum
Bmay
indicate
that
thepregnant
patient
is women
not
a that
candidate
for
12 may
of to
vitamin
B12nasal
occurring
in to
strict
vegetarians
(Isolated
vitamin B12 defispray delivers
an average
of 500 mcg
of cyanocobalamin.
The
average
diet supplies
about
4 to 15 mcg/day of vitamin B12 in a protein-bound form that is
.
This
occur
if
antimetabolites
for
the
vitamin
are
V.National
Inadequate
utilization
of vitamin
BNational
deficiency
is
administered
to patients
suspected
of cyanocobalamin
sensitivity.
Vitamin
B
following
structural
formula:
12
12
consumed
during
pregnancy.
of
the
nasal
formulations
as
compared
to
the
intramuscular
injection.
The
peak
concentrations
this
mode
of
administration.
ciency is very rare).
available
for absorption after normal digestion. Vitamin B12 is not present in foods of plant origin,
employed
thelonger
treatment
neoplasia.
allowed to
progressinfor
thanofthree
months may produce permanent degenerative lesions of
CLINICAL
PHARMACOLOGY
after administration
of intranasal
spray were
reachedfrom
in 1.25
+/- 1.9
hours. The
average
peak
6.
NURSING
MOTHERS
structural
or functional
damage
to the
stomach,
II. Malabsorption
of vitamin
B12 resulting
Patients
with
pernicious
anemia
have
about
3
times
the
incidence
of
carcinoma
of
the
stomach
as
but
is
abundant
in
foods
of
animal
origin.
In
people
with
normal
absorption,
deficiencies
have
been
spinal
cord. Doses
of folic
greaterdisease
than 0.1bymg
per day
may result
in hematologic
remission
GENERAL PHARMACOLOGY AND MECHANISM OF ACTION
Itthe
may
be
to treat
theinacid
underlying
surgical
of anatomic
lesions
leading
concentration ofwhere
B12 obtained
correction
of factor
intranasal
sprayvitamin
Vitamin
Bvitamin
the so
milk
of nursing
mothers
in concentrations
which
approximate
the
intrinsicafter
factorbaseline
is secreted,
or to following
the ileum,administration
where intrinsic
facilitates
in possible
the
general
population,
appropriate
tests
for correction
this
condition
should
be carried
out when
who consume
no productsand
of nucleoprotein
animal origin and
(including
only in strict
vegetarians
Neurologic
manifestations
will not be
prevented
with folic
in small
patients
with
B12 deficiency.
12 appears
to growth,
cell reproduction,
hematopoiesis,
myelinno milk
Vitaminreported
B12 is essential
to
bowel
bacterial
overgrowth,
expulsion
of
fish
tapeworm,
discontinuation
of
drugs
leading
to
was
757.96
+/532.17
pg/mL.
The
bioavailability
of
the
nasal
spray
relative
to
the
intramuscular
mother’s
vitamin
B
blood
level.
Amounts
of
vitamin
B
that
are
recommended
by
the
Food
and
B12 absorption. These conditions include HIV infection, AIDS, Crohn’s disease, tropical
indicated.
products
eggs).
acid, and
if not treated (see
with
12 vitamin B12, irreversible damage will
12result.
synthesis.
Cells or
characterized
by rapid division (e.g., epithelial cells, bone marrow, myeloid cells)
vitamin
malabsorption
"Drug/Laboratory
Interactions"),
use of a gluten
free
diet
in non-women
injection was found
to be
6.1%.
The bioavailability
of the steatorrhea,
B12 nasal spray
was found toenteropathy).
be 10% less Folate
Board,
National
Academy
ofTest
Science-National
Research
Council
lactating
sprue,
and
nontropical
sprue (idiopathic
gluten-induced
3.
DRUG/LABORATORY
TEST
bound requirement
to intrinsic factor
duringBtransit
through the stomach; separation occurs in the
Doses Nutrition
of
vitamin
B
10
mcgINTERACTIONS
daily
may
produce
hematologic
response
infor
patients
with
12 is
12 exceeding of
appear Vitamin
to have B
the
greatest
for vitamin
sprue.
Such measures
remove
the need
tropical
sprue,
or consumed
administration
antibiotics
in
tropical
than the B12 nasal
gel. Thein90%
confidence
for thesevere
loge - than
transformed
12. Vitamin B12 can be converted to coenzyme
(0-t) and Cmax
should
be
during
lactation.
deficiency.
deficiency
these
patients isintervals
usually more
vitamin BAUC
12
Persons
taking
most
antibiotics,
methotrexate
or
pyrimethamine
invalidate
folic
acid
and
vitamin B12
terminal
ileum
in
the
presence
of
calcium,
and
vitamin
B
enters
the
mucosal
cell
for
absorption.
It
folate
deficiency.
Indiscriminate
administration
may
mask
the
true
diagnosis.
12
for long-term administration of vitamin B12.
B 12 in tissues, and as such is essential for conversion of methylmalonate
to succinate and
was 71.71%III.
- 114.19%
and 71.6%
- 118.66%
respectively.
Inadequate
secretion
of intrinsic
factor, resulting from lesions that destroy the gastric
7.
PEDIATRIC
USE
diagnostic
blood
assays.
is then
transported
byhomocysteine,
the transcobalamin
binding
proteins.
A smallfolate.
amount
(approximately
The
validity
of
diagnostic
vitamin
B
or
folic
acid
blood
assays
could
be
compromised
by
synthesis
of methionine
from
a reaction
which
also requires
In the
absence of 1% of
12
in associata
In pernicious anemia
patients,
once
weekly intranasal
dosing
with 500
B12 gelofresulted
mucosa
(ingestion
of corrosives,
extensive
neoplasia),
andmcg
a number
conditions
Requirements
of
vitamin
B
in
excess
of
normal
(due
to
pregnancy,
thyrotoxicosis,
hemolytic
aneIntake
in
pediatric
patients
should
be
in
the
amount
recommended
by
the
Food
and
Nutrition
Board,
12
the
total
amount
ingested)
is
absorbed
by
simple
diffusion,
but
this
mechanism
is
adequate
only
medications,
and this
should be considered
before
relying
on such
tests
therapy.
Colchicine,
para-aminosalicylic
acid and
heavy
alcohol
intake
for for
longer
than 2 weeks may produce
coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl
consistent increase
in pre-dose
serum
B12oflevels
during
one(such
month
treatment
(p < 0.003)
above AIDS,
ed with
a variable
degree
gastric
atrophy
asof
multiple
sclerosis,
HIV infection,
mia, hemorrhage,
malignancy,
hepatic
and renal
disease)Council.
can usually be met with intranasal or oral
National
Academy
of
Science-National
Research
with very large
Oral folate
absorption
is considered
undependable
to rely
in patients
malabsorption
of
vitamin
B
.
tetrahydrofolate,
and adoses.
functional
deficiency
occurs. too
Vitamin
B 12 also may
be on
involved
in with
Vitamin B 12 is not a substitute 12for folic acid and since it might improve folic acid deficient
that
seen
one
month
after
100
mcg
intramuscular
dose
(Figure).
certain
endocrine
disorders,
iron
deficiency,
and
subtotal
gastrectomy).
Total
gastrectomy
supplementation.
pernicious
anemia
or other
conditions
resulting
in malabsorption
of vitamin
B12.
maintaining
sulfhydryl
(SH)
groups
in the reduced
form
required by many
SH-activated
enzyme
true diagnosis.
megaloblastic
anemia,
indiscriminate
use of vitamin
B12 could mask
ADVERSE
REACTIONS
4. CARCINOGENESIS,
MUTAGENESIS,
IMPAIRMENT
OF the
FERTILITY
Distribution always produces vitamin B12 deficiency. Structural lesions leading to vitamin B12 deficienColchicine,
para-aminosalicylic
acid,
heavy alcohol
for longer than
2 weeks may
test
(Schilling
Test).
Nascobal
Nasal
Spray of
is not
for
vitamindescribed
Bcarcinogenic
systems.
Through these
reactions, vitamin
B12 and
is associated
with fatintake
and carbohydrate
metabolism
12 absorption
The
incidence
adverse
experiences
in the
Table
below
are been
based
onnormal
data
from
a
Long-term
in suitable
animals
to evaluate
potential
have
not
done.
There
is no
regional
ileitis, ileal resections,
malignancies,
etc.carrier protein, and is
is bound
to transcobalamin
II, a specific
B-globulin
In the blood, Bcy
Hypokalemia
and studies
thrombocytosis
could
occur upon
conversion
of
severe
megaloblastic
to
12 include
.
produce
malabsorption
B
and protein
synthesis.
Vitaminof Bvitamin
deficiency
results
in
megaloblastic
anemia,
GI
lesions,
and
12
short-term
clinical
trialB in therapy.
vitamin
patients
in hematologic
Nascobal
evidence
from
long-term
use in Bpatients
withserum
pernicious
anemia
thatremission
vitamin
Breceiving
12
12 deficient
12 is carcinogenic.
CONTRAINDICATIONS
distributed and stored primarily in the liver and bone marrow.
Therefore,
potassium
levels
and
the platelet
count
erythropoiesis
with
vitamin
12
neurologic damage that begins with an inability to produce myelin and is followed by gradual
(Cyanocobalamin,
USP)
Gel
for
Intranasal
Administration
(N=24)
and
intramuscular
vitamin
B
Pernicious
anemia
is
associated
with
an
increased
incidence
of
carcinoma
of
the
stomach,
but
this
12
to cobalt and/or
vitamin
B12therapy.
or any component of the medication is a contraindication.
Sensitivity
should be monitored
carefully
during
Elimination
degeneration of the axon and nerve head.
(N=25).
In the
pharmacokinetic
study comparing
Nascobal
Spray with
and vitamin
Nascobal
Gel,
is believed
to be
related to the underlying
pathology
and not Nasal
to treatment
B Nasal
.
WARNINGS
About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; in normal subjects with sufficient
deficiency
may suppress
of polycythemia vera. Treatment with vitamin12B12
Vitaminthe
B12
Cyanocobalamin is the most stable and widely used form of vitamin B12, and has hematopoietic
incidence
of adverse
events the
wassigns
similar.
5.
PREGNANCY
Patients
with
early
Leber’s
disease
(hereditary
optic nerve atrophy) who were treated with vitamin
intrinsic
factor,
all
but
about
1
mcg
is
re-absorbed.
When
B
is
administered
in
doses
which
may unmask
this
condition.
12
activity apparently identical to that of the antianemia factor in purified liver extract. The information
Table
Adverse
Experiences
by
Body
System,
Number
of
Patients
and
Number
Pregnancy
Category
C:
Animal
reproduction
studies
have
not
been
conducted
with
vitamin
B
.
is
12 Itof
B12 suffered severe and swift optic atrophy.
saturate the binding capacity of plasma proteins and the liver, the unbound B12 is rapidly eliminated
below, describing the clinical pharmacology of cyanocobalamin, has been derived from studies with
®fetal
Occurrences
by
Treatment
Intramuscular
and
Intranasal to
Administration
of
If a patient
properly
maintained
with
Nascobal
Nasal
Spray,
intramuscular
vitamin
B12 is woman
also is
notnot
known
whether
vitaminFollowing
B
cause
harm
when
administered
a pregnant
12 can
in the urine. Retention
of Vitamin
B12 in the
is Trough
dose-dependent.
About
80-90% of an intramuscular
Hypokalemia
and
sudden
death
may
occur
in
severe
megaloblastic
anemia
which
is
treated
Figure.
B 12body
Serum
Levels After
Intramuscular
injectable vitamin B12.
Cyanocobalamin.
necessary
for adequate
treatment capacity.
of the patient.
No single
regimen
fits all cases,
the status
or can
affect reproduction
Adequate
andfor
well-controlled
studiesand
have
beenofdone in
dose up to 50 mcgSolution
is retained
this Nasal
percentage
drops
to 55% for of
a 100 mcg dose, and
intensely
vitamin
Folic is
acid
isfinal
notcriterion
a substitute
vitamin
B12 although
it maynotimprove
(IM)inofthe
100body;
mcg and
Gel (IN)
Administration
12.However,
Vitamin B12 is quantitatively and rapidly absorbed from intramuscular and subcutaneous sites of
the patientwith
observed
inBfollow-up
the
for essential
adequacy
of therapy.
women.
vitamin
vitamin
requirements
areB increased
12 is an
decreases to 15% 500
when
a 1000
mcg dose is After
given.Weekly Doses.
megaloblastic
anemia.BExclusive
use of folic
acidand
in Patients
treating
vitamin
vitamin pregnant
B12-deficient
Number
of
(Occurrences)
mcg
Cyanocobalamin
12injection. It is bound to plasma proteins and stored in the liver. Vitamin B12 is excreted in the bile
during
pregnancy.
Amounts
of
vitamin
B
that
are
recommended
by
the
Food
and
Nutrition
allergic
rhinitis
The
effectiveness
of
Nascobal
Nasal
Spray
in
patients
with
nasal
congestion,
12
deficient megaloblastic
anemia could resultAdverse
in progressive and irreversible
neurologicIntramuscular
damage. and Board,
System
Vitamin
B
and undergoes some enterohepatic recycling. Absorbed vitamin B12 is transported via specific B12
12pregnant
NationalBody
Academy
of
Science
- National
Research
Council
for
women
should be
upper respiratory
infections
has
not been
determined.
Therefore,
treatment
with Nascobal
Nasal
Anaphylactic
shock
and death
have beenExperience
reported
after parenteralNasal
vitamin
Gel, B12 administration.
Vitamin B12,No
binding proteins, occurs
transcobalamin
I and
II, toorthe
various tissues.
The
is thered
main
organItfor
powder.
is
Cyanocobalamin
as dark red
crystals
orthorhombic
needles
or liver
crystalline
consumed
during
pregnancy.
Spray should
be deferred
until symptoms
have
subsided.
such reactions have been reported in clinical trials with Nascobal Nasal
Spray or Nascobal
Nasal
500 mcg
100 mcg
vitamin
B12 storage.
very
hygroscopic
in the anhydrous form, and sparingly to moderately soluble in water (1:80). Its
6. NURSING
MOTHERS
2. LABORATORY
TESTS
Gel.
N=24
N=25
pharmacologic
activity is destroyed
by heavy
and strong oxidizing
reducing
agents
reverses or
the
megaloblastic
Parenteral (intramuscular)
administration
of metals
vitamin(iron)
B12 completely
Vitamin
B12 appears
in the
milk Bof ,nursing
mothers
in concentrations
which approximate
the
INDICATIONS AND USAGE
folate
and
iron
levels
should
be
obtained
prior
to
Hematocrit,
reticulocyte
count,
vitamin
Bluntedmother’s
or impeded
response
to12vitaminofB12
may be
due to1are
such
conditions as4by
infection,
(vitamin
by autoclaving
for short
periods of time
(15-20 minutes)
at 121°C.inThe
vitamin
Body as
atherapeutic
Whole
Asthenia
(1) recommended
(4)the Food
anemia C),
andbut
GI not
symptoms
of vitamin
B12 deficiency;
the degree
of improvement
neurologic
Nascobal Nasal Spray is indicated for the maintenance of normal hematologic status in pernicious
vitamin
B12 are
blood
level.
Amounts
vitamin
and
12 that
treatment.
If folate
levels
low,
folic
acid should
alsoBbe
administered.
All hematologic
uremia,
drugs
having
bone
marrow
suppressant
properties
such
as chloramphenicol,
B
are very
unstable
in light.
Back
Pain
0 (0)
1lactating
(1) and women
symptoms
depends
on the
duration
and severity of the lesions, although progression of the lesions
12 coenzymes
anemia patients who are in remission following intramuscular vitamin B12 therapy and who have no
Nutrition
Board,
National
Academy
of
Science-National
Research
Council
for
®
parameters
should
be
normal
when
beginning
treatment
with
Nascobal
Nasal
Spray.
concurrent iron or folic acid deficiency.Generalized Pain
® Nasal
0 (0)
2 (3)
is immediately
arrested.
Spray is a solution of Cyanocobalamin, USP (vitamin B12) for administration as a
Nascobal
nervous system involvement.
should be consumed during lactation.
Vitamin B12 blood levels and peripheral
blood counts must be monitored
initially at one month
Headache
1 (2)*
5 (11) after
spray
to the nasal
mucosa. Each
unit dose
device ofonNascobal
NasalofSpray
contains
0.125
mL of
a
the presence
sufficient
intrinsic
factor
and
Gastrointestinal
absorption
of vitamin
B12 depends
PRECAUTIONS
7.ofPEDIATRIC
USE
® Infection
a
Nascobal
Nasal
Spray
is
also
indicated
as
a
supplement
for
other
vitamin
B
deficiencies,
the
start
treatment
with
Nascobal
Nasal
Spray,
and
then
at
intervals
of
3
to
6
months.
3
(4)
3
(3)
12
500
mcg/0.1
mL
solution
of
cyanocobalamin
with
sodium
citrate,
citric
acid,
glycerin
and
calcium ions. Intrinsic factor deficiency causes pernicious anemia, which may be associated with
1. GENERAL
Intake
in
pediatric
patients
should
be
in
the
amount
recommended
by
the
Food
and
Nutrition
Board,
including:
Peripheral
Vascular
0B(0)
1 Spray
(1)
System
A decline
inCardiovascular
thetest
serum
levels
of B12 after
one month
ofDisorder
treatment
spray
may
indicate
benzalkonium
chloride
in purified water.
spray
solution
a pH between
4.5 and of
5.5.vitamin
Each
subacute combined
degeneration
of the The
spinal
cord.
Prompthas
parenteral
administration
before
Nascobal
Nasal
is
An
intradermal
dose
of
vitamin
B
12 nasal
12 is recommended
National
Academy
ofparenteral
Science-National
Research
Council. with
Digestive
System
Dyspepsia
0
(0)
1
(2)that
that the dose may
need tosuspected
be adjusted
Patients should
be seen
one month
after each
dose
spray
deliversprogression
an averageofofneurologic
500 mcg of
cyanocobalamin.
B12 prevents
damage.
Vitamin
B12 deficiency
is
administered
to patients
of upward.
cyanocobalamin
sensitivity.
Glossitis
1 (1) degenerative
0 (0)
ADVERSE
REACTIONS
adjustment;
continued
levels
of three
serum
B12 may
indicate
that
the patient
is not a candidate
for
allowed
to progress
forlow
longer
than
months
may
produce
permanent
lesions
of
I. Dietary deficiency of vitamin B12 occurring in strict vegetarians (Isolated vitamin B12 defiThe average
diet supplies about 4 to 15 mcg/day of vitamin B12 in a protein-bound form that is
CLINICAL
PHARMACOLOGY
Nausea
1 (1)*
(1) data from a
The
adverse
experiences
described
in the
Table
below
are based1remission
on
this spinal
mode
ofincidence
administration.
the
cord.
Doses of folic
acid greater
than 0.1
mg per day
may
result
in hematologic
ciency is very rare).
available forPHARMACOLOGY
absorption after normal
digestion. Vitamin
B12 is not present in foods of plant origin,
GENERAL
AND MECHANISM
OF ACTION
(1)
Nausea
&
Vomiting
0
(0)
1
short-term
clinical
trial
in
vitamin
B
deficient
patients
in
hematologic
remission
receiving
Nascobal
Neurologic
willcarcinoma
not be prevented
with folic
in
patients
with
vitamin B
II. Malabsorption of vitamin B12 resulting from structural or functional damage to the stomach,
Patients
with
pernicious
anemia
have about
the incidence of
of the stomach
as
12 3 timesmanifestations
12 deficiency.
but is abundant
in foodstoofgrowth,
animal origin.
In people with
normal absorption,
deficiencies and
havemyelin
been
cell reproduction,
hematopoiesis,
and nucleoprotein
Vitamin
B12 is essential
0 (0) and
1 (1) when
(Cyanocobalamin,
Gel
for
Intranasal
Administration
(N=24)
vitamin B12
, irreversible
damage
will result.
acid,
if not treated
withUSP)
vitamin
B12Vomiting
where intrinsic factor is secreted, or to the ileum, where intrinsic factor facilitates vitamin
in theand
general
population,
so appropriate
tests for
this condition
should
be intramuscular
carried out
who division
consume
no products
animal
(including
nocells)
milk
reported only
in characterized
strict vegetarians
synthesis.
Cells
by rapid
(e.g.,
epithelial of
cells,
boneorigin
marrow,
myeloid
Musculoskeletal
System
Arthritis
0
(0)
2
(2)
(N=25).
theexceeding
pharmacokinetic
Nascobal
Nasalresponse
Spray and
Nasal Gel,
B12 absorption. These conditions include HIV infection, AIDS, Crohn’s disease, tropical
indicated.
Doses
of
vitaminInB12
10 mcgstudy
daily comparing
may produce
hematologic
in Nascobal
patients with
products
eggs).
appear
toor
have
the greatest requirement for vitamin B12. Vitamin B12 can be converted to coenzyme
Myalgia
0 (0)
1 (1)
the incidence
of adverseadministration
events
was similar.
sprue, and nontropical sprue (idiopathic steatorrhea, gluten-induced enteropathy). Folate
folate
deficiency.
Indiscriminate
may mask the true diagnosis.
3. DRUG/LABORATORY
to intrinsic
during
throughofthe
stomach; separation
occurs inand
the
Vitamin
B12 is bound
B
and as
such is factor
essential
fortransit
conversion
methylmalonate
to succinate
12 in tissues,
Nervous System TEST INTERACTIONS
Abnormal Gait
0 (0)
1 (1)
deficiency.
deficiency
in
these
patients
is
usually
more
severe
than
vitamin
B
Table
Adverse
Experiences
by
Body
System,
Number
of
Patients
and
Number
of
12
The
validity
of
diagnostic
vitamin
B
or
folic
acid
blood
assays
could
be
compromised
Persons taking most antibiotics, methotrexate
or pyrimethamine invalidate
terminal ileum
in the presence
of calcium, and
vitamin B
mucosal
cellInfor
absorption.
synthesis
of methionine
from homocysteine,
a reaction
which
also the
requires
folate.
the
absence ofIt
12
12
12 enters
Anxiety
0 (0) folic acid and vitamin
1 (1)* Bby
III. Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric
Occurrences
by Treatment
Following
Intramuscular
and
of
medications,
and assays.
this should
be considered
before relying
on such tests
forIntranasal
therapy. Administration
diagnostic
blood
is then transported
by the transcobalamin
proteins.
A small
amount
(approximately
1% of
coenzyme
B12, tetrahydrofolate
cannot bebinding
regenerated
from
its inactive
storage
form, 5-methyl
Dizziness
0 (0)
3 (3)
mucosa
(ingestion
of
corrosives,
extensive
neoplasia),
and
a
number
of
conditions
associatCyanocobalamin.
the total amount and
ingested)
is absorbed
simple diffusion,
but this B
mechanism
is be
adequate
only
tetrahydrofolate,
a functional
folateby
deficiency
occurs. Vitamin
involved
in
Vitamin
B 12para-aminosalicylic
is not a substitute
forand
folic
acidalcohol
and since
might
improve
folic acid
Colchicine,
acid
heavy
intakeit for
longer
than 2 weeks
may1deficient
produce
12 also may
Hypoesthesia
0 (0)
(1)
ed with a variable degree of gastric atrophy (such as multiple sclerosis, HIV infection, AIDS,
with very large
doses. (SH)
Oral absorption
is considered
too required
undependable
to rely
on in patients
with
maintaining
sulfhydryl
groups in the
reduced form
by many
SH-activated
enzyme
could
mask
the
true
diagnosis.
megaloblastic
anemia,
indiscriminate
use
of
vitamin
B
malabsorption of vitamin B12.
12
Incoordination
0 (0) of Patients (Occurrences)
1 (2)*
Number
certain endocrine disorders, iron deficiency, and subtotal gastrectomy). Total gastrectomy
perniciousThrough
anemia these
or other
conditions
resulting
in associated
malabsorption
vitamin
B12.
withoffat
and carbohydrate
metabolism
systems.
reactions,
vitamin
B12 is
Nervousness
0 (0) B
1
4. CARCINOGENESIS,
MUTAGENESIS,
IMPAIRMENT
OF FERTILITY
Hypokalemia
andBody
thrombocytosis
could
occur
upon conversion
of Vitamin
severe
megaloblastic
to(3)*
normal
Intramuscular
System
Adverse
always produces vitamin B12 deficiency. Structural lesions leading to vitamin B12 deficien12
and
protein synthesis.
Vitamin Bacid,
results
in megaloblastic
anemia,
and
Colchicine,
para-aminosalicylic
and heavy
alcohol
intake for longer
thanGI2 lesions,
weeks may
12 deficiency
Paresthesia
1
(1)
1 (1)B
Long-term
studies
in
animals
to
evaluate
carcinogenic
potential
have
not
been
done.
There
is12,no
therapy.
Therefore,
serum
potassium
levels
and
the
platelet
count
erythropoiesis
with
vitamin
B
Experience
Nasal Gel,
Vitamin
cy include regional ileitis, ileal resections, malignancies, etc.
12
neurologic
damage thatof begins
produce malabsorption
vitamin with
B12. an inability to produce myelin and is followed by gradual
Respiratory
System
Dyspnea
0vitamin
(0)
1 (1)
is
carcinogenic.
evidence
from
long-term
use
in
patients
with
pernicious
anemia
that
B
should
be
monitored
carefully
during
therapy.
500
mcg
100
mcg
12
PHARMACOKINETICS
IV. Competition for vitamin B 12 by intestinal parasites or bacteria. The fish tapeworm
degeneration
of the axon and nerve head.
Rhinitis
1
(1)*
2
(2)
N=25 B
(Diphyllobothrium latum) absorbs huge quantities of vitamin B12 and infested patients often
Absorption
Treatment with vitamin
Vitamin B12 deficiency may suppress the signs of polycythemia vera.N=24
Cyanocobalamin
is the most stable and widely used form of vitamin B12, and has hematopoietic
12
a Whole
Asthenia
1 (1)
4 (4)
have associated gastric atrophy. The blind loop syndrome may produce deficiency of vitamay unmask
this as
condition.
aBody
activity
identical
to that
antianemia
factor
in purified
extract. to
The
information
Sore
throat, common coldBack
*There
may be a possible relationship
between these
adverse
A threeapparently
way crossover
study
in of
25the
fasting
healthy
subjects
was liver
conducted
compare
the
Pain
0
(0)
1 (1)
or
folate.
min
B
12
below,
describing
theBclinical
pharmacology
of
cyanocobalamin,
has
been
derived
from
studies
with
®
experiences
and
the
study
drugs.
These
adverse
experiences
could
have
also
been
bioavailability
of the
nasal
spray
to
the
B
nasal
gel
and
to
evaluate
the
relative
bioavailability
Nasal
Spray,
intramuscular
vitamin
B
If
a
patient
is
not
properly
maintained
with
Nascobal
12
12
Generalized Pain
0 (0)
2 (3) 12 is
This may
occur
if antimetabolites
V. Inadequate
utilization
of vitamin
B12.Trough
Figure.
Vitamin
B 12 Serum
Levels
After
Intramuscular for the vitamin are
injectable
vitamin
B12.
the patient’s
clinical
state
otherregimen
concomitant
therapy.
of the nasal
formulations
as compared to the intramuscular injection. The peak concentrations
necessary forproduced
adequatebytreatment
of the
patient.
Noorsingle
fits1 all
of neoplasia.
employedSolution
in the treatment
Headache
(2)*cases, and the 5status
(11) of
(IM) of 100
mcg and Nasal Gel (IN) Administration of
and rapidly
absorbed
frominintramuscular
subcutaneous
sites
of
Vitamin
B12 is quantitatively
after administration
of intranasal
spray were
reached
1.25 +/- 1.9 and
hours.
The average
peak
the patient
is theInfection
final criterion
for adequacy
of therapy.
The observed
intensity inoffollow-up
the reported
adverse
following
the administration
of Nascobal
a experiences
3 (4)
3 (3)
mcg the
Cyanocobalamin
After Weekly
Doses.
It may be possible500
to treat
underlying disease
by surgical
correction of anatomic lesions leading
injection.
It is bound
plasmaafter
proteins
and correction
stored in the
liver. Vitamin
B12 is excreted
in thespray
bile
concentration
of B12 to
obtained
baseline
following
administration
of intranasal
(Cyanocobalamin,
USP)
Gel
for
Intranasal
Administration
and
intramuscular
vitamin
B12 were
patients
with
nasal
congestion,
allergic
rhinitis
The effectiveness
of
Nascobal
Nasal
Spray
in
Cardiovascular System
Peripheral Vascular Disorder
0 (0)
1 (1) and
to small bowel bacterial overgrowth, expulsion of fish tapeworm, discontinuation of drugs leading to
transported
specific B12
and
Absorbed
B12 is relative
was undergoes
757.96 +/- some
532.17enterohepatic
pg/mL. Therecycling.
bioavailability
of thevitamin
nasal spray
to theviaintramuscular
generally
mild.
One patient
reported
severe headache
following
dosing.
Similarly, a
upper respiratory
infections
has not
been
determined.
Therefore,
treatment
with Nascobal
Digestive
System
Dyspepsia
0 intramuscular
(0)
1 (2)Nasal
vitamin
malabsorption
(see
"Drug/Laboratory
Test
Interactions"),
use
of
a
gluten
free
diet
in
nonbinding
transcobalamin
I and
II, to the various
The
liver
is
the
main
organ
for
nasal
spray
was
found
to
be
10%
less
injectionproteins,
was found
to be 6.1%. The
bioavailability
of the Btissues.
experiences
of
moderate
intensity
were
reported
following
intramuscular
dosing
(two
few
adverse
12
Spray should be deferred until symptoms
have subsided.
Glossitis
1 (1)
0 (0)
tropical sprue, or administration of antibiotics in tropical sprue. Such measures remove the need
vitamin
than theBB
nasal gel. The 90% confidence intervals for the loge - transformed AUC(0-t) and Cmax
headaches and rhinitis; one dyspepsia,
arthritis, and dizziness),
1212storage.
Nausea
1 (1)* and dosing 1with
(1) Nascobal
2.
LABORATORY
TESTS
.
for
long-term
administration
of
vitamin
B
71.6%
118.66%
respectively.
was
71.71%
114.19%
and
12
(Cyanocobalamin, USP) GelNausea
for Intranasal
Administration0 (0)
(one headache, 1infection,
and
Parenteral (intramuscular) administration of vitamin B12 completely reverses the megaloblastic
Vomiting
(1)
INDICATIONS AND USAGE
and iron levels should
be obtained prior
to
Hematocrit,
reticulocyte count, vitamin B12,&folate
paresthesia).
anemia
and GI
symptoms
of vitamin
B12 deficiency;
degree
improvement
neurologic
in a
In pernicious
anemia
patients,
once weekly
intranasal the
dosing
with of
500
mcg B12 gelinresulted
Requirements
vitamin
of normal
(due toofpregnancy,
thyrotoxicosis,
ane0 (0)
1 (1)
Nascobal
NasalofSpray
is B
indicated
for the
maintenance
normal hematologic
statushemolytic
in pernicious
12 in excess
treatment. If folate levels are low, Vomiting
folic acid should also be administered.
All hematologic
symptoms
the duration
andBseverity
the lesions,
although
progression
the lesions
consistent depends
increase on
in pre-dose
serum
during
one month
of treatment
(p < of
0.003)
above
mia, hemorrhage,
malignancy,
hepaticfollowing
and renalintramuscular
disease) canvitamin
usually Bbe
met
with
intranasal
or
oral
The
majority
of
the
reported
adverse
experiences
following
dosing
with
Nascobal
12 levelsof
Musculoskeletal
System
Arthritis
0
(0)
2
(2)
therapy
and
who
have
no
anemia
patients who
are in remission
®
12
parameters should be normal when beginning treatment with Nascobal Nasal Spray.
is
immediately
arrested.
that
seen one month
after 100 mcg intramuscular dose (Figure).
supplementation.
intramuscular vitamin
(Cyanocobalamin, USP) Gel for
Intranasal Administration and
Myalgia
0 (0)
1 (1) B12 were
nervous
system involvement.
Vitaminjudged
B12 blood
levels
and peripheral
blood
counts
must
be monitored
initially
at one the
month
to be
intercurrent
events.
For the
other
reported
adverse
experiences,
to
Gastrointestinal
absorption of vitamin B12 depends on the presence of sufficient intrinsic factor and
Distribution
Nervous
System
Abnormal
Gait
0 (0)
1 relationship
(1) after
® Nasal
absorptionfor
testother
(Schilling
Test).
Nascobal Nasal
Spray
is is
notalso
suitable
for vitamin
Bsupplement
Nascobal
Nasal
Spray
indicated
as
a
vitamin
B
deficiencies,
the
start
of treatment
with
Nascobal
and thenOf
at intervals
6 months. judged
12
12
study
drug was
judged
as “possible”
or “remote”.
the adverse
experiences
calcium
ions. Intrinsic
factor deficiency
causes pernicious
anemia,
which may
be associated
with
to transcobalamin
II, a specific
B-globulin
carrier
protein, and
is
In the blood,
B 12 is bound
AnxietySpray,
0 of
(0)3 to
1 (1)* to be of
including:
A
decline
in
the
serum
levels
of
B
after
one
month
of
treatment
with
B
nasal
spray
may
indicate
CONTRAINDICATIONS
“possible”
relationship
to
the
study
drug,
anxiety,
incoordination,
and
nervousness
were
reported
subacute
of the
cord.
Prompt parenteral administration of vitamin
distributedcombined
and storeddegeneration
primarily in the
liverspinal
and bone
marrow.
Dizziness
012
(0)
3 (3)
12
that thefollowing
dose mayintramuscular
need to be adjusted
upward.
should
be seen
month
afterreported
each
Sensitivity to cobalt and/or vitamin B12 or any component of the medication is a contraindication.
vitaminHypoesthesia
B12 andPatients
headache,
nausea,
and
were
following
B
0 one
(0)rhinitis
1 (1) dose
12 prevents progression of neurologic damage.
Elimination
adjustment;
low levels
of serum
B12 USP)
may indicate
that the patient
dosingcontinued
with Nascobal
(Cyanocobalamin,
Gel for Intranasal
Incoordination
0Administration.
(0) is not a candidate
1 (2)* for
I. Dietary deficiency of vitamin B12 occurring in strict vegetarians (Isolated vitamin B12 defiin
a
protein-bound
form
that
is
The
average
supplies
about
4
to
15
mcg/day
of
vitamin
B
12
WARNINGS
is
secreted
into
the
GI
tract
daily
via
the
bile;
in
normal
subjects
with
sufficient
About
3-8 mcgdiet
of B
12
this
mode
of
administration.
Nervousness
0
(0)
1
(3)*
ciency
is
very
rare).
The following adverse reactions have been reported with parenteral vitamin B12:
present in foods of plant origin,
available
for absorption
after normal
VitaminWhen
B12 isBnot
Patients with early Leber’s disease (hereditary optic nerve atrophy) who were treated with vitamin
intrinsic factor,
all but about
1 mcg digestion.
is re-absorbed.
12 is administered in doses which
1 (1)and Precautions).
1 (1) as
II. Malabsorption
vitamin
PatientsGeneralized:
with pernicious anemia
have Paresthesia
about
3 times
the incidence
of carcinoma
of the stomach
but
is abundant
in foods
of animal
origin.proteins
In people
absorption,
deficiencies
have been
12 resulting from structural or functional damage to the stomach,
Anaphylactic
shock
and death
(See Warnings
severe andofswift
opticBatrophy.
B12 suffered
saturate
the binding
capacity
of plasma
andwith
the normal
liver, the
unbound B
12 is rapidly eliminated
Respiratory
Systemso
Dyspnea
0 (0) early
1 (1)when
where and
intrinsic
factor
is secreted,
or tointhe
ileum,megaloblastic
where intrinsicanemia
factor facilitates
in the general
population,
appropriate
tests
this condition
be carried
out
reported
onlyRetention
in strict vegetarians
who
consume
no products of
animal
originof(including
no milk
Cardiovascular:
Pulmonary
edema
andfor
congestive
heart should
failure
in treatment;
peripheral
in the urine.
of B12 in the
body
is dose-dependent.
About
80-90%
an intramuscular
Hypokalemia
sudden
death
may occur
severe
which is vitamin
treated
Rhinitis
1
(1)*
2 (2)
B
absorption.
These
conditions
include
HIV
infection,
AIDS,
Crohn’s
disease,
tropical
indicated.
products
or
eggs).
12
vascular thrombosis.
dose up to 50 mcg is retained in the body; this percentage drops to 55% for a 100 mcg dose, and
intensely with
vitamin B12. Folic acid is not a substitute for vitamin B12 although it may improve
sprue,
and
nontropical
sprue
(idiopathic
steatorrhea,
gluten-induced
enteropathy).
Folate
Hematological:
Polycythemia
vera.
3.
DRUG/LABORATORY
TEST
INTERACTIONS
bound
to intrinsic
factordose
during
transit through the stomach; separation occurs in the
Vitamin
B12tois15%
decreases
when
a 1000 mcg
is given.
vitamin B12-deficient megaloblastic anemia. Exclusive use of folic acid in treating vitamin B12a Sore throat, common cold *There may be a possible relationship between these adverse
in these
patients
usually
severeand
thanirreversible
vitamin B12neurologic
deficiency.damage.
Mildmethotrexate
transient diarrhea.
Gastrointestinal:
Persons
taking
most antibiotics,
or pyrimethamine invalidate folic acid and vitamin B12
terminal ileum in the presence of calcium, and vitamin B12 enters the mucosal cell for absorption. It
deficientdeficiency
megaloblastic
anemia
couldisresult
in more
progressive
experiences
the study
drugs.exanthema.
These adverse experiences could have also been
III. Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric
Dermatological:
Itching;
transitory
is then transported by the transcobalamin binding proteins. A small amount (approximately 1% of
diagnostic
blood
assays. and
Anaphylactic
shock
and
death
have
been
reported
after
parenteral
vitamin
B
administration.
No
12
produced by the
patient’s
clinical state
other body.
concomitant therapy.
mucosa (ingestion of corrosives, extensive neoplasia), and a number of conditions associatMiscellaneous:
Feeling
of
swelling
of theorentire
the total amount ingested) is absorbed by simple diffusion, but this mechanism is adequate only
Colchicine,
para-aminosalicylic
acid
and
heavy
alcohol
intake for longer than 2 weeks may produce
such reactions
have
been degree
reported
in
clinical
trials with
Nascobal
Nasal
SprayHIV
or Nascobal
Nasal
ed
with
a
variable
of
gastric
atrophy
(such
as
multiple
sclerosis,
infection,
AIDS,
The intensity
of Bthe. reported adverse experiences following the administration of Nascobal
with very large doses. Oral absorption is considered too undependable to rely on in patients with
malabsorption
of vitamin
Gel.
certain endocrine disorders, iron deficiency, and subtotal gastrectomy). Total gastrectomy
(Cyanocobalamin, 12USP) Gel for Intranasal Administration and intramuscular vitamin B12 were
pernicious anemia or other conditions resulting in malabsorption of vitamin B12.
4. CARCINOGENESIS,
MUTAGENESIS,
IMPAIRMENT
OF FERTILITY
response
to vitamin
B12 maylesions
be due leading
to such to
conditions
infection,
Blunted or
impeded
therapeutic
always
produces
vitamin
B12 deficiency.
Structural
vitamin Bas
generally mild. One
patient reported
severe headache
following intramuscular dosing. Similarly, a
12 deficienColchicine, para-aminosalicylic acid, and heavy alcohol intake for longer than 2 weeks may
Long-term
animals to evaluate
carcinogenic
have following
not been intramuscular
done. There isdosing
no (two
uremia, cy
drugs
having
bone
marrow
suppressant
propertiesetc.
such as chloramphenicol, and
malignancies,
include
regional
ileitis,
ileal resections,
fewstudies
adverseinexperiences
of moderate
intensity potential
were reported
produce malabsorption of vitamin B12.
concurrent iron or folic acid deficiency.
evidence
from
long-term
use
in
patients
with
pernicious
anemia
that vitamin and
B12 is
carcinogenic.
and dizziness),
dosing
with Nascobal
headaches and rhinitis; one dyspepsia, arthritis,
PHARMACOKINETICS
by
intestinal
parasites
or
bacteria.
The
fish
tapeworm
IV.
Competition
for
vitamin
B
(Cyanocobalamin, USP) Gel for Intranasal Administration (one headache, infection, and
PRECAUTIONS
12
(Diphyllobothrium latum) absorbs huge quantities of vitamin B12 and infested patients often
Absorption
paresthesia).
1. GENERAL
have associated
atrophy.
The B
blind
syndrome may
produce
deficiency
of vita-is
recommended
before
Nascobal
Nasal Spray
An intradermal
test dose gastric
of parenteral
vitamin
The majority of the reported adverse experiences following dosing with Nascobal
12 isloop
A three way crossover study in 25 fasting healthy subjects was conducted to compare the
folate. suspected of cyanocobalamin sensitivity. Vitamin B12 deficiency that is
min B12
administered
to or
patients
(Cyanocobalamin, USP) Gel for Intranasal Administration and intramuscular vitamin B12 were
bioavailability of the B12 nasal spray to the B12 nasal gel and to evaluate the relative bioavailability
mayproduce
occur if permanent
antimetabolites
for the vitamin
are
V. Inadequate
vitamin
allowed
to progress utilization
for longerofthan
threeBmonths
degenerative
lesions
of
12. Thismay
judged to be intercurrent events. For the other reported adverse experiences, the relationship to
of the nasal formulations as compared to the intramuscular injection. The peak concentrations
employed
in theoftreatment
neoplasia.
the
spinal
cord.
Doses
folic acid of
greater
than 0.1 mg per day may result in hematologic remission
study drug was judged as “possible” or “remote”. Of the adverse experiences judged to be of
after administration of intranasal spray were reached in 1.25 +/- 1.9 hours. The average peak
deficiency.
Neurologic
manifestations
will
not
be
prevented
with
folic
in
patients
with
vitamin
B
12
“possible” relationship to the study drug, anxiety, incoordination, and nervousness were reported
It may be possible to treat the underlying disease by surgical correction of anatomic lesions leading
concentration of B12 obtained after baseline correction following administration of intranasal spray
will result.
acid,
and
if notbacterial
treated with
vitamin Bexpulsion
12, irreversible
following intramuscular vitamin B12 and headache, nausea, and rhinitis were reported following
to
small
bowel
overgrowth,
of fishdamage
tapeworm,
discontinuation of drugs leading to
was 757.96 +/- 532.17 pg/mL. The bioavailability of the nasal spray relative to the intramuscular
Doses of
vitamin B12 exceeding
10 mcg dailyTest
mayInteractions"),
produce hematologic
in patients
with
dosing with Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration.
vitamin
malabsorption
(see "Drug/Laboratory
use of aresponse
gluten free
diet in noninjection was found to be 6.1%. The bioavailability of the B12 nasal spray was found to be 10% less
folate
deficiency.
Indiscriminate
administration
may
mask
the
true
diagnosis.
tropical
sprue,
or
administration
of
antibiotics
in
tropical
sprue.
Such
measures
remove
the
need
The
following adverse reactions have been reported with parenteral vitamin B12:
than the B12 nasal gel. The 90% confidence intervals for the loge - transformed AUC(0-t) and Cmax
The
validity administration
of diagnosticofvitamin
vitamin BB12
for
long-term
was 71.71% - 114.19% and 71.6% - 118.66% respectively.
12. or folic acid blood assays could be compromised by
Generalized:
Anaphylactic shock and death (See Warnings and Precautions).
medications, and this should be considered before relying on such tests for therapy.
Cardiovascular:
Pulmonary edema and congestive heart failure early in treatment; peripheral
In pernicious anemia patients, once weekly intranasal dosing with 500 mcg B12 gel resulted in a
Requirements of vitamin B12 in excess of normal (due to pregnancy, thyrotoxicosis, hemolytic aneVitamin
B
is
not
a
substitute
for
folic
acid
and
since
it
might
improve
folic
acid
deficient
vascular thrombosis.
consistent increase in pre-dose serum B12 levels during one month of treatment (p < 0.003) above
12
mia, hemorrhage,
malignancy, hepatic and renal disease) can usually be met with intranasal or oral
megaloblastic anemia, indiscriminate use of vitamin B12 could mask the true diagnosis.
Hematological:
Polycythemia vera.
that seen one month after 100 mcg intramuscular dose (Figure).
supplementation.
Gastrointestinal:
Mild transient diarrhea.
Distribution
Hypokalemia
and
thrombocytosis
could
occur
upon
conversion
of
severe
megaloblastic
to
normal
Nascobal Nasal Spray is not suitable for vitamin B12 absorption test (Schilling Test).
Dermatological:
Itching; transitory exanthema.
In the blood, B 12 is bound to transcobalamin II, a specific B-globulin carrier protein, and is
erythropoiesis with vitamin B12 therapy. Therefore, serum potassium levels and the platelet count
Miscellaneous:
Feeling of swelling of the entire body.
CONTRAINDICATIONS
distributed and stored primarily in the liver and bone marrow.
should be monitored carefully during therapy.
Sensitivity to cobalt and/or vitamin B12 or any component of the medication is a contraindication.
Elimination
Vitamin B12 deficiency may suppress the signs of polycythemia vera. Treatment with vitamin B12
WARNINGS
About 3-8 mcg of B12 is secreted into the GI tract daily via the bile; in normal subjects with sufficient
may unmask this condition.
Patients with early Leber’s disease (hereditary optic nerve
atrophy) who were treated with vitamin
intrinsic factor, all but about 1 mcg is re-absorbed. When B12 is administered in doses which
patient severe
is not properly
with Nascobal® Nasal Spray, intramuscular vitamin B12 is
and swiftmaintained
optic atrophy.
BIf asuffered
saturate the binding capacity of plasma proteins and the liver, the unbound B is rapidly eliminated
study drug was judged as “possible” or “remote”. Of the adverse experiences judged to be of
“possible” relationship to the study drug, anxiety, incoordination, and nervousness were reported
following intramuscular vitamin B12 and headache, nausea, and rhinitis were reported following
dosing with Nascobal (Cyanocobalamin, USP) Gel for Intranasal Administration.
The following adverse reactions have been reported with parenteral vitamin B12:
Generalized:
Anaphylactic shock and death (See Warnings and Precautions).
Cardiovascular:
Pulmonary edema and congestive heart failure early in treatment; peripheral
vascular thrombosis.
Hematological:
Polycythemia vera.
Gastrointestinal:
Mild transient diarrhea.
Dermatological:
Itching; transitory exanthema.
Miscellaneous:
Feeling of swelling of the entire body.
OVERDOSAGE
No overdosage has been reported with Nascobal Nasal Spray, Nascobal (Cyanocobalamin, USP)
Gel for Intranasal Administration or parenteral vitamin B12.
DOSAGE AND ADMINISTRATION
The recommended initial dose of Nascobal Nasal Spray is one spray (500 mcg) administered in
ONE nostril once weekly. Nascobal Nasal Spray should be administered at least one hour before
or one hour after ingestion of hot foods or liquids. Periodic monitoring of serum B12 levels should
be obtained to establish adequacy of therapy.
See LABORATORY TESTS for monitoring B12 levels and adjustment of dosage.
HOW SUPPLIED
Nascobal Nasal Spray, 500 mcg is supplied in boxes of 4 unit dose nasal spray devices and a
package insert (NDC 49884-270-82). Each unit dose spray delivers 500 mcg of cyanocobalamin,
USP.
INFORMATION FOR PATIENTS
Patients with pernicious anemia should be instructed that they will require weekly intranasal
administration of Nascobal Nasal Spray for the remainder of their lives. Failure to do so will result in
return of the anemia and in development of incapacitating and irreversible damage to the nerves of
the spinal cord. Also, patients should be warned about the danger of taking folic acid in place of
vitamin B12, because the former may prevent anemia but allow progression of subacute combined
degeneration of the spinal cord.
(Hot
foods may cause nasal secretions and a resulting loss of medication; therefore, patients
OVERDOSAGE
should
be told tohas
administer
Nascobal
Spray
at least
hour before
or one hour USP)
after
No overdosage
been reported
with Nasal
Nascobal
Nasal
Spray,one
Nascobal
(Cyanocobalamin,
ingestion
of hot foods
or liquids). or parenteral vitamin B12.
Gel for Intranasal
Administration
milk
products
or
eggs)
does
not
ADOSAGE
vegetarian
diet
which
contains
no
animal
products
(including
AND ADMINISTRATION
supply
any vitamin initial
B 12. Therefore,
patientsNasal
following
a diet
be advised
to takein
The recommended
dose of Nascobal
Spraysuch
is one
sprayshould
(500 mcg)
administered
Nascobal
Nasal
Spray
weekly.
The
need
for
vitamin
B
is
increased
by
pregnancy
and
lactation.
12 be administered at least one hour before
ONE nostril once weekly. Nascobal Nasal Spray should
Deficiency
has
been
recognized
in foods
infantsorofliquids.
vegetarian
mothers
who were
even though
or one hour
after
ingestion
of hot
Periodic
monitoring
of breast
serum fed,
B12 levels
should
the
no symptoms
of deficiency
at the time.
be mothers
obtained had
to establish
adequacy
of therapy.
Because the nasal dosage forms of Vitamin B12 have a lower absorption than intramuscular
See LABORATORY
TESTS
monitoring
B12 levels
and adjustment
dosage.
dosage,
nasal dosage
formsforare
administered
weekly,
rather thanofthe
monthly intramuscular
dosage.
As shown in the Figure above, at the end of a month, weekly nasal administration results
HOW SUPPLIED
inNascobal
significantly
higher
serum
Vitamin
B
levels
than
after
intramuscular
administration.
The patient
12
Nasal Spray, 500 mcg is supplied
in boxes of 4 unit dose nasal spray devices
and a
should
also
understand
the importance of
returning
for follow-up
blood 500
testsmcg
every
to 6 months to
package
insert
(NDC 49884-270-82).
Each
unit dose
spray delivers
of 3cyanocobalamin,
confirm
USP. adequacy of the therapy.
STORAGE CONDITIONS
INFORMATION
PATIENTS
Protect
from light.FOR
Keep
covered in carton until ready to use. Store at controlled room temperature
Patients
with(59°F
pernicious
anemia
be instructed that they will require weekly intranasal
15°C
to 30°C
to 86°F).
Protectshould
from freezing.
administration of Nascobal Nasal Spray for the remainder of their lives. Failure to do so will result in
To
report
reactions, contact
Par Pharmaceutical
Companies,
Inc.toatthe
1-800-828return
of suspected
the anemiaadverse
and in development
of incapacitating
and irreversible
damage
nerves of
9393.
the spinal cord. Also, patients should be warned about the danger of taking folic acid in place of
vitamin B12, because the former may prevent anemia but allow progression of subacute combined
degeneration of the spinal cord.
Distributed by:
(Hot foods may cause nasalPar
secretions
and a resulting
loss of
medication; therefore, patients
Pharmaceutical
Companies,
Inc.
should be told to administer Nascobal
Nasal
Spray
least one hour before or one hour after
Valley,
NY,at
10977
Spring
ingestion
of
hot
foods
or
liquids).
Rev. 04/14
OS270-01-1-05
A vegetarian diet which contains no animal products (including milk products or eggs) does not
supply any vitamin B 12. Therefore, patients following such a diet should be advised to take
Nascobal Nasal Spray weekly. The need for vitamin B12 is increased by pregnancy and lactation.
Deficiency has been recognized in infants of vegetarian mothers who were breast fed, even though
the mothers had no symptoms of deficiency at the time.
Because the nasal dosage forms of Vitamin B 12 have a lower absorption than intramuscular
dosage, nasal dosage forms are administered weekly, rather than the monthly intramuscular
dosage. As shown in the Figure above, at the end of a month, weekly nasal administration results
in significantly higher serum Vitamin B12 levels than after intramuscular administration. The patient
should also understand the importance of returning for follow-up blood tests every 3 to 6 months to
confirm adequacy of the therapy.
STORAGE CONDITIONS
Protect from light. Keep covered in carton until ready to use. Store at controlled room temperature
15°C to 30°C (59°F to 86°F). Protect from freezing.
To report suspected adverse reactions, contact Par Pharmaceutical Companies, Inc. at 1-800-8289393.
Rev. 04/14
Distributed by:
Par Pharmaceutical Companies, Inc.
Spring Valley, NY, 10977
OS270-01-1-05