Iron Preparations, Oral (Systemic)

Iron Preparations, Oral (Systemic)
Introductory Information
Ferrous fumarate, ferrous gluconate, ferrous sulfate,

carbonyl iron, and polysaccharide-iron complex are used
orally in the prevention and treatment of iron deficiency.a
Class: 20:04.04 Iron Preparations
Brands*: Feosol®, Feostat®, Feratab®, Fer-Gen-Sol®,

Fergon®, Fer-In-Sol®, Ferrex®, Ferro-DSS® (combination),
Ferro-Sequels® (combination), Ferrous Fumarate with
DSS® Timed (combination), Ferrous Sulfate Tablets EC, Fe-
Tinic®, Hemocyte®, Hytinic®, Icar® Pediatric, Ircon®, Mol-
Iron®, Nephro-Fer®, Niferex®, Slow FE®
*also available generically
Generic Name: Ferric Pyrophosphate

CAS Number: 1332-96-3
Generic Name: Ferrous Gluconate

Generic Name: Ferrous Sulfate

Generic Name: Ferrous Sulfate, Dried

Generic Name: Ferrous Fumarate

Generic Name: Ferrous Carbonate

Generic Name: Polysaccharide-Iron Complex
Uses
Prevention and Treatment of Iron Deficiency
Prevention and treatment of iron deficiency.a Not indicated

for treatment of anemia resulting from causes other than
iron deficiency.a
Dosage and Administration
Administration
Oral Administration
Administer orally between meals (e.g., 2 hours before or 1
hour after a meal).a
For patients who have difficulty tolerating oral iron

supplements, administer smaller, more frequent doses; start
with a lower dose and increase slowly to the target dose; try
a different form or preparation; or take with or after mealsa
or at bedtime.149
Dosage
Dosage expressed in terms of elemental iron. (See Table 1.)
Do not exceed recommended dosage.b
>Table 1. Approximate Elemental Iron Content of

Various Oral Iron Preparationsa
Drug Elemental Iron
Ferric pyrophosphate 120 mg/g
Ferrous gluconate 120 mg/g
Ferrous sulfate 200 mg/g
Ferrous sulfate, dried 300 mg/g
Ferrous fumarate 330 mg/g
Ferrous carbonate, anhydrous 480 mg/g
Carbonyl iron 1000 mg/ga
aCarbonyl iron is elemental iron, not an iron salt.
Pediatric Patients
Iron Deficiency Anemia
>Prevention
Oral: Premature or low-birthweight infants: 2-4 mg/kg daily
starting preferably at 1 month, but at least by 2 months, of
age.a Do not exceed 15 mg daily.a
Normal full-term infants who are not breast-fed or are only
partially breast-fed: 1 mg/kg daily, preferably as iron-
fortified formula, starting at birth and continuing during the
first year of life.109, 133 Do not exceed 15 mg daily.a
Children ≥10 years of age who have begun their pubertal
growth spurt may require daily iron supplementation of 2 or
5 mg daily in males or females, respectively.a
>Table 2. Recommended Dietary Allowance

(RDA)/Adequate Intake (AI) of Iron for Pediatric
Patients188
Age RDAb (mg/day) AIc (mg/day)
Infants 0-6 months of age 0.27

Infants 7-12 months of age 11
Children 1-3 years of age 7
Boys: 11
Children 14-18 years of age
Girls: 15
bBased on the need to maintain a normal functional iron
concentration but only minimal stores,188 RDA is the goal for
dietary intake in individuals.
cEstablished for infants through 6 months of age based on
the observed mean iron intake of infants fed principally

human milk.188
>Treatment
Oral: Children: 3-6 mg/kg daily in 3 divided doses.a
If a satisfactory response is not noted after 3 weeks of oral
iron therapy, consideration should be given to the
possibilities of patient noncompliance, simultaneous blood
loss, additional complicating factors, or incorrect diagnosis.a
Adults
>Prevention
Oral: RDA for healthy men of all ages (≥19 years of age) is 8
mg daily.188
RDA for healthy women 19-50 years of age is 18 mg daily,
and RDA for healthy women ≥51 years of age is 8 mg
daily.188
>Treatment
Oral: Usual therapeutic dosage: 50-100 mg 3 times daily.a
Smaller dosages (e.g., 60-120 mg daily) also recommended
if patients are intolerant of oral iron, but the possibility that
iron stores will be replenished at a slower rate should be
considered.a
If a satisfactory response is not noted after 3 weeks of oral
iron therapy, consider possibility of patient noncompliance,
simultaneous blood loss, additional complicating factors, or
incorrect diagnosis.a
Normal hemoglobin values usually obtained in 2 months
unless blood loss continues.a In severe deficiencies,
continue iron therapy for approximately 6 months.a
Special Populations
Renal Impairment
>Anemia of Chronic Renal Failure in Hemodialysis
Patients Receiving Epoetin Alfa
Oral: Children: 2-3 mg/kg daily in 2 or 3 divided doses.149
Adults: ≥200 mg daily in 2 or 3 divided doses.149
Pregnant Women
RDA for pregnant women 14-50 years of age is 27 mg
daily.188
Lactating Women
RDA for lactating women 14-18 or 19-50 years of age is 10
or 9 mg daily, respectively.188
Cautions
Contraindications
• Primary hemochromatosis.a
• Peptic ulcer, regional enteritis, or ulcerative colitis.a
Warnings/Precautions
Warnings
Children <12 years of age and pregnant or nursing women
should consult a health professional before using iron-
containing preparations.b
Accidental Overdose
Possible fatal poisoning in children <6 years of age;108, 148, b
keep iron-containing preparations out of reach of

children.148, b
If accidental overdosage occurs, immediately contact a

clinician or a poison control center.148, b
Sensitivity Reactions
Allergic Reactions
Possible allergic reactions (e.g., bronchial asthma) with
Fergon® 225-mg tablets, which contain the dye tartrazine
(FD&C yellow No. 5).a Use with caution, particularly in
patients sensitive to aspirin.a
Major Toxicities
Excess Iron Stores
Excess storage of iron with secondary hemochromatosis
possible; not recommended for treatment of hemolytic
anemias (unless an iron-deficient state also exists) or for
patients receiving repeated blood transfusions.a
Do not administer for >6 months except in patients with

continued bleeding, menorrhagia, or repeated pregnancies.a
General Precautions
Infectious Complications
Possible increased pathogenicity of certain
microorganisms,134, 138, 139, 140 including possible adverse
effects on prognosis in HIV-infected individuals;138, 139 not
recommended for use in individuals without documented
iron deficiency.138, 139
Use of Fixed Combination
When used in fixed combination with other agents, consider
the cautions, precautions, and contraindications associated
with the concomitant agents.
Specific Populations
Lactation
Distributed into milk.a
Common Adverse Effects
Constipation, diarrhea, dark stools, nausea, epigastric pain.a
Interactions
Specific Drugs, Foods, and Laboratory Tests
Drug, Food, or
Interaction Comment
Test
Antacids or
Administer
aluminum-
May decrease iron these drugs as
containing
absorptiona far apart as
phosphate
possiblea
binders
Pharmacokinetic Administer at
Calcium
(decrease iron absorption) least 2 hours
supplements
interactiona aparta
Avoid
Possible delayed response
Chloramphenicol concomitant
to iron therapya
use a
Food Iron absorption may be Administer 2
inhibited by polyphenols hours before or
(e.g., from certain 1 hour after a
vegetables), tannins (e.g., meala
from tea), phytates (e.g.,
from bran), and calcium
(e.g., from dairy
products)109, 111, 113, 133
Increased gastric pH and
possibly decreased GI
Administer oral
absorption of oral iron
iron at least 1
H2-receptor preparations that depend
hour prior to
antagonists on gastric acidity for
H2-receptor
dissolution and
absorption192, 193, 194, 195, antagonists195
196, 197, 198
Concomitant
Iron, parenteral Iron toxicitya use not
recommendeda
Pharmacokinetic
(decreased oral absorption
of methyldopa) and
Methyldopa Monitor BPa
pharmacologic (decreased
hypotensive effect)
interactions106
May decrease the
Administer at
cupruretic effect of
Penicillamine least 2 hours
penicillamine, probably by
aparta
decreasing its absorptiona
Pharmacokinetic
Administer at
Quinolone anti- interaction (iron may
least 2 hours
infectives interfere with quinolone
aparta
absorption)a
Tests for
Use a
detection of Possible false-positive
benzidine test
occult blood in results with guaiac testa
insteada
stools
Tetracyclines Pharmacokinetic Administer
interaction (decreased oral tetracycline 3
absorption of both iron hours after or
and tetracyclines)a 2 hours before
oral irona
Administer at
least 2 hours
Possible pharmacokinetic
apart and
Thyroid agents interaction (decreased
monitor
thyroxine absorption)107
thyroid
function107
Concomitant
Increased absorption of
use may be of
iron from GI tract (with
Vitamin C benefit,
>200 mg Vitamin C per 30
particularly in
mg elemental iron)a
infantsa
Pharmacokinetics
Absorption
Bioavailability
Absorption dependent upon the form of iron administered
(e.g., ferrous form more readily absorbed), the dose, degree
of erythropoiesis, diet, and iron stores.a GI absorption of iron
increases in iron-deficient individuals.109
Oral bioavailability of iron can vary from <1% to >50%,109,

110 and the principal factor controlling GI iron absorption is
the amount of iron stored in the body.109, 111
Onset
Symptoms of anemia usually improve within a few days;
normal hemoglobin values usually attained in 2 months
unless blood loss continues.a
Food
Food decreases absorption of inorganic iron.a (See Food
under Interactions.)
Distribution
Extent
Exists in humans almost exclusively complexed to protein or
in heme molecules.a
Crosses the placenta and distributes into milk.a
Elimination
Metabolism
Occurs in a virtually closed system.a
Elimination Route
Most iron liberated by destruction of hemoglobin is
conserved and reused by the body.a Blood loss greatly
increases iron loss.a
Stability
Storage
Oral
Capsules, Solutions, Suspensions, Tablets
Room temperature (15-30°C).a Protect from excessive heat
and moisture.a
Actions
• Corrects erythropoietic abnormalities caused by a
deficiency of iron.a
• Does not stimulate erythropoiesis, nor does it correct
hemoglobin disturbances not caused by iron deficiency.a
Advice to Patients
• Risk of fatal poisoning in children <6 years of age;108, 148

importance of keeping iron-containing products out of
reach of children.148
• Importance of women informing their clinicians if they are
or plan to become pregnant or plan to breast-feed.a
• Importance of informing clinicians of existing or
contemplated concomitant therapy, including prescription
and OTC drugs, as well as any concomitant illnesses.a
• Importance of informing patients of other important
precautionary information.a (See Cautions.)
Preparations
Excipients in commercially available drug preparations may

have clinically important effects in some individuals; consult
specific product labeling for details.
Carbonyl Iron
Dosage Brand
Routes Strengths Manufacturer
Forms Names
15 mg (of
Icar®
Oral Suspension iron) per 1.25 Hawthorn
Pediatric
mL
45 mg (of Feosol®
Tablets GlaxoSmithKline
iron) Caplets
Tablets, 15 mg (of Icar®
Hawthorn
chewable iron) Pediatric
Ferrous Fumarate
Dosage
Routes Strengths Brand Names Manufacturer
Forms
200 mg (66
Oral Tablets Ircon® Kenwood
mg iron)
324 mg
US
(106 mg Hemocyte®
Pharmaceutical
iron)*
325 mg Ferrous
(107 mg Fumarate CMC
iron)* Tablets
350 mg
(115 mg Nephro-Fer® R&D Labs
iron)
Tablets, 100 mg (33
Feostat® Forest
chewable mg iron)
* available from one or more manufacturer, distributor,
and/or repackager by generic (nonproprietary) name
Ferrous Fumarate Combinations
Dosage
Forms
150 mg (50
mg iron) Ferrous
Capsules,
with Fumarate with
Oral extended- Vita-Rx
Docusate DSS® Timed
release
Sodium 100 Capsules
mg*
150 mg (50
Tablets,
mg iron)
extended- Ferro-DSS®
with
release, Caplets® Time-Caps
Docusate
film- (combination)
Sodium 100
coated
mg
Ferro-
Sequels®
(combination) Inverness
(with
povidone)
Ferrous Gluconate
Dosage
Forms
Bulk Powder
225 mg (27 Fergon® (with
Oral Tablets Bayer
mg iron) tartrazine)
Ferrous
IVAX, United
Gluconate
Research
Tablets
Ferrous
300 mg (35
Gluconate Upsher-Smith
mg iron)
Tablets
320 mg (37
mg iron)*
325 mg (38
mg iron)*
Ferrous Sulfate
Dosage
Forms
Bulk Powder
220 mg
Alpharma,
(44 mg Ferrous Sulfate
Oral Solution IVAX, United
iron) per 5 Elixir
Research
mL*
300 mg
(60 mg Ferrous Sulfate Pharmaceutical
iron) per 5 Solution Associates
mL
125 mg
(25 mg Fer-Gen-Sol®
IVAX
iron) per Drops
mL*
Fer-In-Sol®
Drops (with Mead Johnson
alcohol 0.02%)
195 mg Mol-Iron® (with
Schering-
Tablets (39 mg butylparaben
Plough
iron)* and povidone)
300 mg
(60 mg Feratab® Upsher-Smith
iron)*
325 mg
(65 mg
iron)*
Tablets, 325 mg
Ferrous Sulfate
enteric- (65 mg IVAX, Paddock
Tablets EC
coated iron)*
Tablets, 325 mg Ferrous Sulfate United
film- (65 mg Tablets Research
coated iron)
Ferrous Sulfate, Dried

Brand
Routes Dosage Forms Strengths Manufacturer
Names
190 mg (60
Oral Capsules
mg iron)
200 mg (65
Tablets Feosol® GlaxoSmithKline
mg iron)
Tablets,
160 mg (50 Slow
extended- Novartis
mg iron) FE®
release
Polysaccharide-iron Complex
Dosage
Forms
150 mg (of
Oral Capsules Ferrex®-150 Breckenridge
iron)
Fe-Tinic ® 150 Ethex
Hytinic® Hyrex
Niferex®-150
(with benzyl
Ther-Rx
alcohol and
parabens)
100 mg (of Niferex® Elixir
Solution iron) per 5 (with alcohol Ther-Rx
mL 10%)
Tablets, 50 mg (of Niferex® Ther-Rx
film- iron)
coated
Oral iron preparations are also commercially available in

combination with vitamins and minerals and oral
contraceptives.
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Healthcare; 2004.
Levalbuterol (Oral Inhalation)
Bronchodilator; synthetic sympathomimetic amine and

relatively selective, short-acting β2-adrenergic agonist.216, b
Class: 12:12.08.12 Selective beta-2-Adrenergic Agonists
Brands: Xopenex®
Generic Name: Levalbuterol

Synonym: (-)-Albuterol Hydrochloride, (R)-Albuterol
Hydrochloride, (-)-Salbutamol Hydrochloride, (R)-
Salbutamol Hydrochloride
Uses
Bronchospasm in Asthma
Symptomatic management or prevention of bronchospasm

in patients with reversible, obstructive airway disease (e.g.,
asthma).216, 219, 221, 259, b
General
• Adjust dosage carefully according to individual

requirements and response.216
• During acute asthma exacerbations, most patients obtain
optimum benefit, at least initially, when nebulized
levalbuterol is used regularly rather than on demand.216,
249
Administration
Oral Inhalation
Administer by oral inhalation via a metered-dose inhaler or
nebulization.216, b
Oral Inhalation Aerosol

Administer inhalation aerosol only with the actuator
provided by the manufacturer.c
Shake the inhaler well before use.b, c
Test-spray inhalation aerosol 4 times (away from the face)

before first use and whenever the inhaler has not been used
for >3 days.b, c
Avoid spraying the aerosol into the eyes.b, c
Exhale slowly and completely and place the mouthpiece of

the inhaler well into the mouth with the lips closed around
it.c While inhaling slowly and deeply through the
mouth,actuate the aerosol inhaler, withdraw the
mouthpiece, hold the breath for 10 seconds if possible, and
exhale.c
Allow 1 minute to elapse between subsequent inhalations

from the aerosol inhaler.c
Clean the metered-dose inhaler by removing the metal

canister and red mouthpiece (actuator) cap and running
warm water through the plastic mouthpiece for 30 seconds
at least once a week.b, c Shake off excess water and allow
the mouthpiece to air-dry thoroughly, such as overnight.b, c
Insert the metal canister into the mouthpiece and replace
the mouthpiece cap.c Do not attempt to clean the metal
canister or allow the canister to become wet.b, c If the
inhaler is to be used before it is completely dry, shake off
excess water, replace the canister, shake the inhaler well,
and test the inhaler by spraying twice (away from the face)
before administering the dose.b, c After such use, the
mouthpiece should be rewashed and allowed to air dry.b, c
Proper cleaning of the mouthpiece will prevent medication
build-up and blockage.b, c If actuator becomes blocked,
remove medication build-up by washing the actuator.b, c
Discard canister after the labeled number of actuations

have been used.b
Oral Inhalation Solution

For administration of levalbuterol hydrochloride solution for
nebulization in single-use units via a nebulizer, open one
single-use vial and squeeze the entire contents into the
nebulizer reservoir.226
Attach the reservoir to the mouthpiece or face mask and to

the compressor according to the manufacturer's
instructions.226
Place the mouthpiece of the nebulizer in the mouth or put

on the nebulizer face mask and turn on the compressor.226
Breathe as calmly, deeply, and evenly as possible until the
nebulizer stops producing mist (flow rate of nebulizer should
be adjusted to provide the full dose over about 5-15
minutes).226, 226
Clean the nebulizer after use according to the

manufacturer's instructions.226
Continue nebulization therapy as necessary to control

recurrent bronchospasm.216 Optimum benefit is obtained
when nebulization is used regularly.216
Dosage
Available as levalbuterol hydrochloride and levalbuterol

tartrate; dosages are expressed in terms of levalbuterol.216,
b
Pediatric Patients
>Oral Inhalation Aerosol
Children ≥4 years of age: Initially, 90 mcg every 4-6 hours.b
Some patients may find 45 mcg every 4 hours to be
sufficient.b
>Oral Inhalation Solution

Children 6-11 years of age: Initially, 0.31 mg 3 times daily
via nebulization.216 Children 6-11 years of age with more
severe asthma or those not responding adequately to the
0.31-mg dose may benefit from a dosage of up to 0.63 mg 3
times daily.216, 254 Some experts on asthma management
recommend a dosage of 0.025 mg/kg (minimum 0.63 mg,
maximum 1.25 mg) every 4-8 hours in children ≤12 years of
age.259
Adolescents ≥12 years of age: Initially, 0.63 mg 3 times
daily (every 6-8 hours) via nebulization.216, 219, 221
Adolescents ≥12 years of age with more severe asthma or
those not responding adequately to the 0.63-mg dose may
benefit from a dosage of 1.25 mg 3 times daily.216, 219
Some experts on asthma management recommend a
dosage of 0.63-2.5 mg/kg every 4-8 hours in adolescents
>12 years of age.259
Adults
Initially, 90 mcg every 4-6 hours.b Some patients may find
45 mcg every 4 hours to be sufficient.b

Initially, 0.63 mg of levalbuterol 3 times daily (every 6-8
hours) via nebulization.216, 219, 221 Patients with more severe
asthma or those not responding adequately to the 0.63-mg
dose may benefit from a dosage of 1.25 mg 3 times
daily.216, 219
Some experts on asthma management recommend a
dosage of 0.63-2.5 mg/kg every 4-8 hours in adults.259
Prescribing Limits
Pediatric Patients
Children ≥4 years of age: Maximum 90 mcg every 4-6
hours.b

Children 6-11 years of age: Maximum 0.63 mg 3 times
daily.216
Adolescents ≥12 years of age: Maximum 1.25 mg 3 times
daily.216, 219
Adults
Maximum 90 mcg every 4-6 hours.b

Maximum 1.25 mg 3 times daily.216, 219
Special Populations
Renal Impairment
Inhalation aerosol: Use caution when administering high
dosages.b
Geriatric Patients
Inhalation aerosol: Use caution and select initial dosage at
the lower end of dosing range because of age-related
decreases in hepatic, renal, and/or cardiac function and
concomitant disease and drug therapy.b
Inhalation solution: Increase dosage as tolerated with

careful monitoring.216
Cautions
Contraindications
• Known hypersensitivity to levalbuterol or racemic

albuterol or any ingredient in the formulation.216, b
Warnings
Acute or Worsening Asthma
Oral inhalation therapy is intended for the acute
symptomatic relief of bronchospasm.188, 189, 190, 191, 192, 249
If control of mild asthma deteriorates such that regular (i.e.,
more than 4 times daily) use of a short-acting β2-agonist
becomes necessary, institute maintenance therapy (e.g.,
inhaled corticosteroids and/or mast cell stabilizers, long-
acting bronchodilators [e.g., inhaled salmeterol], or oral
extended-release drugs)188, 189, 191, 249 and discontinue
regular use of the short-acting β2-agonist in such patients;
instead, use a short-acting β2-agonist only as a supplement
for relief of acute asthma symptoms.188, 189, 190, 191, 192, 194,
197, 249 Contact a clinician for reevaluation if control of mild
asthma deteriorates.216
Failure to respond to a previously effective dosage of a

short-acting β2-agonist may indicate seriously worsening
asthma.156, 157, 181, 188, 189, 190, 191, 192, 193, 194, 196, 197, 216,
241, 242, 243, 244, 249, b
Reevaluate asthma therapy and
institute alternative regimens or therapy.156, 157, 181, 188, 189,
190, 191, 192, 193, 194, 196, 197, 216, 241, 242, 243, 244, 249, b
Contact a clinician if decreased effectiveness occurs; do not

increase the dose or frequency of administration.216, b
Excessive Doses
Possible fatalities associated with excessive use of inhaled
sympathomimetic drugs.216, b Exact cause of death
unknown; cardiac arrest following severe asthmatic attack
accompanied by hypoxia suspected.b
Paradoxical Bronchospasm
Possible life-threatening acute bronchospasm.216, b
Frequently occurs with the first use of a new canister or
vial.216, b
Discontinue therapy immediately if bronchoconstriction

occurs and institute alternative therapy.216, b
Cardiovascular Effects
Possible clinically important cardiovascular effects, as
measured by pulse rate, blood pressure, and related
symptoms.216, b ECG changes, including T-wave flattening,
prolongation of the QTc interval, and ST-segment
depression, also have been reported.216, b
Cautious use recommended in patients with cardiovascular

disorders (e.g., coronary insufficiency, cardiac arrhythmias,
hypertension).216, b
Immediate hypersensitivity reactions (e.g., urticaria,
angioedema, rash, bronchospasm, anaphylaxis,
oropharyngeal edema) have been reported.216, b Possible
acute bronchospasm.216, b (See Paradoxical Bronchospasm
under Cautions.)
General Precautions
Nervous System Effects
Cautious use recommended in patients with seizure
disorders and in those with unusual responsiveness to
sympathomimetic amines.216, b
Metabolic Effects
Possible hypokalemia, which may increase risk of adverse
cardiovascular effects.216, b (See Cardiovascular Effects
under Cautions.) Serum potassium decrease usually is
transient and usually does not require supplementation.216,
b
Increased blood glucose has occurred following inhalation

via nebulization of levalbuterol.216 Effect may diminish
during continued therapy.216
Cautious use recommended in patients with diabetes

mellitus or hyperthyroidism.216, b
Pregnancy
Category C.216, b
Lactation
Not known whether levalbuterol is distributed into milk.216, b
Discontinue nursing or the drug.216, b
Pediatric Use
Oral inhalation solution: Safety and efficacy not established
in children <6 years of age.216
Oral inhalation aerosol: Safety and efficacy not established

in children <4 years of age.b
Geriatric Use
Data on the use of levalbuterol in geriatric patients ≥ 65
years of age are limited and are insufficient to determine
whether the efficacy and safety of levalbuterol are different
in geriatric patients versus younger patients.216, b
Substantially eliminated by kidneys; assess renal function

periodically since geriatric patients are more likely to have
decreased renal function.b
Inhalation aerosol in adults and adolescents ≥12 years of

age: asthma, pharyngitis, rhinitis, pain (unspecified),
dizziness.b
Inhalation aerosol in children 4-11 years of age: vomiting,

accidental injury, pharyngitis, bronchitis.b
Inhalation solution in adults and adolescents ≥12 years of

age: viral infection, rhinitis, nervousness, tremor, flu
syndrome, sinusitis, increased cough, pain, tachycardia,
turbinate edema, accidental injury, anxiety, dizziness,
dyspepsia, leg cramps, migraine.216
Inhalation solution in children 6-11 years of age: headache,

pharyngitis, rhinitis, asthma, fever, viral infection, rash,
accidental injury, diarrhea, asthenia, pain,
lymphadenopathy, urticaria, abdominal pain, myalgia.
Interactions
Specific Drugs
Drug Interaction Comments

If concomitant
Antagonism of
therapy required,
pulmonary effects,
consider cautious
β-Adrenergic resulting in severe
use of
blocking agents bronchospasm in
cardioselective β-
asthmatic
adrenergic blocking
patients216, b
agents216, b
Careful evaluation of
Decreased serum
serum digoxin
Digoxin digoxin
concentration
concentrations216, b
recommended216, b
Possible decreased
serum potassium
concentrations
Diuretics, and/or ECG
Cautious use
nonpotassium- changes, especially
when the recommended216, b
sparing
recommended β-
agonist dose is
exceeded216, b
MAO inhibitors Increased effect on Extreme caution
vascular system 216 recommended for
concomitant therapy
or in patients
receiving
levalbuterol within 2
weeks of
discontinuance of
these agents216, b
Caution
Sympathomimetic
recommended for
agents (e.g., Increased
concomitant use of
epinephrine, cardiovascular
sympathomimetic
other short-acting adverse effectsb
agents administered
bronchodilators)
by any route216, b
Pharmacokinetics
Absorption
Bioavailability
Higher in children 6-11 years of age than in adults,
supporting a lower dose for children.216 (See Pediatric
Patients under Dosage.)
Onset
Oral inhalation aerosol in adolescents and adults: 5.5-10.2
minutes for a 15% change in forced expiratory volume in 1
second (FEV1).b
Oral inhalation aerosol in children: 4.5 minutes.b
Oral inhalation solution: 10-17 minutes.216
Duration
Oral inhalation aerosol in adults: 3-6 hours.b
Oral inhalation aerosol in children: 3-6 hours.b
Oral inhalation solution: ≤ 8 hours in some patients.216
Distribution
Extent
It is not known whether levalbuterol distributes into milk.216
Elimination
Metabolism
Metabolized by sulfotransferase 1A3 (dopamine
phenolsulfotransferase) in the intestinal wall and liver to
levalbuterol 4'-O-sulfate, an inactive metabolite.b, d, e
Elimination Route
Excreted in urine (≥80%) mainly as parent compound or
primary metabolite and in feces (<20%).b
Half-life
Inhalation aerosol propellant (tetrafluoroethane): 5-7
minutes.b
Levalbuterol inhalation solution: 3.3-4 hours in healthy

adults.216
Special Populations
Pharmacokinetics of inhalation aerosol in patients with
hepatic impairment not studied.b
Stability
Storage
Oral Inhalation
Aerosol
20-25°C with the actuator in downward position; protect
from freezing and direct sunlight.b Do not puncture or
incinerate the canister.b Exposure to temperatures above
49°C may cause canister to burst.b
Solution
20-25°C.216 Store single-use vials in protective foil pouch to
protect from light until used.216
Once the foil pouch has been opened, use any vials
remaining in the pouch within 2 weeks.216 Use vials
removed from the pouch within 1 week.216 Discard vials if
the solution becomes discolored.216
Actions
• Stimulates β-adrenergic receptors with little or no effect

on α-adrenergic receptors.216
• Stimulates the production of cyclic adenosine-3´,5´-
monophosphate (AMP), which mediates numerous cellular
responses, including smooth muscle relaxation and
inhibiting the release of mediators from mast cells in the
airways.216, b
• Relaxes smooth muscles from the trachea to the terminal
bronchial tree.216, b
Advice to Patients
• Importance of providing patient with a copy of the

manufacturer's patient information.216
• Importance of adequate understanding of proper storage,
preparation, and inhalation techniques, including use of
various delivery systems.216, b
• Importance of adherence to dosing schedules of
levalbuterol and concomitant therapy, including not
exceeding the recommended dose or frequency of use
unless otherwise instructed by a clinician.216, b
• If decreased effectiveness occurs, contact a clinician
immediately; do not increase the dose or frequency of
administration.216, b
• Importance of women informing clinicians if they are or
plan to become pregnant or plan to breast-feed.216
(e.g., other inhaled agents) and OTC drugs.216
precautionary information. (See Cautions.)
Preparations

Levalbuterol Tartrate
Dosage
Forms
Xopenex HFA®
45 mcg (of (with dehyrated
Oral levalbuterol) alcohol,
Aerosol Sepracor
Inhalation per metered hydrofluroalkane
spray propellant, and
oleic acid)
Levalbuterol Hydrochloride
Dosage
Forms
Xopenex®
0.21 mg (of (preservative-
Oral Solution, for levalbuterol) free;
Sepracor
Inhalation nebulization per mL available as
(0.63 mg) polyethylene
ampuls)
Xopenex®
0.103 mg
(preservative-
(of
free;
levalbuterol) Sepracor
available as
per mL
polyethylene
(0.31 mg)
ampuls)
Xopenex®
Inhalation
0.417 mg
Solution
(of
(preservative-
levalbuterol) Sepracor
free;
per mL
available as
(1.25 mg)
polyethylene
ampuls)
Comparative Pricing
This pricing information is subject to change at the sole

discretion of DS Pharmacy. This pricing information was
updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to
patients will vary depending on the use of specific retail or
mail-order locations and health insurance copays.
Xopenex 0.31MG/3ML Aerosol (SUNOVION PHARMACEUTICALS):
72/$120.7 or 216/$346.67

72/$123.91 or 216/$354.43

72/$122.47 or 216/$347.26
References
Only references cited for selected revisions after 1984 are

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216. Sepracor Inc. Xopenex® (levalbuterol hydrochloride)

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Olanzapine (Systemic)
Atypical or second-generation antipsychotic agent.2, 4, 7, 14,

16, 17, 18, 19, 20, 22, 26
Class: 28:16.08.04 Atypical Antipsychotics; cn709 (VA

primary)
Brands: Symbyax® (combination), Zyprexa®, Zyprexa®

Zydis®
Generic Name: Olanzapine

CAS Number: 132539-06-1
Chemical Name: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine
Molecular Formula: C17H20N4S
Investigational Drug Number: LY17005
Special Alerts:
[Posted 02/22/2011] ISSUE: FDA notified healthcare

professionals that the Pregnancy section of drug labels for
the entire class of antipsychotic drugs has been updated.
The new drug labels now contain more and consistent
information about the potential risk for abnormal muscle
movements (extrapyramidal signs or EPS) and withdrawal
symptoms in newborns whose mothers were treated with
these drugs during the third trimester of pregnancy.
The symptoms of EPS and withdrawal in newborns may

include agitation, abnormally increased or decreased
muscle tone, tremor, sleepiness, severe difficulty
breathing, and difficulty in feeding. In some newborns, the
symptoms subside within hours or days and do not require
specific treatment; other newborns may require longer
hospital stays.
BACKGROUND: Antipsychotic drugs are used to treat

symptoms of psychiatric disorders such as schizophrenia
and bipolar disorder.
RECOMMENDATION: Healthcare professionals should be

aware of the effects of antipsychotic medications on
newborns when the medications are used during
pregnancy. Patients should not stop taking these
medications if they become pregnant without talking to
their healthcare professional, as abruptly stopping
antipsychotic medications can cause significant
complications for treatment. For more information visit the
FDA website at: [Web] and [Web].
[Posted 01/29/2010] Lilly and FDA notified healthcare

professionals of changes to the Prescribing Information for
olanzapine (Zyprexa) related to its indication for use in
adolescents (ages 13-17) for treatment of schizophrenia
and bipolar I disorder [manic or mixed episodes]. The
revised labeling states that:
Section 1, Indications and Usage: When deciding among

the alternative treatments available for adolescents,
clinicians should consider the increased potential (in
adolescents as compared with adults) for weight gain and
hyperlipidemia. Clinicians should consider the potential
long-term risks when prescribing to adolescents, and in
many cases this may lead them to consider prescribing
other drugs first in adolescents.
Section 17.14, Need for comprehensive Treatment Program
in Pediatric Patients: Olanzapine is indicated as an
integral part of a total treatment program for pediatric
patients with schizophrenia and bipolar disorder that may
include other measures (psychological, educational,
social) for patients with the disorder. Effectiveness and
safety of olanzapine have not been established in
pediatric patients less than 13 years of age.
For more information visit the FDA website at: [Web] and
[Web].
[Posted 05/02/2007] FDA notified healthcare professionals

that the Agency proposed that makers of all antidepressant
medications update the existing black box warning on the
prescribing information for their products to include
warnings about the increased risks of suicidal thinking and
behavior in young adults ages 18 to 24 years old during the
first one to two months of treatment. The proposed labeling
changes also state that scientific data did not show this
increased risk in adults older than 24 years of age and that
adults 65 years of age and older taking antidepressants
have a decreased risk of suicidality. The proposed updates
apply to the entire category of antidepressants. Individuals
currently taking prescribed antidepressant medications
should not stop taking them and should notify their
healthcare professional if they have concerns.
Manufacturers of antidepressant medications will have 30
days to submit their revised product labeling and revised
Medication Guides to FDA for review. See the FDA press
release for the list of products affected by the proposed
antidepressant product labeling changes. For more
information visit the FDA website at: [Web], [Web] and
[Web].

and consumers of important information from two recent
studies that should be considered when making treatment
decisions in pregnant women who take antidepressants.
The studies included pregnant women who were treated
with selective serotonin reuptake inhibitors (SSRIs), or in a
few cases, other antidepressant medications.
One study illustrated the potential risk of relapsed

depression after stopping antidepressant medication during
pregnancy. In this study, women who stopped their
medicine were five times more likely to have a relapse of
depression during their pregnancy than were women who
continued to take their antidepressant medicine while
pregnant.
The second study suggests there may be additional,

though rare, risks of taking SSRI medications during
pregnancy. This study focused on newborn babies with
persistent pulmonary hypertension (PPHN), which is a
serious and life-threatening lung condition that occurs soon
after birth. Babies born with PPHN have high pressure in
their lung blood vessels and are not able to get enough
oxygen into their bloodstream. In this study, PPHN was six
times more common in babies whose mothers took an SSRI
antidepressant after the 20th week of pregnancy compared
to babies whose mothers did not take an antidepressant.
The study was too small to compare the risk of one drug
compared to another. The finding of PPHN in babies of
mothers who used a SSRI antidepressant in the second half
of pregnancy adds to concerns from previous reports that
infants of mothers taking SSRIs late in pregnancy may
experience difficulties such as irritability, difficulty feeding
and in very rare cases, difficulty breathing.
Additionally, the labeling for paroxetine (Paxil) was recently

changed to add information about findings in an
epidemiologic study that suggests that exposure to the
drug in the first trimester of pregnancy may be associated
with an increased risk of cardiac birth defects.
Women who are pregnant or thinking about becoming

pregnant should not stop any antidepressant medication
without first consulting their physician. The FDA is seeking
additional information about the possible risk of PPHN in
newborn babies of mothers who took SSRI antidepressants
in pregnancy. FDA has asked the sponsors of all SSRIs to
change prescribing information to describe the potential
risk for PPHN. For more information visit the FDA website
at: [Web] and [Web].

and consumers of new safety information regarding taking
medications used to treat migraine headaches (triptans)
together with certain types of antidepressant and mood
disorder medications (selective serotonin reuptake
inhibitors (SSRIs) and selective serotonin/norepinephrine
reuptake inhibitors (SNRIs). A life-threatening condition
called serotonin syndrome may occur when triptans are
used together with a SSRI or a SNRI.
Serotonin syndrome occurs when the body has too much of

a chemical found in the nervous system (serotonin). Each
of the above medications (triptans, SSRIs, and SNRIs),
cause an increase in serotonin levels. Symptoms of
serotonin syndrome may include restlessness,
hallucinations, loss of coordination, fast heart beat, rapid
changes in blood pressure, increased body temperature,
overactive reflexes, nausea, vomiting, and diarrhea.
Healthcare professionals prescribing a triptan, SSRI or SNRI

should keep in mind that triptans are often used
intermittently and either the triptan, SSRI or SNRI may be
prescribed by a different physician; weigh the potential risk
of serotonin syndrome with the expected benefit of using
the above combination; discuss the possibility of serotonin
syndrome with patients if a triptan and an SSRI or SNRI will
be used together; and follow patients closely during
treatment if a triptan and an SSRI or SNRI are used
together.
Patients taking a triptan along with an SSRI or SNRI should

talk to their doctor before stopping their medication and
should immediately seek medical attention if they
experience any of the above symptoms. FDA requested
that all manufacturers of triptans, SSRIs and SNRIs update
their prescribing information to warn of the possibility of
serotonin syndrome when these medications are taken
together. For more information visit the FDA website at:
[Web] and [Web].
REMS:
FDA approved a REMS for olanzapine to ensure that the

benefits of a drug outweigh the risks. The REMS may apply
to one or more preparations of olanzapine and consists of
the following: medication guide, elements to assure safe
use, communication plan, and implementation system. See
the FDA REMS page ([Web]) or the ASHP REMS Resource
Center ([Web]).
Boxed Warning
Increased Mortality in Geriatric Patients
• Substantially higher mortality rate (4.5%) in geriatric
patients with dementia-related psychosis receiving
atypical antipsychotic agents (e.g., olanzapine,
aripiprazole, quetiapine, risperidone) compared with
those receiving placebo (2.6%).1, 101
• Most fatalities resulted from cardiac-related events (e.g.,
heart failure, sudden death) or infections (mostly
pneumonia.)1, 101
• Atypical antipsychotics are not approved for the
treatment of dementia-related psychosis.1, 101 (See
Increased Mortality in Geriatric Patients with Dementia-
related Psychosis under Cautions.)
Uses
Pending revision, the material in this section should be

considered in light of more recently available information in
the MEDWATCH notification at the beginning of this
monograph.
Schizophrenia
Symptomatic management of schizophrenia.1
IM for management of acute agitation in patients with

schizophrenia for whom treatment with olanzapine is
appropriate and who require an IM antipsychotic agent for
rapid control of behaviors that interfere with diagnosis and
care.1, 98, 102
Bipolar Disorder
Short-term management (alone or in combination with

lithium or divalproex sodium [e.g., valproate sodium,
valproic acid]) of acute mixed or manic episodes and
maintenance of treatment response in patients with bipolar I
disorder.1, 36, 37
Management (in fixed-combination with fluoxetine) of acute

depressive episodes in patients with bipolar depression
(bipolar disorder, depressed).c
IM for management of acute agitation in patients with

bipolar I disorder for whom treatment with olanzapine is
appropriate and who require an IM antipsychotic agent for
rapid control of behaviors that interfere with diagnosis and
care.1, 99
Administration
Administer orally or by deep IM injection.1 (See Possible

Prescribing and Dispensing Errors under Cautions.)
Oral Administration
Administer orally as conventional tablets, orally
disintegrating tablets, or capsules (in fixed combination with
fluoxetine) once daily without regard to meals.1, c
Administer fixed-combination olanzapine and fluoxetine
capsules in the evening.c
Just prior to administration, gently remove orally

disintegrating tablet from blister packet; do not push tablet
through foil.1 With dry hands, peel open blister package,
place tablet on tongue to dissolve, and swallow with or
without liquid.1
IM Administration
Administer by IM injection slowly and deeply into the muscle
mass.1 Do not administer IV or sub-Q.1
Reconstitution
Reconstitute by adding 2.1 mL of sterile water for injection
to vial containing 10 mg of olanzapine to provide a solution
containing approximately 5 mg/mL.1
Following reconstitution, use immediately (within 1 hour).1

Discard any unused portion.1
Dosage

monograph.
Adults
Schizophrenia
Oral: Initially, 5-10 mg, usually as a single daily dose.1, 20, 26
Within several days, may increase by 5 mg daily, to a target
dosage of 10 mg daily.1, 20
Make subsequent dosage adjustments at intervals of not
less than 7 days, usually in increments or decrements of 5
mg once daily.1, 20
Increasing dosage beyond 10 mg daily usually does not
result in greater efficacy; such increases generally should
occur only after assessment of the patient's clinical status.1
Optimum duration of therapy currently is not known, but
maintenance therapy with antipsychotic agents is well
established.1, 23, 25 In responsive patients, continue as long
as clinically necessary and tolerated, but at lowest possible
effective dosage; reassess need for continued therapy
periodically.1, 20
Bipolar Disorder
>Acute Mania: Monotherapy
Oral: Initially, 10-15 mg once daily.1 Make dosage
adjustments in increments or decrements of 5 mg daily, at
intervals of not less than 24 hours.1
Effective dosage in clinical studies generally ranged from 5-
20 mg daily.1, 36, 37
If elect to use olanzapine for extended periods, periodically
reevaluate the long-term usefulness for the individual
patient.1
>Acute Mania: Combination Therapy

Oral: Initially, 10 mg once daily when administered with
lithium or divalproex sodium.1
Effective dosage of olanzapine in clinical studies generally
ranged from 5-20 mg daily.1
No dosage adjustment for lithium or divalproex sodium is
required when used in combination with olanzapine.1
>Acute Depression: Combination Therapy

monograph.
Oral: Initially, 6 mg in fixed combination with 25 mg of

fluoxetine (Symbyax® 6/25) once daily in the evening.c
Increase dosage according to patient response and
tolerance as indicated.c
In clinical trials, antidepressive efficacy was demonstrated
at olanzapine dosages ranging from 6-12 mg daily and
fluoxetine dosages ranging from 25-50 mg daily.c
If elect to use combined olanzapine and fluoxetine for
extended periods, periodically reevaluate the long-term
risks and benefits for the individual patient.c
>Acute Agitation in Schizophrenia and Bipolar Mania

IM: Initially, 10 mg.1 Consider lower doses (2.5, 5, or 7.5 mg)
when clinically warranted.1
In clinical trials, efficacy of IM olanzapine for controlling
agitation in patients with schizophrenia or bipolar mania
was demonstrated in a dosage range of 2.5-10 mg.1, 98, 99,
102
If agitation persists, may administer subsequent single
doses of up to 10 mg.1 However, efficacy of repeated doses
was not systematically evaluated in controlled trials.1
Assess patients for orthostatic hypotension prior to
administration of any subsequent IM doses.1 (See
Cardiovascular Effects under Cautions.)
Oral therapy should replace IM therapy as soon as possible.1
Prescribing Limits
Adults
Schizophrenia
Oral: Safety of dosages >20 mg daily not established.1, 20
Bipolar Disorder
Oral: Safety of dosages >20 mg daily not established.1
Dosages >18 mg of olanzapine and 75 mg of fluoxetine in
fixed-combination for acute depressive episodes not
evaluated in clinical studies.c
Acute Agitation in Schizophrenia and Bipolar Mania

>IM
Safety of dosages >30 mg daily or of 10-mg IM doses given
more frequently than 2 hours after the initial dose and 4
hours after the second dose not established.1
Special Populations

monograph.
Initially, 5 mg orally daily or 2.5 mg IM in debilitated

patients, in those predisposed to hypotension, in those who
may be particularly sensitive to the effects of olanzapine, or
in those who might metabolize olanzapine slowly (e.g.,
nonsmoking women ≥65 years of age); when indicated,
adjust dosage with caution.1
In fixed combination with fluoxetine for acute depressive

episodes in bipolar disorder, an oral dosage of 6 mg of
olanzapine and 25 mg of fluoxetine (Symbyax® 6/25) is
recommended for initial and maintenance therapy in
patients predisposed to hypotension, in those with hepatic
impairment, or those who might metabolize the drugs(s)
slowly (e.g., female gender, geriatric age, nonsmoking
status); when indicated, adjust dosage with caution.c
Geriatric Patients
Careful dosage titration of oral olanzapine recommended in
patients >65 years of age; initiate therapy at low end of
dosage range.1, 26
Consider a lower initial IM dose of 5 mg.1
Cautions
Contraindications
• Known hypersensitivity to olanzapine or any ingredient in

the formulation.1
Warnings
monograph.
Increased Mortality in Geriatric Patients with Dementia-

related Psychosis
Possible increased risk of death with use of atypical
antipsychotics in geriatric patients with dementia-related
psychosis.1, 101 (See Boxed Warning and see Geriatric Use
under Cautions.)
Atypical antipsychotics are not approved for the treatment

of dementia-related psychosis.1, 101
Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with
ketoacidosis, hyperosmolar coma, or death, reported in
patients receiving atypical antipsychotic agents, including
olanzapine.1, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 70,
71, 72, 73, 77, 95 Closely monitor patients with preexisting
diabetes mellitus for worsening of glucose control and

perform fasting glucose tests at baseline and periodically for
patients with risk factors for diabetes (e.g., obesity, family
history of diabetes).1, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 If
manifestations of hyperglycemia occur, test for diabetes
mellitus.1, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55
Cerebrovascular Effects
Adverse cerebrovascular effects (e.g., stroke, transient
ischemic attack), sometimes fatal, reported in geriatric
patients with dementia-related psychosis receiving
olanzapine.1 (See Geriatric Use under Cautions.)
Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal
syndrome requiring immediate discontinuance of the drug
and intensive symptomatic treatment, has been reported.1
Tardive Dyskinesia
Tardive dyskinesia, a syndrome of potenially irreversible,
involuntary dyskinetic movements, may occur in patients
receiving antipsychotic agents.1 Consider discontinuance of
olanzapine if signs and symptoms of tardive dyskinesia
occur.1
Allergic reactions (e.g., anaphylactoid reaction, angioedema,
pruritus, urticaria, rash) reported.1, c Discontinue olanzapine
if alternative etiology of rash or other allergic manifestation
cannot be identified.c
General Precautions
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescription; similarities in spelling,
dosage intervals, and tablet strengths of Zyprexa® and
Zyrtec® (cetirizine hydrochloride, an antihistamine) may
result in errors.97
Cardiovascular Effects
Orthostatic hypotension reported with oral olanzapine,
particularly during initial dosage titration period.1
Hypotension, bradycardia with or without hypotension,

tachycardia, and syncope reported with IM olanzapine.1
Use oral or IM olanzapine with caution in patients with

known cardiovascular or cerebrovascular disease and/or
conditions that would predispose patients to hypotension
(e.g., dehydration, hypovolemia, concomitant
antihypertensive therapy).1
Risk of clinically important orthostatic hypotension
associated with use of maximum recommended IM dosages
of olanzapine (i.e., three 10-mg IM doses given 2-4 hours
apart).1 If drowsiness or dizziness occurs, patients should
remain recumbent until examination indicates that they are
not experiencing orthostatic hypotension, bradycardia,
and/or hypoventilation.1 Assess patients for orthostatic
hypotension prior to administration of any subsequent IM
doses.1 Administration of additional IM doses to patients
with clinically significant postural change in BP is not
recommended.1
Use oral or IM olanzapine with caution in patients receiving

other drugs that can induce hypotension, bradycardia, or
respiratory and CNS depression (e.g., benzodiazepines).1
(See Specific Drugs under Interactions.)
Nervous System Effects

Possible risk of seizures; use with caution in patients with a
history of seizures or conditions known to lower the seizure
threshold (e.g., dementia of the Alzheimer's type, geriatric
patients).1
Disruption of the body's ability to reduce core body

temperature possible; use caution in patients exposed to
conditions that may contribute to an elevation in core body
temperature (e.g., dehydration, extreme heat, strenuous
exercise, concomitant use of anticholinergic agents).1
Somnolence reported.1 Potential impairment of judgment,

thinking, or motor skills.1
Endocrine Effects
Elevated prolactin concentrations reported; modest
elevation persists during chronic administration.1
Metabolic Effects
Weight gain possible; patients with low body mass index
(BMI) may be more susceptible than normal or overweight
patients.1
Hepatic Effects
Clinically important ALT increases (≥3 times the ULN)
possible; use with caution in patients with manifestations of
hepatic impairment, those with preexisting conditions
associated with limited hepatic functional reserve, and
those treated with potentially hepatotoxic drugs.1
Periodically assess transaminases in patients with hepatic
disease.1
GI Effects
Esophageal dysmotility and aspiration possible;1 use with
caution in patients at risk for aspiration pneumonia (e.g.,
geriatric patients, those with advanced Alzheimer's
dementia).1
Suicide
monograph.
Attendant risk with psychotic illnesses; closely supervise

high-risk patients.1 Prescribe in the smallest quantity
consistent with good patient management to reduce the risk
of overdosage.1
Anticholinergic Effects
Constipation, dry mouth, and tachycardia may occur,
possibly related to the drug's anticholinergic effects; use
with caution in patients with clinically important prostatic
hypertrophy, angle-closure glaucoma, or history of paralytic
ileus.1
Phenylketonuria
Each 5, 10, 15, or 20 mg Zyprexa® Zydis® orally
disintegrating tablet contains aspartame (e.g.,
Nutrasweet®), which is metabolized in the GI tract to
provide 0.34, 0.45, 0.67, or 0.9 mg of phenylalanine per
tablet, respectively.1, 30, 31, 32, 33, 34
Combination Therapy with Lithium, Divalproex Sodium, or

Fluoxetine
Consider cautions, precautions, and contraindications
associated with lithium, divalproex sodium, or fluoxetine
when olanzapine is used in conjunction with these drugs.1, c
Pregnancy
Category C.1

monograph.
Lactation
Distributed into milk in humans.1 Women receiving
olanzapine should not breast-feed.1
Pediatric Use
monograph.
Safety and efficacy not established in children <18 years of

age.1, 35
Geriatric Use
Safety in patients ≥65 years of age with schizophrenia does
not appear to differ from that in younger adults with
schizophrenia; however, tolerability profile of olanzapine in
geriatric patients with dementia-related psychosis may
differ from that in younger patients with schizophrenia.1
Lower initial dosages and slower titration during the initial

dosing period may be advisable in some geriatric patients.
(See Special Populations under Dosage and
Administration.)1
Possible increased risk of death in geriatric patients with

dementia-related psychosis.1, 101 Substantial (1.6- to 1.7-
fold) increase in mortality rate reported in geriatric patients
with dementia who received atypical antipsychotic agents
(e.g., olanzapine, aripiprazole, quetiapine, risperidone)
fortreatment of behavioral disorders; most fatalities resulted
from cardiac-related events (e.g., heart failure, sudden
death) or infections (mostly pneumonia).1, 101 In addition,
adverse cerebrovascular effects, sometimes fatal, reported
in geriatric patients with dementia-related psychosis
receiving olanzapine.1 (See Cerebrovascular Effects under
Cautions.)
Atypical antipsychotics are not approved for the treatment

of dementia-related psychosis.1, 101 (See Boxed Warning.)

With oral therapy, somnolence, dry mouth, dizziness,
asthenia, constipation, dyspepsia, personality disorder (i.e.,
non-aggressive objectionable behavior), weight gain,
increased appetite, tremor, postural hypotension, akathisia.1
With parenteral therapy, somnolence.1
Interactions

monograph.
Metabolized by CYP1A2 and CYP2D6; CYP2D6 appears to be

a minor pathway. Also metabolized by direct
glucuronidation.1 Appears to have little potential to inhibit
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP1A2 or glucuronyl transferase enzyme inhibitors and

inducers; pharmacokinetic interaction (altered olanzapine
metabolism).1
Specific Drugs
Drug Interaction Comment

Potential additive CNS
effects; concomitant use
with alcohol potentiates Advise patients
Alcohol 1
orthostatic hypotension to avoid alcohol
observed with
olanzapine1
Antacids Pharmacokinetic
(aluminum- and interaction unlikely1
magnesium-
containing)
Pharmacokinetic
Biperiden
interaction unlikely1
Potential additive CNS
and cardiovascular Concurrent use
effects (excessive of IM olanzapine
sedation and with parenteral
cardiorespiratory benzodiazepines
depression) during not
Benzodiazepines concurrent parenteral recommended1
(parenteral) administration1 If administered
(e.g., Increased somnolence concurrently,
lorazepam) during concurrent carefully
parenteral evaluate for
administration of excessive
olanzapine and sedation and
lorazepam; no effect on cardiorespiratory
pharmacokinetics of depression1
either drug1
Charcoal may be
Decreased peak plasma useful in
Charcoal concentrations and AUC treatment for
of oral olanzapine1 olanzapine
overdose1
Pharmacokinetic
Cimetidine
Use with
CNS agents Additive CNS effects1
caution1
Pharmacokinetic
Desipramine
Diazepam (oral) Potential additive CNS Use with
and orthostatic caution1
hypotension effects; no
effect on diazepam
pharmacokinetics1
Dopamine Potential antagonistic
agonists effects1
Not considered
Small increase in
clinically
maximum plasma
important;c
olanzapine
Fluoxetine dosage
concentrations and
modification not
decrease in olanzapine
routinely
clearance1
recommended1
Decreased clearance
Consider lower
and increased maximum
Fluvoxamine olanzapine
plasma concentrations
dosage 1
of olanzapine 1
Hypotensive Additive hypotensive Use with
agents effects1 caution1
Pharmacokinetic
Imipramine
Potential antagonistic
Levodopa
effects1
No dosage
adjustment of
Pharmacokinetic lithium
Lithium 1
interaction unlikely necessary during
concomitant
administration1
Omeprazole Possible increase in Increase in
olanzapine clearance1 olanzapine
dosage may
need to be
considered1
Increase in
olanzapine
Possible increase in
Rifampin dosage may
olanzapine clearance1 need to be
considered1
Pharmacokinetic
Theophylline
No dosage
adjustment of
Clinically important
valproate
Valproate pharmacokinetic
necessary during
interaction unlikely1 concomitant
administration1
Pharmacokinetic
Warfarin
Pharmacokinetics
Absorption
Bioavailability
Well absorbed after oral administration, with peak plasma
concentrations attained in approximately 6 hours.1 Rapidly
absorbed following IM administration, with peak plasma
concentrations generally attained within 15-45 minutes.1
About 40% of oral dose is metabolized before reaching

systemic circulation.1
Conventional and orally disintegrating olanzapine tablets

are bioequivalent.1
IM administration of a 5-mg dose results in a maximum
plasma olanzapine concentration that is an average of
about fivefold higher than that resulting from a 5-mg oral
dose.1 AUCs are similar following oral and IM
administration.1
Food
Food does not affect rate or extent of oral absorption.1
Distribution
Extent
Extensively distributed throughout the body.1
Olanzapine crosses the placenta.b Distributed into milk in

humans; mean infant dose at steady state estimated to be
about 1.8% of maternal dose.1
Plasma Protein Binding

93% (mainly albumin and α1-acid glycoprotein).1
Elimination
Metabolism
Metabolized to inactive metabolites, principally via direct
glucuronidation and oxidation by CYP1A2 and the flavin-
containing monooxygenase system, with minor contribution
of CYP2D6.1, a
Elimination Route
Excreted in urine (57%) and feces (30%); 7% of dose is
excreted in urine as unchanged drug.1
Half-life
21-54 hours.1
Special Populations
In patients with severe renal impairment, pharmacokinetics
were similar to healthy individuals.1
Although hepatic impairment may be expected to reduce

clearance, a study in patients with clinically important
cirrhosis (Child-Pugh class A and B) revealed little effect on
the pharmacokinetics of olanzapine.1
In geriatric patients, the mean elimination half-life was

about 1.5 times that of younger patients.1
In women, clearance of olanzapine is approximately 30%

lower than in men; there were no apparent differences
between men and women in efficacy or adverse effects.1
In smokers, olanzapine clearance is about 40% higher than

in nonsmokers, although dosage adjustment is not
recommended.1
Combined effects of age, smoking and gender may

contribute to substantial pharmacokinetic differences in
populations.1
Stability
Storage
Oral
Tablets and Orally Disintegrating Tablets
20-25°C (may be exposed to 15-30°C).1 Protect from light
and moisture.1
Fixed-combination (with Fluoxetine) Capsules
Tight containers at 25°C (may be exposed to 15-30°C).c
Protect from moisture.c
Parenteral
Powder for Injection
20-25°C (may be exposed to 15-30°C).1 Protect from light
and avoid freezing.1
The reconstituted solution may be stored for up to 1 hour at

20-25°C, if necessary; after 1 hour, discard any unused
portion.1
Compatibility
For information on systemic interactions resulting from

concomitant use, see Interactions.
Parenteral
Drug Compatibility
>Admixture Compatibility1
Incompatible
Diazepam
Haloperidol
Actions
• Exact mechanism of antipsychotic action has not been

fully elucidated; may involve antagonism at serotonin type
2 (5-hydroxytryptamine [5-HT2A, 5-HT2C]), type 3 (5-
HT3),16 type 6 (5-HT6),4, 18, 19, 20, 21 and dopamine
receptors.1, 4, 6, 7, 16, 17, 18, 19, 20, 21, 22
• Antagonism at other receptors (e.g., α1-adrenergic
receptors, muscarinic receptors, histamine H1 receptors)
may contribute to other therapeutic and adverse effects
(e.g., orthostatic hypotension, anticholinergic effects,
sedative effects) observed with olanzapine.1, 2, 6, 7, 16, 17,
20
• Possesses little or no affinity for β-adrenergic, γ-
aminobutyric acid (GABA), or benzodiazepine receptors.1,
16, 20
Advice to Patients

monograph.
• Risk of excessive weight gain, orthostatic hypotension,

disruption of regulation of body temperature, and
somnolence.1
• Importance of avoiding overheating or dehydration.1
• Importance of informing patients with phenylketonuria
that olanzapine orally disintegrating tablets contain
aspartame.1, 30, 31, 32, 33, 34
• Importance of avoiding driving, operating machinery, or
performing hazardous tasks until the patient gains
experience with drug's effects.1
and OTC drugs and dietary or herbal supplements, as well
as any concomitant illnesses (e.g., diabetes mellitus,
seizures, dementia).1, c
• Importance of avoiding alcohol during olanzapine
therapy.1
plan to become pregnant or plan to breast-feed.1
precautionary information.1, c (See Cautions.)
Preparations

Olanzapine
Dosage
Forms
Tablets, film-
Oral 2.5 mg Zyprexa® Lilly
coated
5 mg Zyprexa® Lilly
7.5 mg Zyprexa® Lilly
Zyprexa®
Tablets, orally Zydis® (with
5 mg aspartame Lilly
disintegrating
and
parabens)
Zyprexa®
Zydis® (with
and
parabens)
Zyprexa®
Zydis® (with
and
parabens)
Zyprexa®
Zydis® (with
and
parabens)
Parenteral For injection 10 mg Zyprexa® Lilly
Intramuscular
Olanzapine Combinations
Dosage
Forms
6 mg with
Fluoxetine
Symbyax®
Oral Capsules Hydrochloride Lilly
(combination)
25 mg (of
fluoxetine)
6 mg with
Fluoxetine
Symbyax®
Hydrochloride Lilly
(combination)
50 mg (of
fluoxetine)
12 mg with
Fluoxetine
Symbyax®
Hydrochloride Lilly
(combination)
25 mg (of
fluoxetine)
12 mg with
Fluoxetine
Symbyax®
Hydrochloride Lilly
(combination)
50 mg (of
fluoxetine)
Comparative Pricing

updated 10/2011. For the most current and up-to-date
pricing information, please visit www.drugstore.com. Actual
costs to patients will vary depending on the use of specific
retail or mail-order locations and health insurance copays.
Symbyax 12-25MG Capsules (LILLY): 30/$719.99 or

90/$2,110.00

90/$1,864.88

90/$1,003.96

90/$1,342.99

90/$1,390.93
ZyPREXA 10MG Tablets (LILLY): 30/$624.01 or 90/$1,788.98
ZyPREXA 2.5MG Tablets (LILLY): 30/$327.00 or 90/$950.00
ZyPREXA 20MG Tablets (LILLY): 30/$1,285.99 or

90/$3,791.06
ZyPREXA 7.5MG Tablets (LILLY): 30/$476.98 or 90/$1,397.97
ZyPREXA Zydis 10MG Dispersible Tablets (LILLY): 30/$659.97

or 90/$1,927.89
ZyPREXA Zydis 5MG Dispersible Tablets (LILLY): 30/$469.99

or 90/$1,319.97
Use is not currently included in the labeling approved by
the US Food and Drug Administration.
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96. Eli Lilly and Company. Zyprexa® (olanzapine) tablets

and Zyprexa® Zydis® (olanzapine) orally disintegrating
tablets prescribing information. Indianapolis, IN: 2004
Sep 22.
97. Eisenberg P. Dear healthcare provider letter regarding

dispensing errors involving Zyprexa® (olanzapine).
Indianapolis, IN: Eli Lilly and Company; 2005 Jan.
98. Jones B, Taylor CC, Meehan K. The efficacy of a rapid-

acting intramuscular formulation of olanzapine for
positive symptoms. J Clin Psychiatry. 2001; 62(Suppl.
2):22-4. [IDIS 459557] [PubMed 11232747]
99. Meehan K, Zhang F, David S et al. A double-blind,

randomized comparison of the efficacy and safety of
intramuscular injections of olanzapine, lorazepam, or
placebo in treating acutely agitated patients diagnosed
with bipolar mania. J Clin Psychopharmacol. 2001;
21:389-97. [IDIS 466929] [PubMed 11476123]
100. Eli Lilly and Company. Landmark, placebo-controlled
trial suggests olanzapine may delay and reduce rates of
manic and depressive relapse in patients with bipolar
disorder. May 19, 2003. Press release.
101. Food and Drug Administration. Public health advisory:

deaths with antipsychotics in elderly patients with
behavioral disturbances. Rockville, MD; 2005 Apr 11.
From the FDA website. [Web]
102. Wright P, Birkett M, David SR et al. Double-blind,

placebo-controlled comparison of intramuscular
olanzapine and intramuscular haloperidol in the
treatment of acute agitation in schizophrenia. Am J
11431240]
a. Callaghan JT, Bergstrom RF, Ptak LR et al. Olanzapine.

Pharmacokinetic and pharmacodynamic profile. Clin
Pharmacokinet. 1999; 37:177-93. [PubMed 10511917]
b. Schenker S, Yang Y, Mattiuz E et al. Olanzapine transfer

by human placenta. Clin Exp Pharmacol Physiol. 1999;
26:691-7. [PubMed 10499158]
c. Eli Lilly & Co. Symbyax® (olanzapine and fluoxetine HCl

capsules) prescribing information. Indianapolis, IN; 2003
Dec 30.
Pentosan Polysulfate (Systemic)
Semisynthetic low molecular weight heparinoid; a

uroprotective agent resembling glycosaminoglycans.1, 4, 5, 6,
8
Class: 92:56 Protective Agents; gu900 (VA primary)
Brands: Elmiron®
Generic Name: Pentosan Polysulfate Sodium

CAS Number: 140207-93-8
Chemical Name: 4-O-Methyl-α-D-glucurono)-(1 2)-(1 4)-β-
D-xylopyran hydrogen sulfate sodium salt
Molecular Formula: [C5H6Na2O10S2]n (n = 6 to 12)
Investigational Drug Number: SP54, PZ68
Uses
Interstitial Cystitis
Symptomatic relief of bladder pain or discomfort associated

with interstitial cystitis;1, 2, 6, 7 designated an orphan drug
by FDA for this use.3
Administration
Administer orally.1, 2, 6
Oral Administration
Administer with water ≥1 hour before or 2 hours after
meals.1, 9, 13
Dosage
Available as pentosan polysulfate sodium; dosage expressed

in terms of salt.1
Adults
Interstitial Cystitis
Oral: 100 mg 3 times daily1, 2, 6, 7 for 3 months.1, 7 If after 3
months no improvement or no dose-limiting adverse effects
occur, may continue therapy for another 3 months.1
Manufacturer states that if no improvement of pain is
observed by 6 months, the optimal duration and risks of
continued therapy unknown.1 However, data from a long-
term clinical study indicate overall continued symptomatic
improvement (e.g., pain, urgency, urinary frequency,
nocturia) during 1-2 years of therapy.7
Some clinicians recommend a dosage of 200 mg twice daily
; it appears to be effective and promotes greater patient
compliance.6
Special Populations
Hepatic Impairment
No specific dosage adjustments recommended.1
Renal Impairment
Geriatric Patients
Cautions
Contraindications
• Known hypersensitivity to pentosan polysulfate,

structurally related compounds, or any ingredient in
formulation.1
General Precautions
Hematologic Effects
Pentosan polysulfate is weak anticoagulant.1, 11
Rectal hemorrhage and bleeding complications of

ecchymosis, epistaxis, and gum hemorrhage reported.1
Evaluate patients at increased risk for hemorrhage including

those undergoing invasive procedures, with signs and
symptoms of coagulopathy, or receiving concomitant drugs
that affect hemostasis.1 (See Specific Drugs under
Interactions.)
Delayed immunoallergic thrombocytopenia similar to

heparin-induced thrombocytopenia with symptoms of
thrombosis and hemorrhage reported with sub-Q, IM, or
sublingual administration of a different formulation of
pentosan polysulfate.1, 13
Use with caution in patients with history of heparin-induced

thrombocytopenia.1 Carefully evaluate patients with
thrombocytopenia prior to initiation of therapy.1
Thrombocytopenia and elevations in PT and partial

thromboplastin time (PTT) reported in patients with elevated
liver function test results.1, 10 Such effects not observed in
healthy men receiving ≤1.2 g of pentosan polysulfate
sodium daily (a dosage greater than the recommended 100
mg 3 times daily) for 8 days.1
Concomitant Illnesses
Carefully evaluate patients with diseases such as
aneurysms, hemophilia, GI ulcerations, polyps, or diverticula
prior to initiation of therapy.1
Hepatic Effects
Mild and usually transient elevations (<2.5 times ULN) of
serum aminotransferases, alkaline phosphatase, γ-glutamyl
transpeptidase, and LDH concentrations reported in about
1.2% of patients.1 Such abnormalities usually occur 3-12
months after initiation of therapy and generally not
associated with jaundice or other clinical signs and
symptoms.1 These elevations may remain unchanged or
rarely progress with continued use.1
Alopecia
Alopecia, primarily alopecia areata (limited to single area on
scalp), reported; may occur within first 4 weeks of initiation
of therapy.1
Pregnancy
Category B.1
Lactation
Not known whether pentosan polysulfate is distributed into
milk.1 Use with caution in nursing women.1
Pediatric Use
Safety and efficacy in pediatric patients <16 years of age
not established.1
Hepatic Impairment
Use with caution.1 (See Hepatic Effects under Cautions.)
Rectal hemorrhage,1 alopecia,1, 7, 9 diarrhea,1, 7, 9 nausea,1,

2, 7, 9 headache,5, 7, 9 blood in stool,9 rash,1, 5, 7, 9
dyspepsia,1, 7, 9 abdominal pain,1, 7 abnormal liver function

tests,1, 7, 9 dizziness,1, 7, 9 bruising.9
Interactions
Drugs That Affect Hemostasis
Potential pharmacodynamic effect (increased risk of

hemorrhage) with concurrent use of drugs that affect
hemostasis.1, 12
Monitor for hemorrhage during concurrent administration.1,

5
Specific Drugs

Increased risk of Monitor for
Anticoagulants,
oral bleeding1 hemorrhage1,
5
Increased risk of Monitor for

Heparin
bleeding1 hemorrhage1
Increased risk of bleeding
with aspirin (high Monitor for
NSAIAs
dosages) and other hemorrhage1
NSAIAs1
Thrombolytic Increased risk of Monitor for
agents (e.g., bleeding1 hemorrhage1
alteplase,
streptokinase)
Pharmacokinetics
Absorption
Bioavailability
Following oral administration, approximately 3% absorbed.1,
13
Onset
Early or mild interstitial cystitis: Pain relief occurs within 6-8
weeks.6
Moderate to severe interstitial cystitis: In majority of

patients, pain relief occurs in approximately 6 months.6, 7
Duration
Pain relief may persist for >29 months (in some patients).7
Food
Effect of food on absorption of pentosan polysulfate
unknown.1, 13 In clinical trials, pentosan polysulfate was
administered with water 1 hour before or 2 hours after
meals.1
Special Populations
Not known whether bioavailability of parent drug or active
metabolites is increased in patients with hepatic impairment
or splenic disorders.1
Distribution
Extent
In animals, distributed into uroepithelium of GU tract, with
lower amounts distributed into liver, spleen, lung, skin,
periosteum, and bone marrow.1 Small amounts distributed
into RBCs in animals.1
Not known whether pentosan polysulfate is distributed into

milk.1
Elimination
Metabolism
Following IV administration, 68% of a dose undergoes partial
desulfation in liver and spleen; partial depolymerization in
kidneys reported.1, 4
Elimination Route
Following oral administration, excreted in urine (6.3%; range
about 4.8-8%), principally as metabolites, and in feces
(84.1%; range about 68-92%) as unabsorbed drug.1, 4
Half-life
Following oral administration, 4.8 or 26.5 hours for
unchanged drug or unchanged drug and metabolites,
respectively.1, 4
Stability
Storage
Oral
Capsules
15-30°C.1
Actions
• Semisynthetic low molecular weight heparinoid is a

uroprotective agent structurally similar to naturally
occurring glycosaminoglycans.1, 4, 5, 6, 8
• The main cause of interstitial cystitis appears to be a
defective mucous glycosaminoglycans layer of the bladder
that may cause increased bladder epithelial permeability.6,
7, 8 Such permeability allows movement of irritating urine
solutes into interstitium and causes tissue injury.8

• Although the mechanism of action of pentosan polysulfate
sodium in the management of interstitial cystitis has not
been fully elucidated, the drug appears to replenish the
defective mucous (glycosaminoglycans) layer and restore
bladder integrity (by adhering to surface of bladder); acts
as a buffer to control cell permeability and prevent
irritating solutes from reaching epithelial cells.1, 2, 6
• Weak anticoagulant following oral administration
compared with heparin (1/15 activity of heparin); may
increase bleeding times.1, 9, 11
• Given parenterally, inhibits generation of factor Xa.11
• In ex vivo study, inhibits thrombin-induced platelet
aggregation.1
Advice to Patients
• Importance of taking pentosan as prescribed, including

not altering frequency of use.1, 9
• Importance of taking the drug with water ≥1 hour before
or 2 hours after meals.1, 9
• Importance of contacting emergency room and/or poison
control center immediately if recommended dosage is
exceeded.9
• Importance of informing patients that the drug is intended
for their use only and for the specific condition for which it
was prescribed.1 Do not give this drug to others.1, 9
• Importance of informing patients of risk of bleeding.1, 9
• Importance of patients undergoing surgery to contact their
clinician about discontinuance of therapy.9
• Importance of women informing their clinician if they are
or plan to become pregnant or plan to breast-feed.1, 9
(e.g., warfarin, heparin) and OTC drugs (e.g., some
NSAIAs), as well as any concomitant illnesses (e.g., liver
disease, conditions requiring surgery).9
precautionary information.1 (See Cautions.)
Preparations

Pentosan Polysulfate Sodium
Dosage
Forms
Elmiron® (with
Oral Capsules 100 mg Ortho-McNeil
propylene glycol)
Comparative Pricing

updated 03/2011. For the most current and up-to-date
pricing information, please visit www.drugstore.com. Actual
costs to patients will vary depending on the use of specific
retail or mail-order locations and health insurance copays.
Elmiron 100MG Capsules (JANSSEN): 90/$405.99 or

270/$1186.03

References
1. Ortho-McNeil. Elmiron® (pentosan polysulfate sodium)

prescribing information. Raritan, NJ; 2006 Sep.
2. Parsons CL, Benson G, Childs SJ et al. A quantitatively

controlled method to study prospectively interstitial
cystitis and demonstrate the efficacy of
pentosanpolysulfate. J Urol. 1993; 150:845-8. [PubMed
7688432]
3. Food and Drug Administration. List of orphan
designations and approvals. Rockville, MD; 2007 Oct 4.
From FDA website [Web]. Accessed 2008 Jan 31.
4. Simon M, McClanahan RH, Shah JF et al. Metabolism of

[3H]pentosan polysulfate sodium (PPS) in healthy human
volunteers. Xenobiotica. 2005; 35:775-84. [PubMed
16278190]
5. Modi NB, Kell S, Simon M et al. Pharmacokinetics and

pharmacodynamics of warfarin when coadministered
with pentosan polysulfate sodium. J Clin Pharmacol.
2005; 45:919-26. [PubMed 16027402]
6. Dell JR, Butrick CW. Multimodal therapy for painful

bladder syndrome/interstitial cystitis. J Reprod Med.
2006; 51:253-60. [PubMed 16676920]
7. Hanno PM. Analysis of long-term Elmiron therapy for

interstitial cystitis. Urology. 1997; 49 (Suppl 5A):93-9.
[PubMed 9146008]
8. Parsons CL. The role of the urinary epithelium in the

pathogenesis of interstitial cystitis/prostatitis/urethritis.
Urology. 2007; 69 (Suppl 4A):9-16. [PubMed 17462486]
9. Ortho-McNeill. Elmiron® (pentosan polysulfate sodium)

patient information. Raritan, NJ; 2006 Sep.
10. Rodgers GM. Acquired coagulation disorders. In: Greer

JP, Foerster J, Lukens JN et al, eds. Wintrobe's clinical
hematology. 11th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2004:1673-4.
11. Fischer AM, Dautzenberg MD, Aurousseau MH et al.
Comparison between the effect of pentosan polysulfate
heparin and antithrombin III injections in antithrombin III
deficient patients. Thromb Res. 1985; 37:295-307.
[PubMed 2579452]
12. Sanofi-Aventis. Lovenox® (enoxaparin sodium)

injection prescribing information. Bridgewater, NJ; 2007
May.
13. Ortho-McNeil Janssen, Titusville, NJ: Personal

communication.
Ranibizumab (EENT)
Recombinant humanized immunoglobulin G1 kappa (IgG1

kappa) monoclonal antibody fragment; a vascular
endothelial growth factor A (VEGF-A) antagonist.1, 3, 4, 5, 6
Class: 52:92 EENT Drugs, Miscellaneous; op900 (VA

primary)
Brands: Lucentis®
Generic Name: Ranibizumab

CAS Number: 347396-82-1
Chemical Name: Disulfide with human-mouse monoclonal
rhuFAB V2 light chain anti-(human vascular endothelial
growth factor) Fab fragment (human-mouse monoclonal
rhuFAB V2 γ1-chain) immunoglobulin G1
Molecular Formula: C2158H3282N562O681 S12
Uses
Neovascular Age-related Macular Degeneration
Treatment of neovascular (wet) age-related macular

degeneration.1, 4
Administration
Ophthalmic Administration
Administer by intravitreal injection only into the affected
eye(s).1
Prior to intravitreal administration, withdraw entire contents
(0.2 mL) of ranibizumab injection through a sterile 5-micron,
19-gauge filter needle (provided by manufacturer) into a 1-
mL tuberculin syringe using aseptic technique.1, 4 Next,
replace filter needle with a sterile 30-gauge, 1/2-inch needle
(provided by manufacturer) for intravitreal injection.1 To
obtain appropriate dose (0.5 mg), expel contents in
tuberculin syringe until plunger tip is aligned with the line
that marks 0.05 mL on the syringe.1
Inject under controlled aseptic conditions (including use of

sterile gloves, sterile drape, a sterile eyelid speculum [or
equivalent]) following adequate anesthesia and
administration of a broad-spectrum anti-infective agent.1
Monitor patients for elevation of IOP and for development of

endophthalmitis following intravitreal injection.1 Monitoring
for increased IOP may include evaluation of optic nerve
head perfusion immediately after injection, tonometry
within 30 minutes following injection, and biomicroscopy
between 2-7 days following injection.1
Each vial should be used only for treatment of a single eye.1

If contralateral eye requires treatment, use a new vial;
change sterile field, syringe, gloves, drape, eyelid speculum,
and filter and injection needles before administering to the
other eye.1
Dosage
Adults
Neovascular Age-related Macular Degeneration
>Ophthalmic Administration
Intravitreal injection: 0.5 mg (0.05 mL) into the affected
eye(s) once every month (approximately 28 days).1
After first 4 injections, may reduce dosage to one injection
every 3 months if monthly injections are not feasible;
however, because this reduced dosage is less effective in
maintaining visual acuity, evaluate patients regularly.1
Safety and efficacy beyond 2 years of therapy not
established.1
Special Populations
Renal and Hepatic Impairment

Dosage adjustment not expected to be necessary.1 (See
Hepatic Impairment and also Renal Impairment under
Cautions.)
Geriatric Patients
No dosage adjustment required.1
Cautions
Contraindications
• Ocular or periocular infections.1

• Known hypersensitivity (e.g., severe intraocular
inflammation) to ranibizumab or any ingredient in the
formulation.1
Warnings
Endophthalmitis and Other Serious Ocular Effects
Intravitreal injections, including those with ranibizumab,
associated with endophthalmitis and retinal detachments.1,
4, 5, 6 Always use proper aseptic injection technique.1, 4 (See
Ophthalmic Administration under Dosage and

Administration.) Monitor patients closely for signs of
endophthalmitis (e.g., redness, sensitivity to light, pain,
changes in vision) during the week following injection to
permit early treatment.1, 4 (See Advice to Patients.)
Traumatic cataract reported rarely.1, 4, 5
Increased IOP
Increased IOP observed within 60 minutes of intravitreal
injection.1, 4, 6 Monitor IOP and perfusion of optic nerve head
and manage appropriately.1, 4
Thromboembolic Events
Arterial thromboembolic events reported.1, 5 Potential risk of
arterial thromboembolic events following intravitreal
injection of VEGF antagonists.1
Stroke
According to interim safety analysis of an ongoing study
(SAILOR study), incidence of stroke appeared to be higher
with 0.5-mg dose than with 0.3-mg dose.7, 8 Patients with
prior history of stroke appeared to be at increased risk for a
subsequent stroke.7
General Precautions
Immunogenicity
Development of low-titer antibodies reported.1 Clinical
relevance unclear, but iritis or vitritis noted in some patients
with the highest levels of immunoreactivity.1
Pregnancy
Category C.1
Lactation
Not known whether ranibizumab is distributed into milk.1
Caution if used in nursing women.1
Pediatric Use
Safety and efficacy not established.1
Adult Use
Safety and efficacy not established in adults <50 years of
age.4
Geriatric Use
No substantial differences in efficacy or systemic exposure
(after correcting for Clcr) relative to younger adults.1
Hepatic Impairment
Pharmacokinetics not studied; dosage adjustment not
expected to be necessary.1
Renal Impairment
Pharmacokinetics not studied; however, limited data
indicate clearance not substantially affected by renal
impairment.1 Dosage adjustment not expected to be
necessary.1
Conjunctival hemorrhage,1, 4 eye pain,1, 4 vitreous floaters,1,

4 increased IOP,1, 4 intraocular inflammation.1, 4
Interactions
No formal drug interaction studies to date.1

Photodynamic Therapy with Verteporfin
Serious intraocular inflammation reported; most cases

occurred when ranibizumab was administered
approximately 7 days after verteporfin photodynamic
therapy.1
Pharmacokinetics
Absorption
Bioavailability
Following monthly intravitreal injection, peak serum
concentrations attained were substantially below that
necessary to inhibit the biologic activity of VEGF-A by 50%.1
Serum concentrations predicted to be approximately 90,000
times lower than vitreal concentrations.1
Peak serum concentrations predicted to be reached

approximately 1 day after monthly intravitreal
administration of 0.5 mg per eye.1
Elimination
Half-Life
Estimated average vitreous half-life: Approximately 9 days.1
Stability
Storage
Parenteral
Injection
2-8°C.1 Do not freeze; protect from light.1 Store in original
carton until use.1
Actions
• Binds to active forms of human VEGF-A, including cleaved

form (VEGF110), and inhibits their biologic activity.1, 3, 4
• VEGF-A induces neovascularization (angiogenesis) and
increases vascular permeability, which appears to play a
role in the pathogenesis and progression of neovascular
(wet) age-related macular degeneration,1, 3, 4 a leading
cause of blindness in adults >60 years of age in developed
countries.2, 3, 4
• Binding to VEGF-A prevents VEGF-A from binding to VEGF
receptors (i.e., VEGFR-1, VEGFR-2) on the surface of
endothelial cells, reducing endothelial cell proliferation,
angiogenesis, and vascular permeability.1, 4
• Shown to reduce foveal retinal thickening and vascular
permeability associated with age-related macular
degeneration; however, foveal retinal thickness data did
not provide information useful in influencing treatment
decisions, and the area of vascular permeability was not
correlated with visual acuity.1
Advice to Patients
• Risk of developing endophthalmitis.1 Importance of

informing ophthalmologist immediately if change in vision
occurs or if treated eye becomes red, sensitive to light, or
painful.1
• Importance of women informing their clinician if they are
or plan to become pregnant or plan to breast-feed.1
and OTC drugs, as well as any concomitant illnesses (e.g.,
ocular or periocular infections).1
precautionary information. (See Cautions.)
Preparations

Ranibizumab (Recombinant)
Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
10
Injection, Lucentis® (preservative-
mg/mL
for free; available as single-
Ophthalmic (0.5
intravitreal dose vial with filter and
mg/0.05
use only injection needles)
mL)
Genentech
References
1. Genentech, Inc. Lucentis® (ranibizumab) injection

prescribing information. South San Francisco, CA; 2008
Apr.
2. World Health Organization. Magnitude and causes of

visual impairment. Fact Sheet No. 282; 2004 Nov. From
WHO website ([Web]). Accessed 2006 Sep 13.
3. Rosenfeld PJ, Rich RM, and Lalwani GA. Ranibizumab:

Phase III clinical trial results. Ophthalmol Clin N Am.
2006; 19:361-72.
4. Genentech, Inc, South San Francisco, CA: Personal

communication.
5. Brown DM, Kaiser PK, Michels M et al for the ANCHOR

Study Group. Ranibizumab versus verteporfin for
neovascular age-related macular degeneration. N Engl J
Med. 2006; 355:1432-44. [PubMed 17021319]
6. Rosenfeld PJ, Brown DM, Heier JS et al for the MARINA

Study Group. Ranibizumab for neovascular age-related
macular degeneration. N Engl J Med. 2006; 355:1419-31.
[PubMed 17021318]
7. Barron H. Dear healthcare provider letter: important

safety information about Lucentis®. South San Francisco,
CA: Genentech, Inc.; 2007 Jan 24.
8. Food and Drug Administration. Lucentis (ranibizumab

injection) [February 1, 2007]. Medwatch alert. Rockville,
MD; February 2007. From FDA website ([Web]).
(Accessed 2009 Oct 12.)
9. Brown DM, Michels M, Kaiser PK et al. Ranibizumab

versus verteporfin photodynamic therapy for neovascular
age-related macular degeneration: Two-year results of
the ANCHOR study. Ophthalmology. 2009; 116:57-65.
[PubMed 19118696]
Tetrabenazine (Systemic)
A monoamine-depleting agent; a benzoquinolizine

derivative.1
Class: 28:92 Central Nervous System Agents, Miscellaneous
Brands: Xenazine®
Generic Name: Tetrabenazine

CAS Number: 58-46-8
Chemical Name: cisrac-1,3,4,6,7,11b-hexahydro-9,10-
dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one
Molecular Formula: C19H27NO3
Investigational Drug Number: Ro 1-9569
Synonym: Nitoman
Boxed Warning
• Tetrabenazine may increase risk of depression and
suicidal thinking and behavior (suicidality) in patients with
Huntington's disease; balance this risk with clinical need.1
• Closely observe all patients initiating tetrabenazine
therapy for emergence or clinical worsening of
depression, suicidality, or unusual changes in behavior;
involve family members and/or caregivers in this
process.1 (See Risk of Depression and Suicidality under
Cautions.)
• Exercise particular caution when treating patients with a
history of depression or prior suicide attempts or ideation,
which are increased in frequency in Huntington's
disease.1
• Tetrabenazine is contraindicated in patients who are
actively suicidal and in patients with untreated or
inadequately treated depression.1
REMS:
FDA approved a REMS for tetrabenazine to ensure that the

benefits of a drug outweigh the risks. The REMS may apply
to one or more preparations of tetrabenazine and consists
of the following: medication guide and communication
plan. See the FDA REMS page ([Web]) or the ASHP REMS
Resource Center ([Web]).
Uses
Huntington's Chorea
Symptomatic management of chorea associated with

Huntington's disease in adults;1, 2, 17, 18, 19, 20, 24, 25, 38, 40,
46, 48 designated an orphan drug by FDA for this use.3, 4, 18
Patients receiving tetrabenazine may experience slight

worsening of cognition, functional capacity, mood, or
rigidity; not known whether these effects persist, worsen, or
resolve over time.1, 47 Periodically reevaluate long-term
risks and benefits of the drug for the individual patient.1, 47
Other Hyperkinetic Movement Disorders
Has been used with some success for the symptomatic

management of other hyperkinetic movement disorders
(also called hyperkinesias),22, 29, 30, 31, 32, 33, 35, 37, 38, 39, 40,
42, 47, 48, 53 including hemiballismus ,48, 53 senile chorea ,48,
53 Tourette's syndrome (Gilles de la Tourette's syndrome)
(see Pediatric Use under Cautions),30, 35, 38, 42, 53, 54 tic
disorder ,47, 53and tardive dyskinesia (including severe
and/or refractory cases).30, 36, 37, 38, 40, 47, 48, 50, 51, 53, 54
General
• Observe closely for clinical worsening or emergence of

depression, suicidal thoughts or behavior (suicidality), or
unusual changes in behavior.1, 28, 47 (See Boxed Warning
and see also Risk of Depression and Suicidality under
Cautions.)
REMS Program
• FDA has approved a REMS for tetrabenazine.4, 10, 13, 18, 41

• The goals are to reduce the risk of treatment-emergent
depression and suicidality in patients receiving the drug,
to promote informed prescribing and proper dosing of
tetrabenazine, and to minimize the risk of drug
interactions.4, 10, 13, 41
• The program consists of educational materials for health
care professionals, patients, and caregivers, including a
medication guide to be dispensed with every
tetrabenazine prescription;1, 4, 10, 13, 18, 41 tetrabenazine
must be obtained in the US via a specialty pharmacy
network.13, 17 For additional information, contact the
Xenazine® Information Center at 888-882-6013 or consult
the Xenazine® website at [Web].5, 9, 13, 17, 28, 43
Administration
Oral Administration
Administer orally without regard to meals.1, 18, 24, 28
Do not double the next dose if a dose is missed.1

Dosage
If used with a potent CYP2D6 inhibitor, dosage adjustment

required.1 (See Interactions.)
Carefully titrate dosage over several weeks to determine an

individualized dosage for chronic use that reduces chorea
and is well tolerated.1, 28, 48
May discontinue treatment without tapering the dosage.1

Retitrate dosage if therapy is resumed following an
interruption of >5 days or a treatment interruption due to a
change in medical condition or concomitant drug therapy.1
May resume treatment at the previous maintenance dosage
(without titration) following treatment interruption of <5
days.1
Adults
Huntington's Chorea
Oral: Initially, 12.5 mg given once daily in the morning.1
Increase dosage after one week to 12.5 mg twice daily.1
Adjust subsequent dosages in 12.5-mg increments at
weekly intervals.1
Administer daily dosages ≥37.5 mg in 3 divided doses.1 If
daily dosage is ≤50 mg, the maximum recommended single
dose is 25 mg.1
Manufacturer recommends CYP2D6 genotype testing prior
to administering dosages >50 mg daily to determine
whether patient is poor, intermediate, or extensive
metabolizer of CYP2D6 substrates. However, some clinicians
prefer to adjust tetrabenazine dosage based on clinical
response and tolerability.
>Table 1. Maximum Recommended Adult Dosage of

Tetrabenazine Based on CYP2D6 Phenotype1
Maximum Maximum Daily
CYP2D6 Phenotype
Single Dose Dosage
Poor metabolizer 25 mg 50 mg
Intermediate or extensive
metabolizer 37.5 mg 100 mga
aAdminister dosages >50 mg daily in 3 divided doses and

make dosage adjustments in 12.5-mg increments at weekly
intervals.1
Stop dosage titration and reduce daily dosage if adverse

effects (e.g., excessive sedation, akathisia, restlessness,
parkinsonism, depression, insomnia, anxiety) occur;
consider drug discontinuance or initiation of specific
treatment (e.g., antidepressant therapy) if adverse effects
do not resolve.1
Daily dosages >100 mg are not recommended;1 however,
higher dosages have been used in some patients.44

Oral: Initial dosage of 25 mg once or twice daily has been
used in clinical studies in patients with various
hyperkinesias, and then increased in 25-mg daily
increments every 1-3 days until optimal therapeutic
response, intolerable adverse effects, or maximum dosage
of 100-200 mg daily was achieved.38, 39, 40
One non-US manufacturer recommends initial dosage of 25
mg given 3 times daily, with titration in 25-mg daily
increments every 3 or 4 days until maximum tolerated
dosage (not exceeding 200 mg daily) is achieved in patients
with hyperkinetic movement disorders other than tardive
dyskinesia .48 If no improvement occurs at maximum
tolerated dosage within 7 days, drug is unlikely to be
effective despite increase in dosage or duration of
treatment.48
>Tardive Dyskinesia
Oral: One non-US manufacturer recommends initial dosage
of 12.5 mg daily, with subsequent dosage titration based on
response;48 discontinue if no clear benefit or if adverse
effects cannot be tolerated.48
>Tourette's Syndrome
Oral: Clinical experience is limited; some clinicians
recommend initial dosage of 12.5-25 mg given once daily at
bedtime or twice daily, with titration to a target dosage of
25 mg given 3 times daily and a maximum dosage of 50 mg
given 3 times daily.35, 42
Prescribing Limits
Adults
Huntington's Chorea
Oral: 100 mg daily.1
Poor metabolizer phenotype: 50 mg daily.1

Oral: 100-200 mg daily.35, 38, 39, 40, 42
Special Populations
Hepatic Impairment
Contraindicated in hepatic impairment.1, 18 (See Hepatic
Impairment under Cautions; see Absorption: Special
Populations, under Pharmacokinetics; and see also
Elimination: Special Populations, under Pharmacokinetics.)
Renal Impairment
No dosage adjustment required.1, 43
Geriatric Patients
No dosage adjustment required.1, 43 However, at least one
manufacturer recommends reduced initial and maintenance
dosages.53
Cautions
Contraindications
• Actively suicidal or untreated or inadequately treated

depression.1, 18
• Hepatic impairment.1, 18
• Concomitant therapy with an MAO inhibitor.1, 17, 18 (See
Specific Drugs under Interactions.)
• Concomitant therapy with reserpine.1, 18 (See Specific
Drugs under Interactions.)
Warnings
Periodic Evaluation of Need for Continued Therapy
Slight worsening in mood, cognition, rigidity, and functional
capacity may occur; unknown whether these effects persist,
resolve, or worsen with continued treatment.1, 2
Periodically reevaluate need for continued therapy by

assessing benefits on choreiform movements and possible
adverse effects (e.g., depression, cognitive decline,
parkinsonism, dysphagia, sedation, somnolence, akathisia,
restlessness, disability).1, 47 Dosage reduction or drug
discontinuance may help distinguish between drug-induced
adverse effects and disease progression.1 Underlying chorea
may improve over time, thereby possibly decreasing the
need for tetrabenazine.1
Importance of Careful Dosing

Individualize and carefully titrate dosage slowly over several
weeks to determine a dosage that reduces chorea and is
well tolerated.1, 19, 21, 47
Possible dose-dependent adverse effects (e.g., depression,

fatigue, insomnia, sedation or somnolence, parkinsonism,
akathisia) may resolve or lessen with dosage adjustment or
specific treatment.1 Consider tetrabenazine discontinuance
if adverse effect does not resolve or decrease.1
Dosages >50 mg daily should not be given without CYP2D6

genotyping.1 (See Dosage under Dosage and Administration
and see also Determining CYP2D6 Metabolizer Status under
Cautions.)
Risk of Depression and Suicidality

Increased risk for depression and for suicidal ideation and
behavior (suicidality) in patients with Huntington's disease.1,
2 Tetrabenazine increases such risk which may increase with
higher dosages.1, 18, 19, 24, 49 Depression or worsening of

depression reported in 19-35% of tetrabenazine-treated
patients; completed suicide, attempted suicide, and suicidal
ideation reported.1, 43 Depression more likely to occur or
worsen in patients with history of depression.49
Closely observe patients for emergence or worsening of

depression, suicidality, or unusual changes in behavior.1
Inform patients, caregivers, and families of these risks and
instruct them to promptly report any behaviors of concern
to the treating clinician.1 Immediately evaluate any patient
with Huntington's disease who expresses suicidal ideation.1
Reduce tetrabenazine dosage if depression or suicidality

occurs; consider initiating treatment with, or increasing the
dosage of, a concomitant antidepressant.1, 6 Consider drug
discontinuance if depression or suicidality does not resolve.1
Exercise caution when treating patients with a history of

depression or prior suicide attempts or ideation; such
patients may be at an increased risk for suicidal behavior.1
Contraindicated in patients who are actively suicidal or

those with untreated or inadequately treated depression.1
Balance potential risks of depression and suicidality with

clinical need for control of choreiform movements.1
Determining CYP2D6 Metabolizer Status

Testing for CYP2D6 status recommended prior to
administering tetrabenazine dosages >50 mg daily.1 Limit
dosage to 50 mg daily for poor metabolizer phenotype.1
(See Dosage under Dosage and Administration and see also
Absorption: Special Populations, under Pharmacokinetics.)
Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal
syndrome characterized by hyperpyrexia, muscle rigidity,
altered mental status, and autonomic instability, has been
reported with tetrabenazine and other drugs that reduce
dopaminergic transmission.1, 16, 17, 24, 25, 26, 27
Immediately discontinue therapy and initiate supportive and

symptomatic therapy if NMS occurs.1, 16, 17, 24, 25, 26, 27
Careful monitoring required if therapy is reinstituted
following recovery; the risk that NMS can recur should be
carefully considered.1
General Precautions
Akathisia
Possibly dose dependent; reported in up to 20% of
tetrabenazine-treated patients.1
Monitor for akathisia and symptoms of restlessness and

agitation; reduce tetrabenazine dosage if akathisia
develops; drug discontinuance may be necessary in some
patients.1
Parkinsonism
Symptoms suggestive of parkinsonism (e.g., bradykinesia,
hypertonia, rigidity) reported in 3-15% of tetrabenazine-
treated patients and appear to be dose dependent.1 May be
difficult to distinguish between drug-induced effect and
rigidity associated with progression of Huntington's
disease.1 For some patients, drug-induced parkinsonism
may result in more functional disability than untreated
chorea.1
If parkinsonism develops, consider dosage reduction; some

patients may require drug discontinuance.1
Dysphagia
Dysphagia, sometimes associated with aspiration
pneumonia, reported in 4-10% of tetrabenazine-treated
patients.1 Causal relationship not established, since
dysphagia is a manifestation of Huntington's disease and
esophageal dysmotility and dysphagia also are reported
with drugs that reduce dopaminergic transmission, including
tetrabenazine.1
Use tetrabenazine and other drugs that reduce
dopaminergic transmission with caution in patients with
Huntington's disease at risk for aspiration pneumonia.1
Sedation and Somnolence

Reported in 17-57% of patients receiving the drug in clinical
studies.1 Sedation is the most common dose-limiting
adverse effect.1 (See Advice to Patients.)
Prolongation of QT Interval
Small increase in corrected QT (QTc) interval reported.1
Avoid use in patients concurrently receiving other drugs
known to prolong the QTc interval and in patients with
congenital long QT syndrome or history of cardiac
arrhythmias.1, 18 (See Drugs that Prolong QT Interval under
Interactions.)
Factors that may increase the risk of torsades de pointes

and/or sudden death in association with drugs that prolong
the QTc interval include bradycardia, hypokalemia or
hypomagnesemia, concomitant use of other drugs that
prolong the QTc interval, and presence of congenital QTc
interval prolongation.1
Hypotension and Orthostatic Hypotension

Postural dizziness and dizziness reported.1, 2 Consider
monitoring orthostatic vital signs in patients who are
vulnerable to hypotension.1
Hyperprolactinemia
Elevated prolactin concentrations reported.1 Perform
appropriate laboratory testing and consider drug
discontinuance if symptomatic hyperprolactinemia
suspected.1
Tardive Dyskinesia
Tardive dyskinesia, a syndrome of potentially irreversible,
involuntary, dyskinetic movements, reported with
antipsychotic agents.1 No clear cases reported with
tetrabenazine,1, 38, 47 but other extrapyramidal adverse
effects typically associated with antipsychotic agents (e.g.,
parkinsonism, akathisia) possible.1
Consider drug discontinuance if signs and symptoms

suggestive of tardive dyskinesia appear.1
Concomitant Illnesses
Experience in patients with certain concomitant diseases
limited.1
Has not been evaluated in patients with recent history of MI

or unstable cardiovascular disease.1 (See Prolongation of QT
Interval under Cautions and see also Hypotension and
Orthostatic Hypotension under Cautions.)
Use with caution in patients with a history of depression or

suicidality or with diseases, conditions, or treatments that
may cause depression or increased suicidality.1
Contraindicated in patients with untreated or inadequately

treated depression, those who are actively suicidal, or those
with hepatic impairment.1, 18 (See Contraindications and see
also Risk of Depression and Suicidality under Cautions and
see also Hepatic Impairment under Cautions.)
Binding to Melanin-containing Tissues

Binds to melanin-containing tissues, possibly resulting in
accumulation and toxicity with long-term use; clinical
importance unknown.1, 18 Opthalmologic monitoring in
clinical studies was inadequate to exclude possibility of
injury after long-term drug exposure.1, 18
Pregnancy
Category C.1, 18
Lactation
Not known whether tetrabenazine or its metabolites
distribute into milk;1, 18 however, at least one study
suggests that the drug is distributed into human milk.53, 54,
57 Discontinue nursing or the drug.1, 18
Pediatric Use
Safety and efficacy not established in pediatric patients.1, 18,
28
Has been effective in a limited number of pediatric patients

with hyperkinetic movement disorders, including Tourette's
syndrome and severe chorea , to date.33, 35, 42, 54, 55 May
have a similar adverse effect profile in pediatric patients as
in adults, possibly with fewer parkinsonian adverse
effects.33
Based on clinical experience, one manufacturer suggests

starting tetrabenazine at approximately 50% of the adult
dose and titrating the dosage slowly according to tolerance
and patient response.53 54, 55
Geriatric Use
Pharmacokinetics not evaluated in geriatric individuals.1
(See Geriatric Patients under Dosage and Administration.)
Hepatic Impairment
Decreased tetrabenazine metabolism in patients with mild
to moderate hepatic impairment.1 Safety and efficacy of
increased exposure to the drug and its metabolites
unknown; dosage adjustments to ensure safe use are not
possible in hepatic impairment.1 Use contraindicated.1
Renal Impairment
Pharmacokinetics not evaluated in renal impairment.1
Sedation, somnolence, insomnia, fatigue, depression,

anxiety, irritability, balance difficulties, extrapyramidal
adverse effects (e.g., akathisia, bradykinesia, parkinsonism,
hypertonia), nausea, vomiting, ecchymosis, falls, laceration
of the head, upper respiratory tract infection.1, 2, 18, 21, 22,
25, 38, 47
Interactions
Metabolized by carbonyl reductase to the active metabolites

α-dihydrotetrabenazine and β-dihydrotetrabenazine, which
are metabolized principally by CYP2D6.1
Neither tetrabenazine nor its α- and β-dihydrotetrabenazine

metabolites are substrates or inhibitors of the P-glycoprotein
transport system.1
Drugs Affecting Hepatic Microsomal Enzymes
Potent CYP2D6 inhibitors: Potential pharmacokinetic

interaction (increased exposure to α-dihydrotetrabenazine
and β-dihydrotetrabenazine).1, 7, 18 When therapy with a
potent CYP2D6 inhibitor is initiated in a patient already
stabilized on tetrabenazine, use caution and reduce
tetrabenazine dosage by 50%.1, 17 When tetrabenazine is
initiated in a patient already stabilized on a potent CYP2D6
inhibitor, maximum recommended tetrabenazine dosage is
50 mg daily, with maximum single dose of 25 mg.1 (See
Specific Drugs under Interactions.)
Moderate or weak CYP2D6 inhibitors: Effects on

pharmacokinetics of tetrabenazine not established.1, 18
Inducers or inhibitors of CYP isoenzymes 1A2, 2A6, 2C9,

2C19, or 2E1: Pharmacokinetic interaction unlikely.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP 1A2, 2B6, 2D6, 2C8, 2C9, 2C19, 2E1, 3A,
3A4: Pharmacokinetic interaction unlikely.1
Drugs Affecting or Affected by P-glycoprotein

Transport
Clinically important interactions unlikely.1
Drugs that Prolong QT Interval
Potential pharmacologic interaction (additive effect on QT-

interval prolongation); avoid concomitant use of other drugs
known to prolong the QTc interval.1, 18 (See Specific Drugs
under Interactions and see Prolongation of QT Interval under
Cautions.)
Specific Drugs

Alcohol Potential worsening
of sedation and
somnolence1
Antiarrhythmics
(class Ia and III;
e.g., Increased risk of QT
Avoid concomitant
amiodarone, interval
use1, 18
procainamide, prolongation1, 18
quinidine,
sotalol)
Possible
exaggeration of QTc
Antipsychotic prolongation, NMS, Avoid concomitant
agents and/or use1
extrapyramidal
reactions1
Increased risk of QT
Avoid concomitant
Chlorpromazine interval
use1, 18
prolongation1, 18
Potential worsening
CNS
of sedation and
depressants
somnolence1
Possible CNS
Desipramine excitation and
hypertension53
Pharmacokinetic
Digoxin interaction unlikely1,
7, 13
Possible
exaggeration of QTc
Dopamine prolongation, NMS,
antagonists and/or
extrapyramidal
reactions1
Fluoxetine Possible increased Patient already
exposure to stabilized on
tetrabenazine's tetrabenazine: Initiate
active metabolites1, fluoxetine with
7, 18 caution; reduce
tetrabenazine dosage
by 50%1, 17
Patient already
stabilized on
fluoxetine: Maximum
of 50 mg daily and 25
mg as single dose1
Possible reduced
therapeutic effects
of levodopa,
exacerbation of
Parkinson's disease
Levodopa
symptoms;
amelioration of
tetrabenazine-
induced
parkinsonism34, 43
MAO inhibitors Possible CNS Concomitant use
excitation and contraindicated;1, 17,
hypertension53 18 use caution when
initiating
tetrabenazine therapy
following MAO
inhibitor
discontinuance13, 15
At least one
manufacturer
recommends allowing
at least 14 days to
elapse between
discontinuance of
tetrabenazine and
initiation of MAO
inhibitor and vice
versa53
Avoid concomitant
Moxifloxacin interval
1, 18 use1, 18
prolongation
Patient already
stabilized on
tetrabenazine: Initiate
Increased peak paroxetine with
plasma caution; reduce
concentrations, AUC, tetrabenazine dosage
Paroxetine and half-lives of by 50%1, 17
tetrabenazine's Patient already
1,
active metabolites stabilized on
7, 18 paroxetine: Maximum
mg as single dose1
Quinidine Possible increased Patient already
exposure to stabilized on
tetrabenazine's tetrabenazine: Initiate
1,
active metabolites quinidine with
7, 18 caution; reduce
by 50%1, 17
Patient already
stabilized on
quinidine: Maximum
mg as single dose1
Concomitant use
contraindicated1, 17
Wait for signs of
chorea to re-emerge
after discontinuing
reserpine before
Possible serotonin initiating
and norepinephrine tetrabenazine
Reserpine
depletion in the therapy1
CNS1 Allow at least 20 days
to elapse after
reserpine
discontinuance prior
to initiating
tetrabenazine
therapy1, 17, 18
Avoid concomitant
Thioridazine interval
1, 18 use1, 18
prolongation
Avoid concomitant
Ziprasidone interval
1, 18 use1, 18
prolongation
Pharmacokinetics
Absorption
Bioavailability
Following oral administration, ≥75% absorbed.1
Peak plasma concentrations of active metabolites α-

dihydrotetrabenazine and β-dihydrotetrabenazine reached
within 1-1.5 hours; peak plasma concentration of O-
dealkylated-dihydrotetrabenazine (another major
metabolite) is reached approximately 2 hours following a
dose.1
Duration
16-24 hours.53
Food
No effect on mean or peak plasma concentrations or AUC of
α-dihydrotetrabenazine and β-dihydrotetrabenazine.1
Special Populations
Patients with mild to moderate chronic hepatic impairment:
Mean peak plasma tetrabenazine concentrations were 7- to
190-fold higher and AUCs of α-dihydrotetrabenazine and β-
dihydrotetrabenazine were approximately 30-39% greater
compared with values in healthy individuals.1
Poor CYP2D6 metabolizers: Exposures to α-

dihydrotetrabenazine and β-dihydrotetrabenazine were
about threefold and ninefold higher, respectively, compared
with values in extensive metabolizers.1
Distribution
Extent
Not known whether the drug or its metabolites are
distributed into milk in humans;1, 18 one study suggests that
the drug is distributed into human milk and crosses the
placenta.53, 54, 57
Plasma Protein Binding

Tetrabenazine: 82-85%.1
α-Dihydrotetrabenazine: 60-68%.1
β-Dihydrotetrabenazine: 59-63%.1
Elimination
Metabolism
Rapidly and extensively metabolized mainly in the liver by
carbonyl reductase to active metabolites α-
dihydrotetrabenazine and β-dihydrotetrabenazine, which are
further O-dealkylated, principally by CYP2D6, to O-
dealkylated-dihydrotetrabenazine.1
Elimination Route
Eliminated in urine (about 75%) and feces (7-16%).1 In
urine, <10% eliminated as α-dihydrotetrabenazine or β-
dihydrotetrabenazine.1
Half-life
α-Dihydrotetrabenazine: 4-8 hours.1
β-Dihydrotetrabenazine: 2-4 hours.1
Special Populations
Patients with hepatic impairment: Elimination half-lives
prolonged to approximately 17.5 hours for tetrabenazine, 10
hours for α-dihydrotetrabenazine, and 8 hours for β-
dihydrotetrabenazine.1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15-30°C).1
Actions
• Reversibly inhibits uptake of monoamines (e.g., dopamine,

norepinephrine, serotonin, histamine) into synaptic
vesicles and depletes monoamine stores from nerve
terminals.1, 2, 13, 17, 18, 19, 20, 21, 23, 24, 25
• Precise mechanism of antichorea effects not established,
but appears to be related to drug's ability to reversibly and
selectively inhibit vesicular monoamine transporter type 2
(VMAT2) in CNS, thereby decreasing uptake of
monoamines into synaptic vesicles and depleting
monoamine stores from nerve terminals.1, 2, 7, 8, 13, 17, 18,
19, 20, 21, 23, 24, 25
• Preferentially depletes dopamine; dose required to deplete

norepinephrine or serotonin is approximately fivefold
higher than that required to deplete dopamine.2, 7, 17, 21,
23 Preferential depletion of dopamine in striatum may
contribute to antichorea effects.4, 13, 18, 22

• Exhibits weak in vitro binding affinity for dopamine type 2
(D2) receptors.1, 13, 21, 23 Does not possess binding affinity
for GABA, glutamate, glycine, histamine, or norepinephrine
receptors or ion channels.7
Advice to Patients
• Tetrabenazine medication guide must be provided to the

patient each time the drug is dispensed;4, 10 importance of
patient and caregiver reading the medication guide prior
to initiation of tetrabenazine therapy and each time the
prescription is refilled.1, 4, 13, 28
• Risk of new or worsening depression and suicidality;
importance of patients or their families being alert to and
immediately reporting emergence of suicidality, new or
worsening depression, or other unusual changes in
behavior.1, 28
• Importance of informing patients that tetrabenazine is
used to treat the involuntary movements (chorea) of
Huntington's disease and that the drug does not cure the
cause of the involuntary movements and does not treat
other symptoms of Huntington's disease (e.g., problems
with thinking and emotions).28
• Importance of informing patients and their families that
the dosage of tetrabenazine will be gradually increased to
reach the optimal dosage.1, 28 Importance of being alert to
possible development of adverse effects (e.g., sedation,
akathisia, parkinsonism, depression, difficulty swallowing,
fatigue, insomnia) that may require a dosage reduction or
tetrabenazine discontinuance.1, 25, 47 Importance of
informing patient that a blood test may be needed if a
dosage exceeding 50 mg daily is considered.1, 28
• Importance of taking tetrabenazine exactly as prescribed
at the correct time each day.10 Importance of informing
patients not to take a double dose of the drug if a dose of
tetrabenazine is missed.1, 28
• Importance of informing patients that involuntary
movements may return or worsen within 12-18 hours after
the last dose if therapy is discontinued or a dose is
missed.28 Importance of patients informing clinicians if
tetrabenazine has been discontinued for >5 days and
importance of patients not taking additional doses of the
drug until they notify their clinician.10, 28
• Risk of sedation, somnolence, and psychomotor
impairment; importance of exercising caution while
operating hazardous machinery, including driving a motor
vehicle, until patient is receiving a maintenance dosage of
tetrabenazine and has gained experience with the drug's
effects.1, 18, 28
• Importance of informing patients that concomitant use of
alcohol or other CNS depressants may worsen the sedative
effects of tetrabenazine.1, 18, 28
and OTC drugs and dietary and herbal supplements, as
well as any concomitant illnesses (e.g., liver disease).1, 28
plan to become pregnant or plan to breast-feed.1, 28
precautionary information.1, 28 (See Cautions.)
Preparations

Distribution of tetrabenazine is restricted.4, 10, 13, 17, 18, 41

(See REMS Program under Dosage and Administration.)
Tetrabenazine
Dosage
Forms
Oral Tablets 12.5 mg Xenazine® Lundbeck
Xenazine®
25 mg Lundbeck
(scored)

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Iron Preparations, Oral (Systemic)

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Iron Preparations, Oral (Systemic)

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Iron Preparations, Oral (Systemic)

Ferrous fumarate, ferrous gluconate, ferrous sulfate,

Class: 20:04.04 Iron Preparations

Brands*: Feosol®, Feostat®, Feratab®, Fer-Gen-Sol®,

*also available generically

Generic Name: Ferric Pyrophosphate

Generic Name: Ferrous Gluconate

Generic Name: Ferrous Sulfate

Generic Name: Ferrous Sulfate, Dried

Generic Name: Ferrous Fumarate

Generic Name: Ferrous Carbonate

Prevention and Treatment of Iron Deﬁciency

Prevention and treatment of iron deﬁciency.a Not indicated

Dosage and Administration

For patients who have diﬃculty tolerating oral iron

Dosage expressed in terms of elemental iron. (See Table 1.)

Do not exceed recommended dosage.b

>Table 1. Approximate Elemental Iron Content of

>Table 2. Recommended Dietary Allowance

Infants 0-6 months of age 0.27

the observed mean iron intake of infants fed principally

keep iron-containing preparations out of reach of

If accidental overdosage occurs, immediately contact a

Do not administer for >6 months except in patients with

Common Adverse Eﬀects

Constipation, diarrhea, dark stools, nausea, epigastric pain.a

Speciﬁc Drugs, Foods, and Laboratory Tests

Oral bioavailability of iron can vary from <1% to >50%,109,

the amount of iron stored in the body.109, 111

Crosses the placenta and distributes into milk.a

• Risk of fatal poisoning in children <6 years of age;108, 148

Excipients in commercially available drug preparations may

Ferrous Sulfate, Dried

Oral iron preparations are also commercially available in

Only references cited for selected revisions after 1984 are

101. Standing Committee on the Scientiﬁc Evaluation of

102. Polk RE, Healy DP, Sahai J et al. Eﬀect of ferrous

103. Merck & Co Inc. Noroxin® (norﬂoxacin precribing

104. Polk RE. Drug-drug interactions with ciproﬂoxacin and

105. Janknegt R. Drug interactions with quinolones. J

106. Campbell N, Paddock V, Sundaram R. Alteration of

107. Campbell NRC, Hasinoﬀ BB, Stalts H et al. Ferrous

108. Centers for Disease Control and Prevention. Toddler

109. Centers for Disease Control and Prevention.

110. Halberg L. Bioavailability of dietary iron in man. Annu

111. Bothwell TH. Overview and mechanisms for iron

112. Allen LH. Pregnancy and iron deﬁciency: unresolved

113. Siegenberg D, Baynes RD, Bothwell TH et al. Ascorbic

115. Pollitt E. Iron deﬁciency and cognitive function. Annu

116. Idjradinata P, Pollitt E. Reversal of developmental

117. Lozoﬀ B, Jimenez E, Wolf AW. Long-term

118. Goyer RA. Nutrition and metal toxicity. Am J Clin Nutr.

119. Li R, Chen X, Yan H et al. Functional consequences of

120. Scholl TO, Hediger ML, Fischer RL et al. Anemia vs

121. Puolakka J, Janne O, Pakarinen A et al. Serum ferritin

123. Hemminki E, Rimpela U. A randomized comparison of

124. Hemminki E, Meriainen J. Long-term follow-up of

125. Looker AC, Dallman PR, Carroll MD et al. Prevalence

126. Pizarro F, Yip R, Dallman PR et al. Iron Status with