PHENYTOIN SODIUM INJECTION USP LIQUID

Canada - English - Health Canada

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Active ingredient:
PHENYTOIN SODIUM
Available from:
SANDOZ CANADA INCORPORATED
ATC code:
N03AB02
INN (International Name):
PHENYTOIN
Dosage:
50MG
Pharmaceutical form:
LIQUID
Composition:
PHENYTOIN SODIUM 50MG
Administration route:
INTRAMUSCULAR
Units in package:
2/5ML
Prescription type:
Prescription
Therapeutic area:
HYDANTOINS
Product summary:
Active ingredient group (AIG) number: 0101375003; AHFS: 28:12.12
Authorization status:
APPROVED
Authorization number:
00780626
Authorization date:
2005-09-30

Documents

Phenytoin Sodium Injection USP

Page 1 of 25

PRODUCT MONOGRAPH

Pr

PHENYTOIN SODIUM INJECTION USP

50 mg/mL

Anticonvulsant agent

Sandoz Canada Inc.

Date of Revision: June 21, 2017

145 Jules-Léger

Boucherville, QC, Canada

J4B 7K8

Control Number: 205185

Phenytoin Sodium Injection USP

Page 2 of 25

Pr

PHENYTOIN SODIUM INJECTION USP

50 mg/mL

PART I: HEALTH PROFESSIONAL INFORMATION

THERAPEUTIC CLASSIFICATION

Anticonvulsant agent

INDICATIONS

AND CLINICAL USE

Phenytoin Sodium Injection USP is indicated for the control of generalized tonic-clonic status

epilepticus, and for the prevention and treatment of seizures occurring during neurosurgery.

Phenytoin Sodium Injection USP should be used only when oral phenytoin administration is not

possible.

CONTRAINDICATIONS

Phenytoin is contraindicated:

In patients who with a history of hypersensitivity to phenytoin or to other hydantoins.

In patients who have sinus bradycardia, sino-atrial block, second and third degree AV block,

and Adams-Stokes syndrome.

In conjunction with delavirdine due to potential for loss of virologic response and possible

resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

For intra-arterial administration in view of the high pH of the preparation.

WARNINGS AND PRECAUTIONS

CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION

The rate of intravenous phenytoin sodium injection administration should not exceed 50

mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in

pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. In

elderly patients, those who are gravely ill, or those with cardiovascular disease, the drug

should be administered at a rate not exceeding 25 mg/minute, and if necessary, at a slow

rate of 5 to 10 mg/minute. Careful cardiac monitoring is needed during and after

administering intravenous phenytoin sodium injection. Although the risk of cardiovascular

toxicity increases with infusion rates above the recommended infusion rate, these events

have also been reported at or below the recommended infusion rate. Reduction in rate of

administration or discontinuation of dosing may be needed (see WARNINGS AND

PRECAUTIONS and DOSAGE AND ADMINISTRATION).

As non-emergency therapy, phenytoin should be administered more slowly as either a

Phenytoin Sodium Injection USP

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loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity

associated with intravenous phenytoin, oral phenytoin should be used whenever possible.

Because adverse cardiovascular reactions have occurred during and after infusions, careful

cardiac monitoring is needed during and after the administration of intravenous

phenytoin. Reduction in rate of administration or discontinuation of dosing may be needed.

Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac

arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular

fibrillation which have resulted in asystole, cardiac arrest, and death.

Severe complications are most commonly encountered in critically ill patients, elderly patients,

and patients with hypotension and severe myocardial insufficiency. However, cardiac events

have also been reported in adults and children without underlying cardiac disease or

comorbidities and at recommended doses and infusion rates.

Withdrawal-Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased

seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need

for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication

arises, this should be done gradually. However, in the event of an allergic or hypersensitivity

reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative

therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN)

and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of

symptoms is usually within 28 days, but can occur later.

Phenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug

related.

If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative

therapy should be considered. If a rash occurs, the patient should be evaluated for signs and

symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan

hypersensitivity). The patient must be warned to call his/her physician in case of skin rash (see

Skin Rash, PRECAUTIONS).

Studies in patients of Chinese ancestry have found a strong association between the risk of

developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B

gene, in patients using carbamazepine. Limited evidence suggests that HLA-B* l502 may be a

risk factor for the development of SJS/TEN in patients of Asian ancestry taking other

antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be

given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-

Phenytoin Sodium Injection USP

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B*1502.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for

appropriate clinical vigilance and patient management. The role of other possible factors in the

development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose,

compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring

have not been studied.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan

hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin.

Some of these events have been fatal or life-threatening. DRESS typically, although not

exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ

system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or

myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because

this disorder is variable in its expression, other organ systems not noted here may be involved. It

is important to note that early manifestations of hypersensitivity, such as fever or

lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are

present, the patient should be evaluated immediately. Phenytoin should be discontinued if an

alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin

hypersensitivity (see CONTRAINDICATIONS). Additionally, in these patients, consider

alternatives for those anti-convulsant drugs that are structurally similar to phenytoin, such as

carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g.,

trimethadione). Similarly, if there is a history of hypersensitivity reactions to these structurally

similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been

reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in

isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum

transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin

hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute

hepatotoxicity, phenytoin should be immediately discontinued and not re-administered.

Hematopoietic System

Hematopoietic complications, some fatal, have occasionally been reported in association with

administration of phenytoin. These have included thrombocytopenia, leukopenia,

granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

Complete blood counts should be carried out before treatment is instituted and periodically

thereafter.

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There have been a number of reports suggesting a relationship between phenytoin and the

development of lymphadenopathy (local or generalized) including benign lymph node

hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect

relationship has not been established, the occurrence of lymphadenopathy indicates the need to

differentiate such a condition from other types of lymph node pathology. Lymph node

involvement may occur with or without symptoms and signs resembling DRESS. In all cases of

lymphadenopathy, follow-up observation for an extended period is indicated and every effort

should be made to achieve seizure control using alternative antiepileptic drugs.

Local Toxicity (including Purple Glove Syndrome)

Soft tissue irritation and inflammation has occurred at the site of injection with and without

extravasation of intravenous phenytoin (See DOSAGE AND ADMINISTRATION for IV

administration of Phenytoin Sodium Injection USP.

Edema, discolouration and pain distal to the site of injection (described as “purple glove

syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft

tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The

syndrome may not develop for several days after injection. Although resolution of symptoms

may be spontaneous, skin necrosis and limb ischemia have occurred and required such

interventions as fasciotomies, skin grafting, and in rare cases, amputation.

Subcutaneous or perivascular administration should be avoided because of the highly alkaline

nature of the solution.

Intramuscular phenytoin administration may cause pain, necrosis, and abscess formation at the

injection site (see DOSAGE AND ADMINISTRATION).

Alcohol Use

Acute alcohol intoxication may increase phenytoin serum levels while chronic alcoholism may

decrease it. Alcohol should be avoided during treatment with phenytoin

Psychiatric

Suicidal Ideation and Behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents

in several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for

signs of suicidal ideation and behaviour and appropriate treatment should be considered.

Patients (and caregivers of patients) should be advised to seek medical advice should signs of

suicidal ideation or behaviour emerge. An FDA meta-analysis of randomized placebo controlled

trials, in which antiepileptic drugs were used for various indications, has shown a small

Phenytoin Sodium Injection USP

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increased risk of suicidal ideation and behaviour in patients treated with these drugs. The

mechanism of this risk is not known.

There were 43,892 patients treated in the placebo controlled clinical trials that were included in

the meta-analysis. Approximately 75% of patients in these clinical trials were treated for

indications other than epilepsy and, for the majority of non-epilepsy indications the treatment

(antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy

represented approximately 25% of the total number of patients treated in the placebo controlled

clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo)

was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms

were being treated with one or more antiepileptic drug). Therefore, the small increased risk of

suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on

antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that

received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The

study design does not allow an estimation of the risk of suicidal ideation and behaviour for

patients with epilepsy that are taking antiepileptic drugs, due both to this population being the

minority in the study, and the drug-placebo comparison in this population being confounded by

the presence of adjunct antiepileptic drug treatment in both arms.

Exacerbation of Porphyria

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should

be exercised in using this medication in patients suffering from this disease.

General

In patients on long term phenytoin therapy, vitamin D and folic acid are given to prevent side

effects respectively affecting bones and hematopoiesis. Long-term use of antiepileptics such as

phenytoin, phenobarbital, primidone, carbamazepine, lamotrigine and sodium valproate is

associated with a risk of decreased bone mineral density that may lead to weakened or brittle

bones.

A small percentage of individuals who have been treated with phenytoin have been shown to

metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and

lack of induction; it appears genetically determined.

Hyperglycemia, resulting from the drug’s inhibitory effect on insulin release, has been reported.

Phenytoin may also raise the serum glucose level in diabetic patients.

Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes.

Appropriate diagnostic procedures should be performed as indicated.

Phenytoin is not effective for absence seizures. Therefore, if tonic-clonic and absence seizures

are both present, combined drug therapy is needed.

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Patients should be aware of the importance of a good dental hygiene in order to prevent gingival

hyperplasia.

Serum levels of phenytoin sustained above the optimal range may produce confusional states

referred to as “delirium”, “psychosis”, or “encephalopathy” or rarely irreversible cerebellar

dysfunction. Accordingly, at the first sign of acute toxicity, determination of phenytoin plasma

levels is recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are

excessive; if symptoms persist, termination is recommended.

Activities Requiring Mental Alertness: Caution is recommended in patients performing skilled

tasks (e.g. driving or operating machinery) as treatment with phenytoin may cause central

nervous system adverse effects such as dizziness and drowsiness. Phenytoin in appropriate doses

may as such impair driving skills but epilepsy itself dictates the practice of driving. Patients

affected by drowsiness should not drive or operate machinery.

Special Populations

Pregnant Women:

An increase in seizure frequency may occur during pregnancy because of altered phenytoin

pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in

the management of pregnant women as a guide to appropriate adjustment of dosage. However,

postpartum restoration of the original dosage will probably be indicated.

Risks to the Fetus:

If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug,

the patient should be apprised of the potential harm to the fetus.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other

adverse development outcomes. Increased frequencies of major malformations (such as orofacial

clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit

hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been

reported among children born to epileptic women who took phenytoin alone or in combination

with other antiepileptic drugs during pregnancy. There have also been several reported cases of

malignancies, including neuroblastoma, in children whose mothers received phenytoin during

pregnancy. The overall incidence of malformations for children of epileptic women treated with

antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold

that in the general population.

However, the relative contribution of antiepileptic drugs and other factors associated with

epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute

specific developmental abnormalities to particular antiepileptic drugs.

Patients should consult with their physicians to weigh the risks and benefits of phenytoin during

pregnancy.

Phenytoin Sodium Injection USP

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Pregnancy Registry:

Pregnant patients taking phenytoin should be encouraged to enroll in the North American

Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free

number 1-888-233-2334, and must be done by patients themselves. Information on the registry

can also be found at the following website: http://www.aedpregnancyregistry.org/.

Postpartum Period:

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-

dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug

induced condition can be prevented with vitamin K administration to the mother before delivery

and to the neonate after birth.

Nursing Women:

Infant breast feeding is not recommended for women taking phenytoin. Phenytoin is secreted

into human milk. Limited observations in patients suggest that phenytoin concentration in breast

milk is approximately one-third of the corresponding maternal plasma concentration.

Elderly:

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing

may be required.

Hepatic impairment:

The liver is the main site of biotransformation of phenytoin; patients with impaired liver

function, elderly patients, or those who are gravely ill may show early toxicity. The drug should

be given with caution to these patients (see DOSAGE AND ADMINISTRATION, Dosing

Considerations (Special Populations).

Monitoring and Laboratory Tests:

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations

of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).

ADVERSE REACTIONS

The margin between therapeutic and toxic levels of phenytoin is very narrow. Moreover, there is

a considerable variation from patient to patient in relation to blood and tissue concentrations.

Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin

paragraph below) and DRESS (see WARNINGS AND PRECAUTIONS) have been observed.

Anaphylaxis has also been reported.

There have also been reports of hirsutism (more noticeable in young females), systemic lupus

Phenytoin Sodium Injection USP

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erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.)

Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and

ventricular conduction depression and ventricular fibrillation. Severe complications are most

commonly encountered in elderly or critically ill patients (see WARNINGS AND

PRECAUTIONS).

Nervous System: The most common adverse reactions encountered with phenytoin therapy are

nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia,

slurred speech, diplopia, decreased coordination, somnolence, and mental confusion. Dizziness,

vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also

been observed. There have also been rare reports of phenytoin-induced dyskinesias, including

chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other

neuroleptic drugs.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving

long-term phenytoin therapy.

Musculoskeletal and Connective Tissue: Rickets; osteomalacia; polyarthropathy. Thickening of

the skull, coarsening of facial features, or gingival hyperplasia.

Respiratory: Rare reports of pulmonary infiltrates or fibrosis, with symptoms including fever,

troubled or quick, shallow breathing, unusual tiredness or weakness, loss of appetite and weight,

and chest discomfort have also occurred.

Alterations in respiratory function, respiratory arrest, and Pneumonitis.

Skin: Dermatological manifestations sometimes accompanied by fever

have included

scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common;

other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have

included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic

epidermal necrolysis (see WARNINGS AND PRECAUTIONS section). There have also been

reports of hypertrichosis.

Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or

without extravasation of intravenous phenytoin (see WARNINGS AND PRECAUTIONS).

Gastrointestinal: Nausea, vomiting, constipation, enlargement of the lips.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have

occasionally been reported in association with administration of phenytoin. These have included

thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or

without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred

following prolonged use, these conditions usually respond to folic acid therapy.

Phenytoin Sodium Injection USP

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Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and

Hodgkin’s disease have been reported (see WARNINGS AND PRECAUTIONS section).

Hepatobiliary: Hepatitis, acute hepatotoxicity, acute hepatic failure, hepatomegaly (see

WARNINGS AND PRECAUTIONS, Hepatic Injury).

Phenytoin Sodium Injection USP contains propylene glycol which may cause alcohol-like

symptoms.

Phenytoin Sodium Injection USP contains 10% Alcohol USP. This may be harmful for those

suffering from alcoholism and should be taken into account in pregnant or breast-feeding

women, and high-risk groups such as patients with liver disease.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie’s disease.

Other effects: Hyperglycemia (resulting from phenytoin’s inhibitory effect on insulin release),

myasthenia gravis. Anticonvulsants can diminish sexual potency and fertility in young male

epileptics. Phlebitis, under IV administration. In some patients high serum triglycerides and

cholesterol levels have been reported (due to the effect of phenytoin on lipid metabolism).

DRUG INTERACTIONS

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive

displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and

CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to

saturable metabolism. Inhibition of metabolism may produce significant increases in circulating

phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of

hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially

helpful when possible drug interactions are suspected.

The most commonly occurring drug interactions are listed below:

Note: The list is not intended to be inclusive or comprehensive. Individual Product Monographs

should be consulted.

Drugs that affect phenytoin concentrations:

Drugs that may increase phenytoin serum levels include: acute alcohol intake, amiodarone,

antiepileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles

(fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol,

chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine,

fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid,

methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides

Phenytoin Sodium Injection USP

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(e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine,

tolbutamide, trazodone, and warfarin.

Co-administration with topiramate reduces serum topiramate levels by 59%, and has the

potential to increase phenytoin levels by 25% in some patients. The addition of topiramate

therapy to phenytoin should be guided by clinical outcome.

Drugs that may decrease phenytoin levels include: anticancer drugs usually in combination (e.g.,

bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol

abuse, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, and

vigabatrin.

Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital,

sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic

acid, and sodium valproate serum levels is unpredictable.

The addition or withdrawal of the agents in patients on phenytoin therapy may require an

adjustment of the phenytoin dose to achieve optimal clinical outcome.

Drugs affected by phenytoin:

Drugs that should not be co-administered with phenytoin: delavirdine (see

CONTRAINDICATIONS).

Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole,

itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide,

irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide,

theophylline, and Vitamin D.

Increased and decreased prothrombin time (PT)/International Normalized Ratio (INR) responses

have been reported when phenytoin is coadministered with warfarin.

Phenytoin decreases plasma concentrations of certain HIV antivirals (efavirenz,

lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate,

topiramate, oxcarbazepine, quetiapine, lamotrigine), atorvastatin, calcium, cyclosporine, digoxin,

fluvastatin, folic acid, mexiletine, nifedipine,nisoldipine, praziquantel, simvastatin, and

verapamil.

Co-administration with lamotrigine doubles the plasma clearance and reduces the elimination

half-life of lamotrigine by 50%. This clinically important interaction requires dosage adjustment

for lamotrigine. There is no significant change in phenytoin plasma levels in the presence of

lamotrigine.

Co-administration with topiramate reduces serum topiramate levels by 59%, and has the

potential to increase phenytoin levels by 25% in some patients. The addition of topiramate

Phenytoin Sodium Injection USP

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therapy to phenytoin should be guided by clinical outcome.

Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir,

the active metabolite. Phenytoin when given with the combination of fosamprenavir and

ritonavir may increase the concentration of amprenavir.

Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking

agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients

chronically administered phenytoin. Whether or not phenytoin has the same effect on other

nondepolarizing agents is unknown. Patients should be monitored closely for more rapid

recovery from neuromuscular blockade than expected, and infusion rate requirements may be

higher.

Use of intravenous phenytoin in patients maintained on dopamine may produce sudden

hypotension and bradycardia. This appears to be dose-dependent. If anticonvulsant therapy is

necessary during administration of dopamine, an alternative to phenytoin should be considered.

Concurrent use of intravenous phenytoin with lidocaine or beta-blockers may produce additive

cardiac depressant effects. Phenytoin may also enhance metabolism of lidocaine.

The addition or withdrawal of phenytoin during concomitant therapy with the above agents may

require adjustment of the dose of these agents to achieve optimal clinical outcome.

Drug-Enteral Feeding/Nutritional Preparations Interaction

Literature reports suggest that patients who have received enteral feeding preparations and/or

related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore

suggested that phenytoin not be administered concomitantly with an enteral feeding preparation.

More frequent serum phenytoin level monitoring may be necessary in these patients.

Drug/Laboratory Test Interactions

Phenytoin may decrease serum concentrations of thyroxine (T4). It may also produce lower than

normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased

serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

Care should be taken when using immunoanalytical methods to measure plasma phenytoin

concentrations following fosphenytoin administration.

Incompatibility

Phenytoin sodium only remains in solution when the pH is considerably alkaline (about 10 to

12). The mixing of phenytoin sodium injection with other drugs or its addition to infusion

solutions is not recommended.

DOSAGE AND ADMINISTRATION

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Because of the increased risk of adverse cardiovascular reactions associated with rapid

administration, intravenous administration should not exceed 50 mg per minute in adults.

In pediatric patients, the drug should never be administered at a rate exceeding 1-3

mg/kg/min or 50 mg per minute, whichever is slower.

As non-emergency therapy, phenytoin should be administered more slowly as either a

loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity

associated with intravenous phenytoin, oral phenytoin should be used whenever possible.

Because adverse cardiovascular reactions have occurred during and after infusions, careful

cardiac, blood pressure, and respiratory function monitoring is needed during and after

the administration of intravenous phenytoin. Reduction in rate of administration or

discontinuation of dosing may be needed.

Because of the risk of local toxicity, intravenous phenytoin should be administered directly

into a large peripheral or central vein through a large-gauge catheter. Prior to the

administration, the patency of the IV catheter should be tested with a flush of sterile saline.

Each injection of parenteral phenytoin should then be followed by a flush of sterile saline

through the same catheter to avoid local venous irritation due to the alkalinity of the

solution.

The addition of parenteral phenytoin to dextrose and dextrose-containing solutions should

be avoided due to lack of solubility and resultant precipitation.

*IV route:

Intravenous administration should be used with caution in patients with hypotension and

severe myocardial or respiratory insufficiencies.

Electrocardiographic and blood pressure monitoring is recommended during intravenous

therapy. The patient should be observed for signs of respiratory depression.

3.

In adults, the rate of administration should not exceed 50 mg/minute and should

even be slower (50 mg over 2 or 3 minutes) for the elderly, those who are gravely ill,

and those with cardiovascular disease.

4.

In neonates, the rate of administration should not exceed 1 to 3 mg/kg/minute.

5.

The IV injection should be done in a large vein through a large gauge needle or IV

catheter. The injection of the drug should be followed by administration of isotonic

sodium chloride injection through the same needle or IV catheter to avoid local irritation

of the vein caused by the alkalinity of the phenytoin sodium solution.

Phenytoin Sodium Injection USP

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Phenytoin should not be added to IV infusions (due to lack of solubility and risk of

precipitation) nor should it be given as a continuous infusion (risk of phlebitis due to the

alkaline pH).

Due to slow and erratic absorption of phenytoin, the IM route is not recommended for

emergency treatment of status epilepticus because the attainment of peak levels may

require up to 24 hours. Intramuscular phenytoin may cause pain, necrosis, and abscess

formation at the injection site.

Passage from oral to intramuscular administration may cause a drop in phenytoin plasma

level due to the poor absorption of phenytoin when administered by intramuscular route.

Studies established that the best regimen for the transfer of phenytoin by mouth to the IM

route was the following: dosage should be increased by 50% in order to maintain a

constant concentration of phenytoin in the plasma. Upon returning patients to phenytoin

by oral route, a dose equivalent to 50% of the original oral dose should be administered

for the same period as that during which, the IM route was used to allow for continued

absorption of phenytoin from the intramuscular site. However, for periods of treatment

greater than one week, blood level monitoring is recommended. When patients cannot

take phenytoin orally for more than one week, gastric intubation may be considered.

The dosage of phenytoin should be adjusted to the needs of each patient to achieve

adequate control of seizures and to avoid toxicity (concentrations usually required: 10 to

20 mcg/mL).

Usual dosage for parenteral administration:

Treatment of status epilepticus: 150 to 250 mg of phenytoin sodium administered by slow

intravenous injection. An additional 100 to 250 mg may be given 30 minutes later if

necessary. Dosage for children is usually determined according to weight in proportion to

the dosage for a 68 kg adult. Pediatric dosage may also be calculated on the basis of 250

mg/m

of body surface.

Neurosurgery: prophylactic intramuscular administration of 100 to 200 mg of phenytoin

every 4 hours during surgery and the post-operative period.

IV Substitution for Oral Phenytoin Therapy

When treatment with oral phenytoin is not possible, IV phenytoin can be substituted for oral

phenytoin at the same total daily dose. Phenytoin is 100% bioavailable by the IV route, with oral

phenytoin approximately 90% bioavailable. For this reason, plasma phenytoin concentrations

may increase modestly when IV phenytoin is substituted for oral phenytoin.

Because there is approximately an 8% increase in drug content with the free acid form over that

of the sodium salt, dosage adjustments and serum level monitoring may be necessary when

switching from a product formulated with the free acid to a product formulated with the sodium

salt and vice versa.

Phenytoin Sodium Injection USP

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Dosing Considerations (Special Populations)

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in

patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of

total phenytoin plasma concentrations should be made with caution. Unbound phenytoin

concentrations may be more useful in these patient populations.

Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less

frequent dosing may be required.

Do not mix with other IV solutions unless it respects the condition mentioned in

"incompatibility".

OVERDOSAGE

Early symptoms of overdosage are slurred speech, digestive disturbances (nausea, vomiting),

tremor, hyperflexia and lethargy. Other signs are nystagmus, ataxia, and dysarthria. The patient

may become comatose and hypotensive.

There are marked variations among individuals with respect to phenytoin plasma levels where

toxicity may occur. Most patients experience blurred vision and nystagmus at serum phenytoin

concentrations of 20 mcg/mL, ataxia and unsteady gait at 30 mcg/mL and lethargy at more than

40 mcg/mL. As high a concentration as 50 mcg/mL has been reported without evidence of

toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum

concentration over 100 mcg/mL with complete recovery.

The lethal dose in children is unknown. In adults it is estimated to be in the order of 2 to 5 g.

Death is generally due to respiratory and circulatory depression.

Treatment of Overdosage

There is no known antidote; consequently the treatment is not specific. Respiratory and

circulatory functions should be carefully monitored and appropriate supportive measures should

be employed. The effectiveness of hemodialysis and peritoneal dialysis has been seriously

questioned. As phenytoin’s volume of distribution is relatively small, blood transfusion,

particularly at high drug concentrations, should contribute significantly to total drug removal.

Total exchange transfusion has been used in the treatment of severe intoxication in children.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne

in mind

For management of a suspected drug overdose, contact your Regional Poison Control Centre

immediately.

Phenytoin Sodium Injection USP

Page 16 of 25

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamic properties

Phenytoin sodium inhibits the spread of seizure activity in the motor cortex. It appears that by

promoting sodium efflux from neurons, phenytoin sodium tends to stabilise the threshold against

hyperexcitability caused by environmental changes or excessive stimulation capable of reducing

membrane sodium gradient. This includes the reduction of post tetanic potentiation of synapses.

Loss of post tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical

areas. Phenytoin thereby reduces the over-activity of brain stem centres responsible for the tonic

phase of grand mal seizures.

Phenytoin sodium’s antiarrhythmic action may be attributed to the normalization of influx of

sodium and calcium to cardiac Purkinje fibres. Abnormal ventricular automaticity and membrane

responsiveness are decreased. It also shortens the refractory period, and therefore shortens the

QT interval and the duration of the action potential.

Hydantoins induce production of liver microsomal enzymes, thereby accelerating the metabolism

of concomitantly administered drugs.

Pharmacokinetic properties

The onset of action after an intravenous dose is 30 to 60 minutes and the effect persists up to 24

hours. Phenytoin is about 90% protein bound. Protein binding may be lower in neonates and

hyperbilirubinemic infants; also altered in patients with hypoalbuminaemia, uraemia or acute

trauma, and in pregnancy. Optimum control without clinical signs of toxicity occurs most often

with serum levels between 10 and 20 μg/mL. In renal failure or hypoalbuminaemia, 5 to 12

mcg/mL or even less may be therapeutic.

Phenytoin is metabolised in the liver, the major inactive metabolite is 5-(p-hydroxyphenyl)-5-

phenylhydantoin (HPPH). The rate of metabolism is increased in younger children, pregnant

women, in women during menses and in patients with acute trauma. The rate decreases with

advancing age. Phenytoin may be metabolised slowly in a small number of individuals due to

genetic factors, which may cause limited enzyme availability and lack of induction.

The plasma half-life is normally from 10 to 15 hours. Because phenytoin exhibits saturable or

dose-dependent pharmacokinetics, the apparent half-life of phenytoin changes with dose and

serum concentration. At therapeutic concentrations of the drug, the enzyme system responsible

for metabolising phenytoin becomes saturated. Thus a constant amount of drug is metabolised,

and small increases in dose may cause disproportionately large increases in serum concentrations

and apparent half-life, possibly causing unexpected toxicity.

STORAGE AND STABILITY

Store between 15

C and 30

C; freezing should be avoided. A precipitate may form if the

Phenytoin Sodium Injection USP

Page 17 of 25

injection is refrigerated or frozen; however, this will dissolve after warming to room

temperature.

Protect from light. Slightly yellowish discolouration of the injection will not affect potency or

efficacy, but the injection should not be used if the solution is not clear or if a precipitate is

present.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Phenytoin Sodium Injection USP is a sterile solution of the drug containing 40% propylene

glycol, 10% (v/v) ethyl alcohol in water for injection. Sodium hydroxide is added during

manufacture of the injection to adjust the pH to 12.

Phenytoin Sodium Injection USP is a clear, colourless solution contained in an amber ampoule.

Each mL of Phenytoin Sodium Injection USP contains 50 mg of phenytoin sodium. Available in

2 mL and 5 mL single use vials, boxes of 10.

Phenytoin Sodium Injection USP

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PHARMACEUTICAL INFORMATION

Proper name: Phenytoin Sodium

Chemical Name:

5,5 - Diphenyl - 2,4 Imidazolidinedione Monosodium Salt,

5,5 - Diphenylhydantoin sodium salt.

Molecular Formula:

Molecular Weight:

274.25 g/mol

Structure:

phenytoin sodium

Description:

Phenytoin sodium occurs as a white, odourless, hygroscopic

powder and is freely soluble in water, soluble in alcohol, and

freely soluble in warm propylene glycol. It is insoluble in ether

and chloroform.

Phenytoin Sodium Injection USP

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REFERENCES

Omega Laboratories Ltd.

TREMYTOINE Product Monograph.

Control no 176329. Revision date: March 3, 2015

Phenytoin Sodium Injection USP

Page 20 of 25

PART III: PATIENT MEDICATION INFORMATION

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

Pr

Phenytoin Sodium Injection USP

Read this carefully before you or your child start taking Phenytoin Sodium Injection USP and

each time you get a refill. This leaflet is a summary and will not tell you everything about this

drug. Talk to your healthcare professional about your or your child’s medical condition and

treatment and ask if there is any new information about Phenytoin Sodium Injection USP.

Serious Warnings and Precautions

Cardiovascular Risk

You will receive Phenytoin Sodium Injection USP through injection into the vein or

muscle. If your doctor injects this medication into the vein too fast, your blood pressure

may drop quickly, and you may experience irregular heartbeat. This can be serious.

Therefore, your doctor should observe you closely while you are receiving Phenytoin

Sodium Injection USP and after.

What is Phenytoin Sodium Injection USP used for?

Phenytoin Sodium Injection USP is used for:

the control of generalized tonic-clonic seizures, and psychomotor seizures

the prevention and treatment of seizures that may begin during or after surgery to the

brain or nervous system.

How does Phenytoin Sodium Injection USP work?

Phenytoin Sodium Injection USP belong to the family of medicines called anticonvulsants. It

acts in the brain to block the spread of seizure activity.

What are the ingredients in Phenytoin Sodium Injection USP?

Medicinal ingredients: phenytoin sodium.

Non-medicinal ingredients: Propylene Glycol USP 40% and Alcohol USP 10% in Water for

Injection.

Phenytoin Sodium Injection USP comes in the following dosage forms:

Liquid: 50 mg/mL

Do not use Phenytoin Sodium Injection USP if you or your child:

Is allergic to the active ingredient (phenytoin sodium), phenobarbital, or any of the other

ingredients.

Have a serious heart condition (such as; sinus bradycardia, sino-atrial block, second and

third degree A.V. block, and Adams-Stokes syndrome).

Is taking delavirdine, a drug used to treat HIV.

Phenytoin Sodium Injection USP

Page 21 of 25

To help avoid side effects and ensure proper use, talk to your healthcare professional about

any health conditions or problems you or your child may have BEFORE taking Phenytoin

Sodium Injection USP, including if you or your child:

Have ever had a rash or unusual reaction while taking phenytoin sodium or any other

antiepileptic drug.

Have kidney or liver problems. Your doctor may need to adjust the dose.

Drink alcohol. Drinking alcohol with Phenytoin Sodium Injection USP may make you

less alert and may make feelings of anger, confusion or sadness worse.

Suffer from seizures that spread to the whole brain.

Are pregnant or planning to become pregnant. You must only take Phenytoin Sodium

Injection USP during pregnancy if your doctor tells you to.

If you become pregnant while taking Phenytoin Sodium Injection USP, talk to

your healthcare professional about registering with the North American

Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is

to collect information about the safety of antiepileptic medicine during pregnancy.

You can enroll in this registry by calling 1-888-233-2334.Information on the

registry can also be found at the website http://www.aedpregnancyregistry.org/.

Are nursing or plan to nurse your baby. Nursing while you are taking Phenytoin Sodium

Injection USP is not recommended.

Are taking birth control. Phenytoin Sodium Injection USP may make hormonal birth

control such as “the pill” less effective. Use other forms of safe and effective birth

control when taking Phenytoin Sodium Injection USP until the end of your menstrual

cycle after stopping treatment.

Are diabetic.

Have a blood disorder (such as porphyria).

Have Asian ancestry. You may be at an increased risk of developing serious skin

reactions.

Suffer from absence seizures or seizures caused by low blood sugar (hypoglycaemia) or

other metabolic causes.

Have low blood pressure.

Other warnings you should know about:

Ask your health professional about signs and symptoms of life threatening skin reactions

such as Stevens Johnson Syndrome (SJS; a skin reaction with rash and blisters) and

Toxic Epidermal Necrolysis (TEN; a skin rash often with blisters, lesions and lifting

skin) that have been reported during Phenytoin Sodium Injection USP treatment. Closely

monitor for skin reactions. Most often, SJS or TEN happen in the first weeks of

treatment. If symptoms or signs of SJS or TEN are present, Phenytoin Sodium Injection

USP treatment should be stopped. The best results in managing SJS and TEN come from

early detection and stopping the drug treatment right away (see table of Serious Side

Effects and What to do About Them, below).

Phenytoin Sodium Injection USP

Page 22 of 25

Antiepileptic drugs, including Phenytoin Sodium Injection USP, should not be abruptly

discontinued because of the possibility of increased seizure frequency, including status

epilepticus.

DURING treatment with Phenytoin Sodium Injection USP, tell your health professional if

you or your child develops:

Thoughts of suicide or self-harm

Abnormal vision (blurry or double vision)

Driving and using machines:

Before doing tasks that require special attention, wait until you know how you respond to

Phenytoin Sodium Injection USP. Being dizzy or drowsy can occur. Be careful to avoid

accidental injury or falls.

There are many drugs that may increase or decrease Phenytoin Sodium Injection USP

levels. Also, Phenytoin Sodium Injection USP may affect the levels of many drugs.

Therefore, tell your healthcare professional about all the medicines you or your child are

taking, including any drugs, vitamins, minerals, natural supplements or alternative

medicines, as there may be a need to adjust your medication or monitor you more

carefully.

The following may interact with Phenytoin Sodium Injection USP:

Birth control pills

Other anti-seizure drugs (such as ethosuximide, felbamate, topiramate, oxcarbazepine,

quetiapine, lamotrigine, methsuximide)

Alcohol

Delavirdine

Warfarin

Drugs used to treat fungal infections (such as fluconazole, ketoconazole, itraconazole,

voriconazole)

St. John’s Wort

Drugs used to treat HIV infection (such as efavirenz, lopinavir/ritonavir, indinavir,

nelfinavir, ritonavir, saquinavir)

Beta-Blockers used to treat heart problems

How to take Phenytoin Sodium Injection USP:

This medication is an injection. It will be given to you by your healthcare professional to stop a

seizure.

Usual dose:

Your healthcare professional will decide the dose that is right for you.

Overdose:

Phenytoin Sodium Injection USP

Page 23 of 25

If you think you have been given too much Phenytoin Sodium Injection USP, contact your

healthcare professional,

hospital emergency department or regional Poison Control Centre immediately, even if there

are no symptoms.

Missed Dose:

If you feel that a dose has been missed, contact your healthcare professional.

What are possible side effects from using Phenytoin Sodium Injection USP?

These are not all the possible side effects you may feel when taking Phenytoin Sodium Injection

USP. If you or your child experience any side effects not listed here, contact your healthcare

professional. Please also see Warnings and Precautions.

The most common side effects associated with the use of Phenytoin Sodium Injection USP are:

Sleepiness/drowsiness, feeling tired/fatigue

Headache, dizziness along with the feeling of a spinning movement

Nausea/vomiting

Changes in taste (metallic taste)

Double vision, blurred vision

Poor coordination (dizzy)

Shakiness

Unwanted, male-pattern hair growth in women

Thickening of the gums

Phenytoin Sodium Injection USP can cause abnormal blood test results. Your healthcare

professional will decide when to perform blood tests and will interpret the results.

Serious Side Effects and What to do About Them

Symptom / effect

Talk to your Healthcare

Professional

Get

Immediate

Medical Help

Only if severe

In all cases

Common

Low sodium level in blood (symptoms

like lack of energy, confusion, muscular

twitching or convulsions)

Nervous system problems (symptoms like

dizziness, trouble walking or with

coordination, feeling sleepy and tired,

trouble concentrating, blurred vision,

double vision etc.)

Allergies (symptoms like fever, rash and

swollen lymph nodes, and may be

associated with symptoms involving other

organs, e.g., liver)

Phenytoin Sodium Injection USP

Page 24 of 25

Serious Side Effects and What to do About Them

Symptom / effect

Talk to your Healthcare

Professional

Get

Immediate

Medical Help

Only if severe

In all cases

Uncommon

Liver problems (symptoms like yellowing

of your skin or the whites of your eyes,

nausea or vomiting, loss of appetite,

stomach pain, dark tea-like urine etc.)

Thoughts of suicide or self-harm

Thinning of the bone, bone softening,

bone disease, or fractures (In situations

where healthy people would not normally

break a bone you may have sudden pain

in any location and especially in the wrist,

spine or hip. This may be a fracture.)

Altered numbers and types of blood cells,

symptoms like unexplained tiredness,

weakness, shortness of breath, and

sometimes, feeling like you are going to

pass out and increased bruising,

nosebleeds, sore throats, or infections)

You should tell

your healthcare

professional who

may want to

perform a blood

test

Rare

Severe allergic reactions (symptoms like

swelling of face, eyes, lips, or tongue,

trouble swallowing or breathing, skin

rash)

A rare, serious disorder in which your

skin reacts severely to a medication

(Stevens Johnson Syndrome; SJS). If

symptoms or signs of SJS (e.g. skin rash

often with blisters or lesions) are present,

Phenytoin Sodium Injection USP

treatment should be stopped right away.

Severe skin reaction where the upper

surface of your skin detaches like a

patient who has suffered burns (Toxic

Epidermal Necrolysis [TEN]). If

symptoms or signs of TEN (e.g. skin rash

often with blisters or mucosal lesions and

lifting skin) are present, Phenytoin

Sodium Injection USP treatment should

be stopped right away.

Respiratory depression (shallow slow,

weak breathing)

Heart problems (symptoms like irregular

heartbeat, shortness of breath, chest pain

etc.)

Swelling, irritation, redness and pain at

the site of the injection or in the hand/arm

where the injection was given

If you or your child have a troublesome symptom or side effect that is not listed here or becomes

bad enough to interfere with your daily activities, talk to your healthcare professional

Phenytoin Sodium Injection USP

Page 25 of 25

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to Health

Canada by:

Visiting the Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp-

mps/medeff/report-declaration/index-eng.php) for information on how to report online,

by mail or by fax; or

Calling toll free at 1-866-234-2345 (toll-free);

NOTE: Contact your health professional if you need information about how to manage your

side effects. The Canada Vigilance Program does not provide medical advice.

Storage:

The healthcare professional will store Phenytoin Sodium Injection USP at a temperature between

C and 30

C; freezing should be avoided.

Keep out of reach and sight of children

If you want more information about Phenytoin Sodium Injection USP:

Talk to your healthcare professional

Find the full Product Monograph that is prepared for healthcare professionals and includes this

Patient Medication Information by visiting the Health Canada website (http://hc-sc.gc.ca/index-

eng.php); the manufacturer’s website www.sandoz.com; or, by calling 1-800-361-3062.

This leaflet was prepared by Sandoz Canada Inc.

Last Revised: June 21, 2017

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