PMS-METRONIDAZOLE

Main information

  • Trade name:
  • PMS-METRONIDAZOLE CAPSULE
  • Dosage:
  • 500MG
  • Pharmaceutical form:
  • CAPSULE
  • Composition:
  • METRONIDAZOLE 500MG
  • Administration route:
  • ORAL
  • Units in package:
  • 8/14/100
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • PMS-METRONIDAZOLE CAPSULE
    Canada
  • Language:
  • English

Therapeutic information

  • Therapeutic area:
  • MISCELLANEOUS ANTIPROTOZOALS
  • Product summary:
  • Active ingredient group (AIG) number: 0102572003; AHFS: 08:30.92

Other information

Status

  • Source:
  • Health Canada
  • Authorization status:
  • APPROVED
  • Authorization number:
  • 00783137
  • Authorization date:
  • 31-08-2006
  • Last update:
  • 27-11-2018

Summary of Product characteristics: dosage,interactions,side effects

PRESCRIBING INFORMATION

Pr

pms-METRONIDAZOLE

Metronidazole Capsules, House Standard

500 mg

Antibacterial - Antiprotozoal

PHARMASCIENCE INC.

Date of Revision:

April 13, 2018

6111 Royalmount Ave, Suite #100

Montréal, Canada

H4P 2T4

www.pharmascience.com

Control No. 214759

pms-METRONIDAZOLE Prescribing Information

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PRESCRIBING INFORMATION

Pr

pms-METRONIDAZOLE

Metronidazole Capsules, House Standard

500 mg

THERAPEUTIC CLASSIFICATION

Antibacterial - Antiprotozoal

ACTION AND CLINICAL PHARMACOLOGY

pms-METRONIDAZOLE (metronidazole) is bactericidal against anaerobic bacteria; it exerts

trichomonacidal activity and is also active against

Giardia lamblia

Entamoeba histolytica

. Its

exact mechanism of action has not been entirely determined as yet. It has been proposed that an

intermediate in the reduction of metronidazole, produced only in anaerobic bacteria and protozoa is

bound to deoxyribonucleic acid and electron-transport proteins, inhibits subsequent nucleic acid

synthesis.

INDICATIONS AND CLINICAL USE

pms-METRONIDAZOLE metronidazole) is indicated for the treatment of:

Protozoal Infections

Trichomonal infections in men as well as in women

Hepatic and intestinal amebiasis

Giardiasis

Bacterial Vaginosis

The “1988 Canadian Guidelines for the Treatment of Sexually Transmitted Diseases in Neonates,

Children, Adolescents and Adults” recommends metronidazole for the treatment of this condition.

Bacterial Infections

Treatment

Metronidazole is indicated in the treatment of serious anaerobic intra-abdominal infections due to

susceptible anaerobic bacteria, such as

Bacteroides fragilis

(and other species of Bacteroides),

Clostridium

Fusobacterium

Peptococcus

, and

Peptostreptococcus species

. In the treatment of most

serious anaerobic infections, intravenous metronidazole is usually administered initially. This may be

followed by oral therapy with pms-METRONIDAZOLE capsules at the discretion of the physician.

pms-METRONIDAZOLE Prescribing Information

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Culture and susceptibility studies should be performed to determine the causative organisms and their

susceptibility to metronidazole. Based on clinical judgment and anticipated bacteriological findings,

therapy may be started while awaiting the results of these tests. However, modification of the

treatment may be necessary once these results become available.

In mixed aerobic and anaerobic infections, consideration should be given to the concomitant

administration of an antibiotic appropriate for the treatment of the aerobic component of the infection

(see WARNINGS section).

Metronidazole has also been used in the treatment of a small number of cases of brain or lung

infections (some with abscesses) caused by anaerobic bacteria.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole

and other antibacterial drugs, pms-METRONIDAZOLE should be used only to treat infections that

are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility

information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the

empiric selection of therapy.

CONTRAINDICATIONS

pms-METRONIDAZOLE is contraindicated in patients with a prior history of hypersensitivity to

metronidazole or other nitroimidazole derivatives.

pms-METRONIDAZOLE should not be administered to patients with active neurological disorders

or a history of blood dyscrasia, hypothyroidism or hypoadrenalism.

WARNINGS

General

Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS

section). Unnecessary use of the drug should be avoided. Its use should be reserved for the

conditions described in the INDICATIONS AND CLINICAL USE section.

Metronidazole has no direct activity against aerobic or facultative anaerobic bacteria. In patients with

mixed aerobic-anaerobic infections, appropriate concomitant antibiotics active against the aerobic

component should be considered.

Known or previously unrecognized moniliasis may present more prominent symptoms after

treatment with metronidazole.

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Neurologic

Severe neurological disturbances (i.e., convulsive seizures and peripheral neuropathy) have been

reported in patients treated with metronidazole. These have been observed very infrequently.

Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or

transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.

pms-METRONIDAZOLE should be used with caution in patients with active or chronic severe

peripheral and central nervous system diseases due to the risk of neurological aggravation.

Patients should be advised not to take alcohol or alcohol-containing medicines during

pms-METRONIDAZOLE therapy and for at least one day afterwards because of the possibility of a

disulfiram-like (Antabuse effect) reaction.

Hepatic

pms-METRONIDAZOLE should be used with great caution in patients with a history of hepatic

enzyme increase or liver injury associated with previous administration of metronidazole (see

ADVERSE REACTIONS section).

Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome, with very

rapid onset after treatment initiation, in patients with Cockayne syndrome have been reported with

products containing metronidazole for systemic use. In this population, pms-METRONIDAZOLE

should therefore only be used after careful benefit-risk assessment and only if no alternative treatment

is available. Liver function tests must be performed just prior to the start of therapy, throughout and

after end of treatment until liver function is within normal ranges, or until the baseline values are

reached. If the liver function tests become markedly elevated during treatment, the drug should be

discontinued. Patients with Cockayne syndrome should be advised to immediately report any

symptoms of potential liver injury to their physician and stop taking pms-METRONIDAZOLE.

Susceptibility/Resistance

Development of Drug-Resistant Bacteria

Prescribing pms-METRONIDAZOLE in the absence of a proven or strongly suspected bacterial

infection is unlikely to provide benefit to the patient and risks the development of drug-resistant

bacteria.

PRECAUTIONS

General

Where there is clinical evidence of a trichomonal infection in the sexual partner, he should be treated

concomitantly to avoid reinfection.

A rare case of reversible but profound neurological deterioration has been reported following a single

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oral dose of metronidazole; it is therefore advisable that a patient taking pms-METRONIDAZOLE

for the first time not be left unattended for a period of two hours. The appearance of abnormal

neurologic signs demands prompt discontinuation of pms-METRONIDAZOLE therapy and, when

severe, immediate medical attention. Activated charcoal may be administered to aid in the removal of

unabsorbed drug, if no more than two or three hours have elapsed since administration of the drug.

If for compelling reasons, pms-METRONIDAZOLE must be administered longer than the usually

recommended duration, it is recommended that patients should be monitored for adverse reactions

such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures).

Treatment with pms-METRONIDAZOLE should be discontinued if ataxia or any other symptom of

central nervous system (CNS) involvement occurs.

Patients with severe hepatic disease (including hepatic encephalopathy) metabolize metronidazole

slowly with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly,

for such patients, doses of pms-METRONIDAZOLE below those usually recommended should be

administered and with caution.

Treatment with pms-METRONIDAZOLE should be discontinued should pancreatitis occur once

other causes of this disease are excluded.

Administration of solutions containing sodium ions may result in sodium retention. Care should be

taken when administering metronidazole injection to patients receiving corticosteroids or to those

predisposed to edema.

Patients should be warned that pms-METRONIDAZOLE may darken urine. This is probably due to a

metabolite of metronidazole and seems to have no clinical significance (see ADVERSE

REACTIONS section).

Hematologic

Transient eosinophilia and leukopenia have been observed during treatment with metronidazole.

Hematological tests, especially regular total and differential leukocyte counts are advised if

administration for more than 10 days or a second course of therapy is considered to be necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has been shown to be carcinogenic in the mouse and in the rat.

However similar

studies in the hamster have given negative results. Metronidazole has been shown to be mutagenic in

bacteria

in vitro

. In studies conducted in mammalian cells

in vitro

as well as in rodent

in vivo

, there

was inadequate evidence of mutagenic effect of metronidazole.

Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis. This has

been observed in all six reported studies in that species, including one study in which the animals

were dosed on an intermittent schedule (administration during every fourth week only). At very high

dose levels (approximately 1,500 mg/m

which is approximately 3 times the most frequently

recommended human dose for a 50 kg adult based on mg/m

), there was a statistically significant

increase in the incidence of malignant liver tumors in males. Also, the published results of one of the

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mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary

neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant.

Several long-term oral dosing studies in the rat have been completed. There were statistically

significant increases in the incidence of various neoplasms, particularly in mammary and hepatic

tumors, among female rats administered metronidazole over those noted in the concurrent female

control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to

be negative.

The use of pms-METRONIDAZOLE for longer treatment than usually required should be carefully

weighed since it has been shown to be carcinogenic in mice and rats (see WARNINGS section).

Fertility studies have been performed in mice at doses up to six times the maximum recommended

human oral dose (based on mg/m

) and have revealed no evidence of impaired fertility.

Pregnancy

Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Although

metronidazole has been given to pregnant women without apparent complication, its effects on

human fetal organogenesis are not known; it is advisable that administration of

pms-METRONIDAZOLE be avoided in pregnant patients and be withheld during the first trimester

of pregnancy. In serious anaerobic infections, if the administration of pms-METRONIDAZOLE to

pregnant patients is considered to be necessary, its use requires that the potential benefits to the

mother be weighed against the possible risks to the fetus.

Nursing Mothers

Metronidazole is secreted in breast milk in concentrations similar to those found in plasma.

Administration of pms-METRONIDAZOLE should be avoided in the nursing mother.

Children

Clinical experience in children is very limited. The monitoring of this group of patients is particularly

important.

Laboratory Test Interferences

Metronidazole interferes with serum AST

,

ALT, LDH, triglycerides and hexokinase glucose

determinations which are based on the decrease in ultraviolet absorbance which occurs when NADH

is oxidized to NAD. Metronidazole causes an increase in absorbance at the peak of NADH (340 nm)

resulting in falsely decreased values.

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DRUG INTERACTIONS

Alcohol

Patients taking pms-METRONIDAZOLE should be warned against consuming alcoholic beverages

and drugs containing alcohol during therapy and for at least one day afterwards, because of the

possibility of a disulfiram-like (antabuse effect) reaction (flushing, vomiting, tachycardia). This

reaction appears to be due to the inhibition of the oxidation of acetaldehyde, the primary metabolite of

alcohol.

Busulfan

Plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan

toxicity.

Cyclosporin

Risk of elevation of cyclosporin serum levels. Serum cyclosporin and serum creatinine should be

closely monitored when coadministration is necessary.

Disulfiram

Administration of disulfiram and metronidazole

has been associated with acute psychoses and

confusion in some patients; therefore, these drugs should not be used concomitantly.

5-Fluorouracil

Metronidazole

has been reported to reduce the clearance of 5-fluorouracil resulting in increased

toxicity of 5-fluorouracil.

Lithium

Concomitant use of lithium and metronidazole may result in lithium intoxication due to decreased

renal clearance of lithium. Persistent renal damage may develop. When pms-METRONIDAZOLE

must be administered to patients on lithium therapy, it may be prudent to consider tapering or

discontinuing lithium temporarily when feasible. Otherwise frequent monitoring of lithium,

creatinine and electrolyte levels and urine osmolality should be done.

Oral anticoagulant therapy (Warfarin type)

Metronidazole

has been reported to potentiate the anticoagulant effect of warfarin resulting in a

prolongation of prothrombin time and increased hemorrhagic risk caused by decreased hepatic

catabolism. This possible drug interaction should be considered when pms-METRONIDAZOLE is

prescribed for patients on this type of anticoagulant therapy. In case of coadministration, prothrombin

time should be more frequently monitored and anticoagulant therapy adjusted during treatment with

pms-METRONIDAZOLE.

Phenytoin or Phenobarbital

In single dose studies, metronidazole injection did not interfere with the biotransformation of

diazepam, antipyrine or phenytoin in man. However, patients maintained on phenytoin were found to

have toxic blood levels after oral metronidazole administration. Phenytoin concentration returned to

therapeutic blood level after discontinuance of metronidazole.

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The metabolism of metronidazole has been reported to be increased by concurrent administration of

phenobarbital or phenytoin

.

Vecuronium

A slight potentiation of the neuromuscular blocking activity of vecuronium has been reported in

patients administered metronidazole at a dose of 15 mg/kg.

ADVERSE REACTIONS

Blood and lymphatic system disorders:

Transient eosinophilia, neutropenia, very rare cases of

agranulocytosis and thrombocytopenia have been reported.

Cardiac disorders:

Palpitation and chest pain.

Eye disorders:

Transient vision disorders such as diplopia, myopia, blurred vision, decreased visual

acuity, changes in color vision. Optic neuropathy/neuritis has been reported.

Ear and labyrinth disorders:

Hearing impaired/hearing loss (including hypoacusis, deafness, deafness neurosensory)

Tinnitus

Gastrointestinal disorders:

Diarrhea, nausea, vomiting, epigastric distress, epigastric pain,

dyspepsia, constipation, coated tongue, tongue discoloration/furry tongue (e.g., due to fungal

overgrowth), dry mouth, taste disorders including metallic taste, oral mucositis. Reversible cases of

pancreatitis have been reported infrequently.

General disorders and administration site conditions:

Thrombophlebitis has occurred with IV

Administration. Fever has been reported.

Hepatobiliary disorders:

Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or

mixed hepatitis and hepatocellular liver injury, sometimes with jaundice have been reported.

Cases of liver failure requiring liver transplant have been reported in patients treated with

metronidazole in combination with other antibiotic drugs.

Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome, in patients

with Cockayne syndrome have been reported with products containing metronidazole.

Immune system disorders:

Angioedema, anaphylactic shock.

Infections and infestations:

Rare cases of pseudomembranous colitis have been reported.

Metabolism and nutrition disorders:

An antithyroid effect has been reported by some investigators

but three different clinical studies failed to confirm this. Anorexia has been reported.

Nervous system disorders:

Convulsive seizures, peripheral sensory neuropathy, transient ataxia,

dizziness, drowsiness, insomnia, headache, and aseptic meningitis.

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Very rare reports of encephalopathy (e.g., confusion) and subacute cerebellar syndrome (e.g., ataxia,

dysarthria, gait impairment, nystagmus, and tremor) have been reported, which may resolve with

discontinuation of the drug.

Peripheral neuropathies have been reported in a few patients on moderately high to high-dose

prolonged oral treatment with metronidazole. It would appear that the occurrence is not directly

related to the daily dosage and that an important predisposing factor is the continuation of oral and/or

IV medication for several weeks or months.

Profound neurological deterioration, within two (2) hours after metronidazole

administration has

been reported. The occurrence is not directly related to the dosage level.

Other:

Proliferation of

Candida albicans

in the vagina, vaginal dryness and burning, dysuria;

occasional flushing and headaches, especially with concomitant ingestion of alcohol; altered taste of

alcoholic beverages.

Darkening of the urine has been reported. This is probably due to a metabolite of metronidazole and

seems to have no clinical significance (see PRECAUTIONS section). Reversible lowering of serum

lipids has been reported.

Psychiatric disorders:

Psychotic disorders including confusion, hallucinations, depressed mood.

Reproductive system and breast disorders:

A single case of gynecomastia has been reported which

resolved on discontinuing metronidazole

administration.

Skin and subcutaneous tissue disorders:

Hypersensitivity reactions including flushing, urticaria,

rash, and pruritus, very rare pustular eruptions, fixed drug eruption. Cases of Stevens-Johnson

Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Many of these case

reports revealed the use of concomitant medications known to be associated with SJS or TEN.

OVERDOSAGE

Symptoms

Single oral doses of metronidazole, up to 12 g have been reported in suicide attempts and accidental

overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. Neurotoxic effects,

including seizures and peripheral neuropathy have been reported after 5 to 7 days of oral doses of 6 to

10.4 g every other day.

Treatment

There is no specific antidote. Activated charcoal may be administered to aid in the removal of

unabsorbed drug. General supportive measures are recommended.

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

immediately.

DOSAGE AND ADMINISTRATION

Swallowed capsules whole. DO NOT open, divide, crush or chew the capsules

Treatment of Trichomoniasis

Consideration should be given to use pms-METRONIDAZOLE therapy in female patients, only

when trichomonal infection has been confirmed by appropriate diagnostic techniques. In the male

patient, pms-METRONIDAZOLE is recommended in those who are evidently the source of

reinfection in female consorts and those with demonstrated urogenital trichomoniasis (see

WARNINGS section).

Single-Dose Treatment

For both women and men, 2 g administered as a single dose after a meal.

Standard Ten-day Treatment

Women – 250 mg twice a day, morning and night for 10 consecutive days.

Men – 250 mg twice a day for 10 consecutive days.

For both men and women, it may be occasionally necessary to give a second ten-day course after 4 to

6 weeks.

Treatment of Amebiasis

Adults

Intestinal Amebiasis - 750 mg three times daily for 5 to 7 days.

Amebic abscesses of the liver – 500 mg to 750 mg three times daily for 5 to 7 days.

Children

Administer 35 to 50 mg/kg/day in three divided doses for 5 to 7 days.

Treatment of Giardiasis

Adults

250 mg twice daily for 5 to 7 days

Children

Administer 25 to 35 mg/kg/day in two divided doses for 5 to 7 days.

Note – The efficacy of the recommended dosages for the treatment of Amebiasis and Giardiasis has

been demonstrated. However, the optimal dose, the duration of treatment and the risk of recurrence

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have not been completely established.

Treatment of Bacterial Vaginosis

Adults

500 mg orally twice a day for 7 days

Concurrent treatment of sexual partners is not usually indicated.

Anaerobic Infections

Adults

Treatment

In the treatment of most serious anaerobic infections, intravenous metronidazole is usually

administered initially. This may be followed by oral therapy with pms-METRONIDAZOLE capsules

at the discretion of the physician.

Duration of therapy depends upon clinical and bacteriological assessment. Treatment for 7 days

should be satisfactory for most patients. However, in cases where infection sites cannot be drained or

which are liable to endogenous recontamination by anaerobic pathogens, a longer treatment may be

required.

Oral Administration

500 mg every 8 hours

The 250 mg strength is not marketed by Pharmascience Inc.

Severe hepatic disease

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of

metronidazole and its metabolites. Accordingly, doses below those usually recommended should be

administered and with caution. However, due to a lack of pharmacokinetic information, specific

dosage recommendations cannot be given for these patients. Therefore, close monitoring of blood

metronidazole levels and of the patients for signs of toxicity are recommended (see WARNINGS and

PRECAUTIONS sections).

Severe impairment of renal function and anuria

The elimination half-life of metronidazole in anuric patients is not significantly altered. However, the

elimination half-lives of the metabolites of metronidazole are significantly increased (3- to 13-fold).

Consequently, although metronidazole would not be expected to accumulate in these patients,

accumulation of the metabolites would be expected. The potential for toxicity of these metabolites is

not known.

Patients on hemodialysis

The dose of pms-METRONIDAZOLE does not need to be specifically reduced since accumulated

metabolites may be rapidly removed by hemodialysis.

Patients on peritoneal dialysis

Peritoneal dialysis does not appear to reduce serum levels of metronidazole metabolites.

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Patients with severe impairment of renal function who are not undergoing hemodialysis should be

monitored closely for signs of toxicity.

Children

The safety and effectiveness of metronidazole in children is not known. Due to lack of

pharmacokinetic data, no dosage recommendations can be made (see PRECAUTIONS section).

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PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name:

Metronidazole

Chemical Name:

1-(2-Hydroxyethyl)-2-methyl-5-nitroimidazole

Molecular Formula:

Molecular Mass:

171.15 g/mol

Structural Formula:

Physicochemical Properties

Description:

White crystalline powder with slight yellow tint

Solubility:

Slightly soluble in water, alcohol, chloroform and ether

pKa:

5.8 (saturated solution)

Melting Point:

159°C to 163°C

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DOSAGE FORMS, COMPOSITION AND PACKAGING

Each capsule has a green body printed “500 mg”, blue cap printed “pms”. It contains 500 mg of

metronidazole. Non-medicinal ingredients: Colloidal Silicon Dioxide, Magnesium Stearate and

Microcrystalline Cellulose. The capsule shells contain: AD&C Blue No. 1, AD&C Green No. 3,

D&C Red No. 28, D&C Yellow No. 10, Gelatin, Titanium Dioxide.

The capsules are packaged in HDPE bottles of 100.

STORAGE AND STABILITY

pms-METRONIDAZOLE capsules should be stored between 15°C and 30°C.

Keep out of reach and sight of children.

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MICROBIOLOGY

Bacteriology

Metronidazole is active

in vitro

against most obligate anaerobes but does not appear to possess any

relevant clinical activity against facultative anaerobes or obligate aerobes.

In one study the minimum inhibitory concentrations of metronidazole were determined in 730 strains

of anaerobic bacteria isolated from clinical specimens. The results are summarized in the following

table:

Table 1: ACTIVITY* OF METRONIDAZOLE AGAINST ANAEROBIC BACTERIA

No. of

strains

tested

CUMULATIVE PER CENT SUSCEPTIBLE AT THE INDICATED

CONCENTRATION

(mg/mL)

BACTERIA

0.1

0.5

1.0

2.0

4.0

8.0

16.0

32.0

64.0

128

256

Bacteroides fragilis

group

Bacteroides

melaninogenicus

Other bacteroides

Fusobacterium

nucleatum

Other fusobacterium

Peptococcus and

Gaffkya

Peptostreptococcus

Microaerophilic and

anaerobic

streptococci

Gram-negative cocci

(Acidaminococcus,

Megasphaera,

Veillonella)

Eubacterium

Arachnia

Propionibacterium

Actinomyces

Bifidobacterium

Lactobacillus

Clostridium

perfringens

Other clostridium

* Determined using an agar dilution technique described in the Wadsworth Anaerobic Bacteriology Manual, 2nd ed. University of

California, Los Angeles, Extension Division, 1975.

With rare exceptions, anaerobic gram-negative non-spore forming bacilli and cocci as well as

Clostridium

species were susceptible to concentrations of metronidazole of 16 mg/L or less. A few

strains of

Peptococcus

Peptostreptococcus

required 128 mg or more per litre of metronidazole

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for inhibition. Metronidazole was relatively ineffective against

Streptococcus

strains and the

gram-positive non-spore forming bacilli.

A series of

in vitro

determinations demonstrated that the minimum bactericidal concentrations

against susceptible strains are generally within one dilution of the minimum inhibitory

concentrations.

With

Bacteroides fragilis

fold increases in inoculum size have resulted in two to four fold

increases in M.I.C. and M.B.C. values. The bactericidal effect of metronidazole is not significantly

affected by pH changes within the range of 5.5 to 8.0.

Susceptibility testing

Quantitative methods give the most precise estimate of susceptibility to antibacterial drugs. A

standardized agar dilution method and a broth microdilution method are recommended. A bacterial

isolate may be considered susceptible if the M.I.C. value for metronidazole is not more than 16 mg/L.

An organism is considered resistant if the M.I.C. is greater than 16 mg/L.

Parasitology

Trichomonacidal Activity

In Vitro

activity was studied using decreasing concentrations of metronidazole, which were added to

a series of

Trichomonas vaginalis

cultures maintained at 37°C. A 1:400,000 dilution of

metronidazole killed up to 99% of the

trichomonas

in 24 hours.

In Vivo

, 0.5 mL of a 48-hour culture of

Trichomonas vaginalis

injected under the dorsal skin in a

control and a test group of mice revealed, seven days later, extensive abscess-like lesions swarming

with

trichomonas

in the control group and normal sub-cutaneous tissue free of

trichomonas

in the

animals which had received oral metronidazole in a daily dosage of 12.5 mg/kg of body weight.

Amebicidal Activity

In Vitro

, the minimum inhibitory concentration of metronidazole required to immobilize over a

48-hour period a culture of

Entamoeba histolytica

maintained at 37°C was 3 mg/L.

In Vivo

, the amebicidal activity of metronidazole has been demonstrated in various tests.

In the young rat, an intestinal infestation was induced in the caecum by the inoculation of an amebic

culture or of a homogenate of caecums obtained from young rats previously infested in the same

manner. Metronidazole, 100 mg/kg/day p.o. administered during 4 consecutive days, the first dose

being given 24 hours after infestation, protected all the animals. On the other hand, when the drug was

administered on 4 consecutive days, starting on the day that the animals were infested, it had a CD

of 22 mg/kg/day in the intestinal amebiasis of the young rat. Finally, the CD

when the product was

given in a single dose 24 hours after infestation was 49 mg/kg/day p.o.

In the hamster, hepatic amebiasis was induced by the inoculation of a culture of amebae under the

capsule of Glisson; metronidazole administered orally during 4 consecutive days protected all the

animals at a dosage of 35 mg/kg/day while its CD

was 15 mg/kg/day.

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Activity against Giardiasis

The activity of metronidazole against giardiasis has been demonstrated in mice infested by

Lamblia

muris.

The product administered once a day on two consecutive days had a CD

of 30 mg/kg/day

while its therapeutic index was 1/100.

DETAILED PHARMACOLOGY

Animal Pharmacology

Metronidazole exerted no central nervous system activity except at very high doses. At doses of

0.5g/kg and above, some anticonvulsant activity was demonstrated in mice and rats, spinal reflexes

were inhibited in the anaesthetized cat and hypnosis was produced in the rat.

Metronidazole at doses of 40 to 50 mg/kg administered by intravenous infusion to 4 anaesthetized

dogs produced a slight fall in blood pressure and heart rate for 30 to 60 minutes after the infusion.

There was little or no effect on the electrocardiographic tracings. With both metronidazole and the

vehicle, there was a tendency for dogs to bleed more readily than untreated animals although plasma

prothrombin times remained within normal limits.

Human Pharmacology and Kinetics

Pharmacokinetics

Following oral administration, metronidazole is completely absorbed with plasma concentration

usually reaching a peak within 1 to 2 hours. After single oral 500 mg doses, peak plasma levels of

approximately 13 mg/L were obtained. On a regimen of 500 mg t.i.d. administered by the IV route, a

steady state was achieved after approximately 3 days. The mean peak and trough concentrations

measured at that time were 26 and 12 mg/L respectively, and the elimination half-life was

approximately 7 to 8 hours. Comparison of the pharmacokinetics of oral and IV metronidazole

revealed that the area under the plasma metronidazole concentration against time curves were

essentially identical.

There is negligible percutaneous absorption following topical application of metronidazole 1%

cream. In healthy volunteers who applied a single 100 mg dose of

C-labelled metronidazole 2%

cream to intact skin, no metronidazole could be detected in plasma after 12 hours. Only about 1%

and 0.1% of the applied dose could be found in urine and feces, respectively. After once-daily

application of the 1% cream for 1 month, only traces (about 1% of the C

of a 200 mg oral dose)

could be detected in 25% of patients. In the rest of the patients, no detectable plasma levels were

found.

pms-METRONIDAZOLE Prescribing Information

Page 18 of 31

Figure 1: Mean plasma metronidazole concentrations following a single oral or intravenous dose of metronidazole

(500 mg) (n=9 females

In two kinetic studies in which a single Metronidazole 1.5 g dose was infused intravenously over a

50-60 minutes period in volunteers, a peak level of 30-40 mg/L was obtained 1 hour after the start of

infusion and fell to 10 mg/L at 12 h and 4 mg/L at 24 hour.

pms-METRONIDAZOLE Prescribing Information

Page 19 of 31

Figure 2: Mean plasma metronidazole concentration following a single intravenous dose of metronidazole (1.5 g)

(n=10)

Excretion and Metabolism

The major route of elimination of metronidazole and its metabolites is via the urine (60-80% of the

dose) with fecal excretion accounting for 6 to 15% of the dose. The metabolites that appear in the

urine result primarily from side chain oxidation (i.e., 1-(ß-hydroxyethyl)-2-hydroxymethyl-5-

nitroimidazole and 2-methyl-5 nitroimidazole-1-yl-acetic acid) and glucuronide conjugation, with

unchanged metronidazole accounting for approximately 20% of the total.

Metronidazole is the major component appearing in the plasma with lesser quantities of the 2-

hydroxymethyl metabolite also being present. The ratio of these components varies with time but the

maximum concentration of the metabolite (C

) is approximately 20% of the C

of metronidazole

for the oral route of administration.

pms-METRONIDAZOLE Prescribing Information

Page 20 of 31

Protein Binding

Less than 20% of the circulating metronidazole is bound to plasma proteins.

Tissue Distribution

The concentrations of metronidazole found in various tissues and body fluids are given in the

following table:

Table 2: Concentrations of metronidazole in various tissues and body fluids

TISSUE OR FLUID

DOSE

ADMINISTERED

TISSUE OR FLUID

LEVEL

PLASMA LEVEL

Bile

500 mg q.i.d.

p.o. x 10 days

26 mg/L (on day 5)

20 mg/L (on day 15)

N/A*

Saliva

500 mg p.o.

single dose

7 mg/L

(at 2-3 hour)

Placenta

250 mg p.o.

single dose

0 to 1.4 mg/kg

(at 4-5 hour)

3.0 - 6.9 mg/L

(maternal)

Embryo

250 mg p.o.

single dose

0 - 1.0 mg/kg

3.0 - 6.9 mg/L

(maternal)

Breast milk

200 mg p.o.

1.3 to 3.4 mg/L

1.8 - 3.9 mg/L

Cerebrospinal fluid

500 mg p.o. b.i.d.

11.0 to 13.9 mg/L

8.3 - 15.4 mg/L

Pus (brain abscess)

400 mg p.o. t.i.d.

600 mg IV t.i.d.

35 mg/L

inflamed meninges

43 mg/L

Pus (pulmonary empyema)

400 mg, p.o. q.i.d.

24.2 mg/L

* Not available

Decreased Renal Function

Decreased renal function does not appear to alter the single dose pharmacokinetics of metronidazole,

although the elimination half-life of the metabolites is prolonged.

Hemodialysis

During hemodialysis, the hydroxy metabolite is removed from the plasma about three times more

rapidly than in normal subjects. Comparison of the elimination half-lives of metronidazole and two

metabolites are given in the following table.

pms-METRONIDAZOLE Prescribing Information

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Table 3: Metronidazole elimination in normal subjects and in patients with renal insufficiency following a single

intravenous dose of metronidazole (500 mg)

ELIMINATION HALF LIFE (hours)

Patients

Compound

Normal Subjects

on dialysis

between dialysis

Metronidazole

7.3 ± 1.0

2.6 ± 0.7

7.2 ± 2.4

1-(β-hydroxyethyl)

2-hydroxymethyl-5

nitroimidazole

9.8 ± 1.3

7.8 ± 4.1

34± 43

2-methyl-5-nitroimi

dazole-1-yl-acetic

acid

7.9 ± 4.1

138 ± 82

Therefore, no accumulation should occur in anuric patients undergoing regular dialysis.

Continuous Ambulatory Peritoneal Dialysis

Metronidazole was given IV at 750 mg to five patients undergoing continuous ambulatory peritoneal

dialysis (CAPD). Insignificant changes were noted in the pharmacokinetic parameters of

metronidazole (apparent volume of distribution, elimination half-life, total body clearance).

Peritoneal dialysis does not appear to reduce the serum levels of metronidazole metabolites.

Impaired Liver Function

In patients with impaired liver function, the plasma clearance of metronidazole is decreased and

accumulation can therefore result.

TOXICOLOGY

Acute Toxicity

The LD

values for metronidazole are given in the following Table:

Table 4: Values of LD

50

for metronidazole

SPECIES

SEX

ROUTE

LD

50

(mg/kg)

Mouse

p.o.

i.p.

4,350

3,650

1,170

1,260

p.o.

i.p.

5,000

5,000

1,575

1,575

pms-METRONIDAZOLE Prescribing Information

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Signs of toxicity following oral and intravenous administration of metronidazole were sedation,

ataxia and death in mice, and sedation and death in rats.

The acute toxicity of metronidazole was also tested in dogs. Beagle dogs (male or female, 1 dog per

dose) were administered single oral doses of 500, 750, 1,000, 1,500, 3,000 or 5,000 mg/kg of

metronidazole by gastric intubation. The highest oral dosage which did not produce neurological

disturbances and severe vomiting was 500 mg/kg. At the higher doses, ataxia, loss of spatial

judgment, dozing, walking blindly, a general state of unawareness, convulsion, retching and/or

vomiting were observed. There were no deaths but the dogs which received 1,500 and 5,000 mg/kg

were killed on humane grounds 48 and 2½ hours after dosing, respectively.

Pairs of one male and one female beagle were administered total doses of 125, 200 or 250 mg/kg of

metronidazole. These were given as 4 or 5 separate injections at hourly intervals, except for the 125

mg/kg dose which was given at half-hourly intervals. At 200 mg/kg, the male trembled during the

third injection, the female appeared slightly lethargic following the third injection and its heart rate

was rapid during the final injection. Following the 125 mg/kg and 250 mg/kg doses, no sign nor

evidence of intolerance at the injection sites was observed.

The ocular irritant effects of 0.5%, 1% and 2% topical metronidazole cream and placebo cream were

tested in rabbits. An aliquot (0.1 mL) of one of the cream formulations was placed in the lower lid of

one eye of each of three animals. The eyes were subsequently examined for the appearance and

severity of ocular lesions after 1 hour, and 1,2,3,4, and 7 days after instillation. Mild conjunctival

irritation was noted in several animals in both the active and placebo cream groups. The eyes of the

animals in all treatment groups normalized within 1 to 3 days of instillation. None of the rabbits

showed any corneal or inidial inflammation.

Subacute and Chronic Toxicity

Rats were administered metronidazole orally at doses of 0, 25 and 50 mg/kg for a month, 100 mg/kg

for fifteen days, and 1,000 mg/kg for thirty days. Except for testicular changes which consisted of

minor epithelial desquamation and fewer spermatocytes in the epididymus in the 100 and 1,000

mg/kg groups, no other abnormalities were observed. No interference with fertility or embryogenesis

was observed.

Twenty male and 20 female rats were administered metronidazole intravenously at a dose of

30 mg/kg/day for 4 weeks. There was no evidence of local intolerance at the injection site. A

statistically significant decrease in body weight gain was noted in the males only, with their overall

weight increase being about 90% that of controls. Mean absolute and relative (to bodyweight) thyroid

weights were significantly lower (by approximately 25%) than the control values in both sexes in the

treated group. However, at microscopic examination, the architecture of the thyroid glands of treated

animals was within normal limits. In another study conducted under the same experimental

conditions, assessment of the thyroid function before and at the end of the dosing period revealed no

effect of metronidazole in rats.

Dogs were administered metronidazole orally at doses of 0, 25 and 50 mg/kg for a period of one

month. They showed no physical or biological alteration and no tissue modification. Other dogs

pms-METRONIDAZOLE Prescribing Information

Page 23 of 31

dosed at 75, 110 and 225 mg/kg for a period of six months developed ataxia, muscular rigidity and

tremor. No apparent dulling of the sensorium was noted.

Two male and 2 female dogs were administered metronidazole intravenously at doses of 37.5 mg/kg

5 days per week for 4 weeks. In the two males and in one of the 2 females, the relative weights of the

thyroids were below control values (31% decrease for males and 26% decrease for females).

Teratogenicity Studies

Metronidazole has been evaluated for its embryotoxic and teratogenic potential in the rat, rabbit and

mouse. In four studies performed in the rabbit, the compound was administered orally by capsule, by

buccal intubation or by gastric intubation at doses of 30 to 200 mg/kg/day for periods ranging from 3

to 13 days during pregnancy. Neither embryotoxic nor teratogenic effects related to drug

administration were observed.

In one study metronidazole was administered intravenously to rabbits (18 per group) at doses of 15 or

30 mg/kg/day from days 6-18 of pregnancy inclusive. There were no statistically significant

differences between control and treated groups for any foetal parameter, but discrepancies between

the numbers of corpora lutea and implantation sites suggested that the drug may have caused a

10-15% increase in pre-implantation loss. No embryotoxic or teratogenic effects were observed.

In five rat studies, metronidazole was administered either at a dietary concentration of 0.13% for 18

days of gestation, or by gastric intubation at dose levels from 50 to 200 mg/kg/day for periods ranging

from 10 days (mid-gestation) to 40 days (before and during pregnancy). Drug-related embryotoxic or

teratogenic effects were not observed in any of the five studies.

In rats, metronidazole was administered intravenously at doses of 15 or 30 mg/kg/day from days 5-17

of pregnancy inclusive. There was a statistically significant increase in the mean numbers of

implantations and live foetuses per litter in the metronidazole treated groups, but no difference in any

other foetal parameter.

In one mouse study, two groups of mice were treated from the sixth to the fifteenth day of gestation.

Metronidazole was administered by gastric intubation at doses of 10 and 20 mg/kg/day.

At the dosage utilized, metronidazole was devoid of any teratogenic activity.

In humans, data has been accumulated on 2,500 women who received metronidazole at various stages

during pregnancy. The overall incidence of congenital abnormalities remained within the expected

limits for untreated mothers and an examination of the reports revealed that there was no trend or

consistent pattern in the reported defects nor was there any evidence of causal relationship.

Mutagenicity Studies

The mutagenic potential of metronidazole has been measured in two test systems. In a study using a

bacterial indicator strain to detect mutagenic effects, positive results were reported. The inherent

antimicrobial property of metronidazole further complicates the interpretation respecting genetic and

carcinogenic hazard to man. The other test system, the dominant lethal test, measured the effect of

metronidazole on mammalian germ cells. Male rats administered doses of metronidazole up to

pms-METRONIDAZOLE Prescribing Information

Page 24 of 31

600 mg/kg/day for five consecutive days, were mated to untreated females. Fetal deaths, the primary

measure of dominant lethality, were not increased in those females mated to treated males.

Tumorigenicity Studies

Two separate tumorigenic studies were carried out in two different strains of mice with

metronidazole. Metronidazole was administered in the diet at daily doses of 75, 150 and 600 mg/kg in

both experiments.

A study with the strain of Swiss mice was terminated after 78 weeks, while the other experiment with

CF1 mice was terminated at 92 weeks.

There was no evidence that the administration of metronidazole at any dosage level produced an

adverse effect upon the physical appearance, behavior, body weight and food consumption. However,

the survival in mice in the treated groups was better than that in the controls.

Statistical analysis of necropsy data, gross and microscopic, using life-table and other techniques

revealed a significant increase in the rate of benign lung tumors in the groups of mice treated with 600

mg/kg. With the lower dosage, there was also a trend for increased rate; however, the changes were

not significant. It should, though, be noted that this type of tumor was also seen in up to 30% of mice

in the untreated groups.

In the rat, dose levels of 75, 150 and 300 mg/kg/day were administered orally in the diet for 80

consecutive weeks; a dosage of 600 mg/kg was administered for 13 weeks only. No consistent

deleterious effects were observed with doses of 75 and 150 mg/kg for 28-80 weeks on physical,

behavioral, clinical laboratory or post-mortem examinations. At the dosage of 300 mg/kg, testicular

dystrophy was regularly encountered at 13 weeks or longer and was not reversed by a 28 week

recovery (no drug) period; prostatic atrophy was also seen at 26 weeks. The 600 mg/kg dosage group

showed a high incidence of testicular dystrophy and prostatic atrophy with a pronounced reduction in

the rate of body weight gain. There was a significant increase in the number of benign mammary

tumors only in the females of the 300 mg/kg group.

Two independent tumorigenicity studies conducted in the hamster gave negative results

pms-METRONIDAZOLE Prescribing Information

Page 25 of 31

REFERENCES

Auger P, Bourgouin J, Bagot C. Intravenous metronidazole in the treatment of abdominal

sepsis: once vs three times daily administration. Curr Ther Res 1988; 43: 494-502.

Auger P, Legros G, Girard R, Laverdiere M, Bergeron M, Bourgouin J, Le Morvan P.

Intravenous metronidazole vs oral erythromycin base plus neomycin in the prevention of

infection following elective colorectal surgery. Curr Ther Res 1987; 42: 922-931.

Bost RG.: Metronidazole: Toxicology and Teratology.

Excerpta Medica, I.C.S. 438 Proceedings of the International Metronidazole Conference,

Montreal, May 1976, pp. 112-118.

Brass C, Richard GK, Ruedy J, Prentis J, Hincey EJ. The Effect of Metronidazole on the

Incidence of Postoperative Wound Infection in Elective Colon Surgery. Am J Surg 1978; 135:

91-96.

Brogden RN, Heel RC, Speight TM, Avery GS. Metronidazole in Anaerobic Infections: A

Review of its Activity, Pharmacokinetics and Therapeutic Use. Drugs 1978: 16: 386-417.

Cerat GA, Cerat LL, Mchenry MC, Wagner JG, Hall PM, Gavan TL. Metronidazole in Renal

Failure. Excerpta Medica, I.C.S. 1977; 438: Proceedings of the International Metronidazole

Conference. Montreal, May 1976. 404-414.

Chow AW, Bednorz D, Guze LB. Susceptibility of Obligate Anaerobes to Metronidazole: An

Extended Study of 1,054 Clinical Isolates. Excerpta Medica, 1977 I.C.S. 438: Proceedings of

the International Metronidazole Conference. Montreal, May 1976. 286-292.

Corey WA, Doebbeling BN, Dejong KJ, Britigan BE. Metronidazole-induced acute

pancreatitis. Rev Infect Dis 1991; 13: 1213-1215.

Cosar C, Ganter P, Julou L. Etude expérimentale du métronidazole (8823 R.P.). Activités

trichomonacide et amoebicide. Toxicité et propriétés pharmacologiques générales. Presse

Méd 1961; 69: 1069.

Darbon A, Portal A, Girier L, Pantin J, Leclaire C. Traitement de la giardiase (lambliase) par

le métronidazole -A propos de cent observations. Presse Méd 1962; 70: 15.

Davis JL, Schultz TA, Moseley CA. Metronidazole lowers serum lipids. Am Int Med 1983;

99: 43-44.

Durel P, Roiron V, Siboulet A, Borel LJ. Systemic treatment of trichomoniasis with

nitro-imidazole derivative, R.P. 8823. Presented at the Canadian Symposium on

non-gonococcal urethritis, held in Montreal, September 1959.

Dykers Jr MD, John R. Single-Dose Metronidazole for Trichomonal Vaginitis. New Eng J of

Med 1975; 293 23.

pms-METRONIDAZOLE Prescribing Information

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Fagan TC, Johnson DG, Grosso DS. Metronidazole-induced gynecomastia. JAMA 1985;

254: 3217.

Feo LG, Fetter TR. Flagyl in treatment of male trichomoniasis. J Urol (Baltimore) 1961; 86:

154-156.

Fleury FJ, Van Bergen WS, Prentice RL, Russell JG, Singleton JA, Standard JV. Single Dose

of two grams of metronidazole for trichomonas vaginalis infection. Am J Obstet Gynecol

1977; 128: 320-322.

Gabriel R, Page CM, Weller IVD, Collier J, Houghton CW, Templeton R, Thorne PS. The

Pharmacokinetics of Metronidazole in Patients with Chronic Renal Failure. The Royal

Society of Medicine. International Congress and Symposium. Series No. 18. Proceedings of

the 2nd International Symposium on Anaerobic Infections held in Geneva. April 1979. pp.

49-54.

Giamarellou H, Kanellakopoulou K, Pragastis D, Tagaris N, Daikos GK. Treatment with

metronidazole of 48 patients with serious anaerobic infections. J Antimicrobial Chemother

1977; 3: 347-353.

Houghton GW, Thorne PS, Smith J, Templeton R, Collier J, Moesgaard F,

Lukkegaard-Nielsen M. The Pharmacokinetics of Intravenous Metronidazole (single and

multiple dosing). The Royal Society of Medicine. International Congress and Symposium.

Series No. 18. Proceedings of the 2nd International Symposium on Anaerobic Infections held

in Geneva. April 1979. pp. 35-40.

Houghton GW, Thorne PS, Smith J, Templeton R, Collier J. Comparison of the

Pharmacokinetics of Metronidazole in Healthy Female Volunteers Following either a Single

Oral or Intravenous Dose. Br J Clin Pharmacol 1979; 8: 337-341.

Ingham HF, Selkon JB, Roxby CM. The bacteriology and chemotherapy of cerebral abscesses

secondary to middle ear disease and dental sepsis. The Royal Society of Medicine.

International Congress and Symposium. Series No. 18. Proceedings of the 2nd International

Symposium on Anaerobic Infections held in Geneva. April 1979. pp. 91-96.

Jennison RF, Stenton P, Eatt L. Laboratory studies with the systemic trichomonacide,

metronidazole. J Clin Path 1961; 14: 431.

Jensen JC, Guglar R. Interaction between metronidazole and drugs eliminated by oxidative

metabolism. Clin Pharmacol Ther 1985; 37: 407-410.

McNaught W. Metronidazole in the treatment of intra-abdominal infections. Excerpta

Medica, I.C.S. 438. Proceedings of the International Metronidazole Conference. Montreal,

May 1976. p. 347.

Miller MJ, Scott F, Foster EF. Community control of amebic disease by periodic mass

treatment with metronidazole. Am J Tropical Med Hygiene 1972; 2l: 400-403.

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Muller M. Mode of action of metronidazole on anaerobic micro-organisms. The Royal

Society of Medicine. International Congress and Symposium. Series No. 18. Proceedings of

the 2nd International Symposium on Anaerobic Infections held in Geneva. April 1979. p. 223.

Peterson WF, Stauch JE, Ryder CD. Metronidazole in pregnancy. Am J Obstet Gynecol 1966;

94: 243-249.

Ralph ED, Amatnieks YE. Relative susceptibilities of Gardnerella vaginalis (Haemophilus

vaginalis), Neisseria gonorrheae and Bacteroides fragilis to Metronidazole and its two major

metabolites. Sex Transm Dis 1980; 7: 157-160.

Richards GK, Dion YM, Wink I, Hinchey EJ. Effect of oral and parenteral metronidazole on

the incidence of post-operative wound infection in elective colonic surgery. The Royal

Society of Medicine. International Congress and Symposium. Series No. 18. Proceedings of

the 2nd International Symposium on anaerobic infections held in Geneva. April 1979. pp.

161-166.

Robinson SC, Mirchandani G. Trichomonas vaginalis. Am J Obstet Gynecol 1965; 93:

502-515.

Rubidge CJ, Scragg JN, Powell SJ. Treatment of children with acute amoebic dysentery.

JAMA, 1970; 211: 118.

Schneider J. Traitement de la giardiase (lambliase) par le métronidazole. Bull Soc Path Exot

1961; 54: 84.

Scott F, Miller MJ. Trials with metronidazole in amebic dysentery. JAMA 1970; 2ll: 118.

Squires S, McFadzean JA. Strain sensitivity of Trichomonas vaginalis to metronidazole. Brit J

Vener Dis 1962; 38: 218.

Sutter VL, Finegold SM. In Vitro Studies with Metronidazole against anaerobic bacteria.

Excerpta Medica, I.C.S. 438. Proceedings of the International Metronidazole Conference.

Montreal, May 1976. pp. 279-285.

Templeton R. Metabolism and Pharmacokinetics of Metronidazole: A Review. Excerpta

Medica, I.C.S. 438. Proceedings of the International Metronidazole Conference. Montreal,

May 1976. pp. 28-49.

Teicher MH, Altesman RI, Cole JO, Schatzberg AF. Possible nephrotoxic interaction of

lithium and metronidazole. JAMA 1987; 257: 3365-3366.

Product Mongraph: FLAGYL

, Odan Laboratories Ltd., date of Revision: January 29, 2018,

Control Number 209684.

pms-METRONIDAZOLE Prescribing Information

Page 28 of 31

CONSUMER INFORMATION

Pr

pms-METRONIDAZOLE

Metronidazole capsules, House Standard

500 mg

This leaflet is published and designed specifically for

Consumers. This leaflet is a summary and will not tell you

everything about pms-METRONIDAZOLE. Contact your

doctor or pharmacist if you have any questions about the

drug.

ABOUT THIS MEDICATION

What the medication is used for:

Antibacterial drugs like pms-METRONIDAZOLE treat only

bacterial infections. They do not treat viral infections such as the

common cold. Although you may feel better early in treatment,

metronidazole should be used exactly as directed. Misuse or

overuse of pms-METRONIDAZOLE could lead to the growth

of bacteria that will not be killed by metronidazole (resistance).

This means that metronidazole may not work for you in the

future. Do not share your medicine.

pms-METRONIDAZOLE

belongs to a group of medicines

called antibacterial – antiprotozoal.

It can be used to treat:

infections of the genital tract (such as trichomoniasis: a

sexually transmitted infection, bacterial vaginosis);

stomach, liver and intestinal infections (amebiasis,

giardiasis);

infections (such as intra-abdominal, brain or lung

infections), caused by anaerobic bacteria (bacteria that are

able to survive in the absence of oxygen).

What it does:

pms-METRONIDAZOLE works by killing bacteria and

parasites that cause infections in your body.

When it should not be used:

Do not take pms-METRONIDAZOLE and tell your doctor if:

You are allergic (hypersensitive) to metronidazole,

nitroimidazole (e.g., tinidazole) or any of the ingredients in

pms-METRONIDAZOLE (see What the nonmedicinal

ingredients are).

You have a disease of the nervous system.

You have a history of blood disease, hypothyroidism

(underactive thyroid gland) or hypoadrenalism

(underactive adrenal glands).

Do not take pms-METRONIDAZOLE if any of the above

applies to you. If you are not sure, talk to your doctor or

pharmacist before taking pms-METRONIDAZOLE.

What the medicinal ingredient is:

pms-METONIDAZOLE contains a medicine called

metronidazole.

What the non-medicinal ingredients are:

Colloidal Silicon Dioxide, Magnesium Stearate and

Microcrystalline Cellulose. The capsule shells contain: AD&C

Blue No. 1, AD&C Green No. 3, D&C Red No. 28, D&C

Yellow No. 10, Gelatin, Titanium Dioxide.

What dosage forms it comes in:

Capsules:

500 mg.

WARNINGS AND PRECAUTIONS

BEFORE you use pms-METRONIDAZOLE, talk to

your doctor or pharmacist if you:

are pregnant, think you are, or plan to get pregnant

are breastfeeding, or planning to breastfeed, as

metronidazole is excreted in human breast milk

have liver problems

have any allergies to this drug or its ingredients (see

What the nonmedicinal ingredients are) or a known

allergy to nitroimidazoles (e.g., tinidazole)

have an active or chronic severe disease of the nervous

system

have any blood disorder (e.g., leukemia, hemophilia, or

other). Your doctor may order periodic blood tests.

have a thyroid condition or hypoadrenalism

(underactive adrenal glands).

Contact your doctor if the following occurs while taking

pms-METRONIDAZOLE

You feel sleepy, dizzy, confused, see or hear things that

are not there (hallucinations), have fits (convulsions),

have temporary eyesight problems (e.g., blurred or double

vision). If this happens do not drive or use machinery or

-tools

You feel tingling, pain, numbness or weakness in the arms

or legs (peripheral neuropathy)

Unnecessary use of pms-METRONIDAZOLE should be

avoided and prolonged treatment duration should be carefully

weighed by your doctor. Its use should be reserved for the

conditions described in the “What the medication is used for”

section.

pms-METRONIDAZOLE Prescribing Information Page 29 of 31

Avoid alcohol during pms-METRONIDAZOLE treatment and

for at least one day following treatment to avoid an adverse

reaction.

If a sexual partner shows signs of infection, the partner should

be examined and treated by the doctor too.

If you have liver problems, your doctor may tell you to use a

lower dose or to use the medicine less often.

pms-METRONIDAZOLE may darken your urine and this is

not considered a concern.

Cases of severe liver toxicity/acute liver failure, including

deaths, in patients with Cockayne syndrome have been reported

with products containing metronidazole.

If you are affected by Cockayne syndrome your doctor should

also monitor your liver function frequently while you are being

treated with metronidazole and afterwards.

Tell your doctor immediately and stop taking metronidazole if

you develop stomach pain, loss of appetite, nausea, vomiting,

fever, malaise, fatigue, jaundice (e.g., yellowing of skin and

eyes), dark urine putty or mastic colored stools or itching.

Please tell your doctor or pharmacist if you are taking or have

recently taken any other medicines. This includes medicines

obtained without a prescription, including herbal medicines.

This is because pms-METONIDAZOLE can affect the way

some other medicines work. Also, some other medicines can

affect the way pms-METRONIDAZOLE works.

In particular tell your doctor if you are taking any of the

following medicines:

Medicines used to thin the blood such as warfarin

Lithium

Phenobarbital

Phenytoin

5-fluorouracil (or 5-FU)

Busulfan

Cyclosporin

Disulfiram

Vecuronium

If you are not sure, talk to your doctor or pharmacist before

taking pms-METRONIDAZOLE.

Do not drink any alcohol while you are taking

pms-METRONIDAZOLE and for at least 1 day after

finishing your course. Drinking alcohol while using

pms-METRONIDAZOLE might cause unpleasant side

effects, such as feeling sick (nausea), being sick (vomiting),

stomach pain, hot flushes, very fast or uneven heartbeat

(palpitations) and headache.

PROPER USE OF THIS MEDICATION

Swallowed capsules whole. DO NOT open, divide, crush or

chew the capsules

Usual adult dose:

TREATMENT OF TRICHOMONIASIS

Single-Dose Treatment

For both women and men, 2 g (4 capsules) administered as a

single dose after a meal.

Standard Ten-day Treatment

Women: 250 mg twice a day, morning and night for 10

consecutive days.

Men: 250 mg twice a day for 10 consecutive days.

For both men and women, it may be occasionally necessary to

give a second ten-day course after 4 to 6 weeks.

The 250 mg strength is not marketed by Pharmascience Inc.

TREATMENT OF AMEBIASIS

Adults

Intestinal Amebiasis – 750 mg three times daily for 5 to 7 days.

Amebic abscesses of the liver – 500 to 750 mg three times daily

for 5 to 7 days.

Children

Administer 35 to 50 mg/kg/day in three divided doses for 5 to 7

days.

TREATMENT OF GIARDIASIS

Adults

250 mg twice daily for 5 to 7 days

Children

Administer 25 to 35 mg/kg/day in two divided doses for 5 to 7

days.

TREATMENT OF BACTERIAL VAGINOSIS

Adults

500 mg twice a day for 7 days

Concurrent treatment of sexual partners is not usually indicated.

INTERACTIONS WITH THIS MEDICATION

pms-METRONIDAZOLE Prescribing Information Page 30 of 31

ANAEROBIC INFECTIONS

Adults

In the treatment of most serious anaerobic infections,

intravenous metronidazole is usually administered initially. This

may be followed by oral therapy with

pms-METRONIDAZOLE.

Oral Administration

500 mg every 8 hours. Treatment for 7 days should be

satisfactory for most patients.

Overdose:

In case of drug overdose, contact a health care practitioner,

hospital emergency department or regional Poison Control

Centre immediately, even if there are no symptoms.

Missed Dose:

If you forget to take pms-METRONIDAZOLE, take it as soon

as you remember. However, if it is almost time for your next

dose, skip the missed dose. Do not use a double dose to make up

for a forgotten dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, pms-METRONIDAZOLE can cause side

effects, although not everybody gets them.

These side effects may include:

Unpleasant taste in the mouth

Furred tongue

Feeling sick (nausea), being sick (vomiting), upset

stomach, stomach pain or diarrhea

Hearing loss

Noise such as buzzing, ringing, or whistling heard in the

ear.

Loss of appetite

Feeling sleepy or dizzy

This is not a complete list of side effects. For any unexpected

side effects while taking pms-METRONIDAZOLE, contact

your doctor or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist

Only if

severe

In all

cases

Allergic reaction with

symptoms such as swelling

of the mouth, throat, hands,

difficulty in breathing or

swallowing, itching, rash,

red spots and blisters

Diarrhea

Liver problems including

cases of liver failure with

symptoms such as intense

fatigue, yellowing of the skin

and eyes, dark urine,

abdominal pain

Nervous system problems

with symptoms such as

inability to coordinate

voluntary movements,

problems using your arms

and legs, problems with

speaking or feel confused,

convulsions, tingling

sensation on the skin, stiff

neck associated with

headache, extreme

sensitivity to bright light

Fever, unexpected

infections, mouth ulcers,

bruising, bleeding gums, or

extreme tiredness

Pancreatitis (inflammation of

the pancreas) with symptoms

such as severe abdominal

pain which may reach

through to your back,

especially associated with

nausea, vomiting and fatigue

Problems with your eyesight

such as blurred or double

vision

Feeling depressed

Pain in your eye

s

Mental problems such as

feeling confused and seeing

or hearing things that are not

there (hallucinations)

pms-METRONIDAZOLE Prescribing Information Page 31 of 31

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

call your

doctor or

pharmacist

Only if

severe

In all

cases

Numbness, tingling, pain, or

a feeling of weakness, in the

arms or legs

TO STORE IT

HOW TO STORE IT

Keep pms-METRONIDAZOLE in a safe place where children

cannot reach or see it.

pms-METRONIDAZOLE should be stored between 15°C and

30°C.

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

(https://www.canada.ca/en/health-canada/services/dru

gs-health-products/medeffect-canada/adverse-reaction

-reporting.html) for information on how to report

online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

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.

MORE INFORMATION

This document plus the full Product Monograph, prepared for

health professionals can be obtained by contacting

Pharmascience Inc. at 1-888-550-6060

This leaflet was prepared by:

Pharmascience Inc.

Montréal, Québec

H4P 2T4

www.pharmascience.com

Last revised: April 13, 2018

3-12-2018

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