MAR-METRONIDAZOLE CAPSULE

Canada - English - Health Canada

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Active ingredient:
METRONIDAZOLE
Available from:
MARCAN PHARMACEUTICALS INC
ATC code:
P01AB01
INN (International Name):
METRONIDAZOLE
Dosage:
500MG
Pharmaceutical form:
CAPSULE
Composition:
METRONIDAZOLE 500MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
MISCELLANEOUS ANTIPROTOZOALS
Product summary:
Active ingredient group (AIG) number: 0102572003; AHFS: 08:30.92
Authorization status:
APPROVED
Authorization number:
02491370
Authorization date:
2019-08-07

Documents in other languages

Page 1 of 31

PRODUCT MONOGRAPH

Pr

MAR-METRONIDAZOLE

(Metronidazole Capsules)

Manufacturer’s Standard

500 mg Capsules

Antibacterial - Antiprotozoal

Marcan Pharmaceuticals Inc.

2 Gurdwara Road, Suite #112,

Ottawa, ON, K2E 1A2

Date of Preparation:

August 06, 2019

Submission Control No. 215186

Page 2 of 31

PRODUCT MONOGRAPH

Pr

MAR-METRONIDAZOLE

(Metronidazole Capsules)

Manufacturer’s Standard

500 mg Capsules

THERAPEUTIC CLASSIFICATION

Antibacterial - Antiprotozoal

ACTION AND CLINICAL PHARMACOLOGY

Metronidazole is bactericidal against anaerobic bacteria; it exerts trichomonacidal activity and is

also active against Giardia lamblia and 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 USES

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 MAR-METRONIDAZOLE capsules at the discretion

of the physician.

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.

Page 3 of 31

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 abcesses) caused by anaerobic bacteria.

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

METRONIDAZOLE and other antibacterial drugs, MAR-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

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

to metronidazole or other nitroimidazole derivatives.

MAR-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 USES section.

MAR-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 MAR-METRONIDAZOLE.

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.

MAR-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.

Page 4 of 31

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

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

disulfiram-like (Antabuse effect) reaction.

Hepatic

MAR-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, MAR-

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 MAR-METRONIDAZOLE.

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing MAR-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 oral dose of metronidazole; it is therefore advisable that a patient taking MAR-

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 MAR-

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, MAR-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).

Page 5 of 31

Treatment with MAR-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 MAR-METRONIDAZOLE below those usually

recommended should be administered and with caution.

Treatment with MAR-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 MAR-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.

Haematological 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 1500 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 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 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).

Page 6 of 31

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 MAR-

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

of pregnancy. In serious anaerobic infections, if the administration of MAR-

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 MAR-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.

DRUG INTERACTIONS

Alcohol: Patients taking MAR-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.

Page 7 of 31

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 MAR-

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 MAR-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 MAR-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.

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

I.V. administration. Fever has been reported.

Page 8 of 31

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, aseptic meningitis.

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 I.V. medication for several weeks or months.

Profound neurological deterioration, within 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.

Page 9 of 31

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.

SYMPTOMS AND TREATMENT OF 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.

DOSAGE AND ADMINISTRATION

The 250 mg strength is not marketed by Marcan Pharmaceuticals Inc.

TREATMENT OF TRICHOMONIASIS

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

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

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

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

WARNINGS section).

Oral Administration:

Single-Dose Treatment

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

Standard Ten-day Treatment

Women - One 250 mg tablet twice a day, morning and night for 10 consecutive days.

Men – One 250 mg tablet 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 – Three 250 mg tablets three times daily for 5 to 7 days.

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

Page 10 of 31

Amebic abscesses of the liver – Two to three 250 mg tablets 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:

One 250 mg tablet 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 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 MAR-METRONIDAZOLE

capsules at the discretion of the physician.

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

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.

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).

Page 11 of 31

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 MAR-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.

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).

Page 12 of 31

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name:

Metronidazole

Chemical Name:

2-(2-Methyl-5-nitro-1H-imidazol-1-yl) ethanol

Structural Formula:

Molecular Formula:

Molecular Weight:

171.2 g / mol

Physical Form:

White or yellowish, crystalline powder

Solubility:

Slightly soluble in water, in acetone, in alcohol and in methylene chloride

5.8 (water solution)

Melting Point:

159-163

COMPOSITION

Oral Capsules: Light grey opaque cap, pale green opaque body, size ‘0’, hard gelatin capsule,

imprinted ‘500’ on body circularly with black ink, filled with white to pale yellow crystalline

powder.

Each capsule contains: metronidazole 500 mg.

Non-medicinal ingredients: silicon dioxide, D&C Red No. 33, D&C Yellow No.10, FD&C

Blue No. 1, FD&C Green No. 3, gelatin, lactose monohydrate, magnesium stearate, sodium

lauryl sulfate, titanium dioxide and black ink.

STABILITY AND STORAGE RECOMMENDATIONS

MAR-METRONIDAZOLE oral capsules should be stored between 15 and 30

AVAILABILITY OF DOSAGE FORMS

MAR-METRONIDAZOLE oral capsules: Available in bottles of 100 capsules.

Page 13 of 31

CLINICAL TRIALS

COMPARATIVE BIOAVAILABILITY STUDIES

randomized,

single-dose,

double-blinded,

balanced,

two-treatment,

two-period,

two-

sequence, crossover, oral bioequivalence study of MAR-METRONIDAZOLE capsules, 500

mg (Marcan pharmaceutical Inc.) and

FLAGYL

capsules, 500 mg (Sanofi-Aventis Canada

Inc.) was conducted in 32 healthy, Asian, adult subjects (30 males and 2 females) under fasting

conditions. A summary of the results from the 32 subjects who completed the study is presented

in the following table.

Metronidazole

1 x 500mg

From measured data

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90 % Confidence

Interval

(ng*hr/mL)

146440.16

149186.41 (18.52)

149066.01

151801.72 (19.23)

98.2

95.8 - 100.7

0-inf

(ng*hr/mL)

152969.22

156047.07 (19.28)

155588.63

158804.84 (20.55)

98.3

96.0 - 100.7

(ng/mL)

12725.70

13109.31 (25.83)

12009.19

12277.68 (21.95)

106.0

100.3 - 111.9

1.00 (0.17 - 3.50)

1.25 (0.33 - 4.00)

9.94 (19.13)

9.97 (19.39)

* MAR-METRONIDAZOLE (metronidazole) capsules, 500 mg (Marcan Pharmaceutical Inc.)

FLAGYL

(metronidazole) capsules, 500 mg (Sanofi-Aventis Canada Inc.)

§ Expressed as the median (range) only

€ Expressed as the arithmetic mean (CV %) only

Page 14 of 31

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

CUMULATIVER 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

Bacteroids

melaninogenicus

Other bacteroides

Fusobacterium

nucleatum

Other fusobacterium

Peptococcus

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

Page 15 of 31

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

few strains of Peptococcus and Peptostreptococcus required 128 mg or more per litre of

metronidazole 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 10

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 adminsitered 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

when the product was given in a single dose 24 hours after infestation, was 49 mg/kg/day

p.o.

Page 16 of 31

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.

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

30mg/kg/day while its therapeutic index was 1/100.

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 anaesthetised cat and hypnosis was produced in the rat.

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

4 anaesthetised 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 500mg t.i.d. administered by the i.v.

route, a steady state was achieved after approximately three 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 i.v.

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.

Page 17 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.

Figure 2. Mean plasma metronidazole concentration following a single intravenous dose of

metronidazole (1.5 g) (n=10).

Page 18 of 31

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

metronidazole for the oral route of administration.

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

(brain abscess)

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

600 mg i.v. t.i.d.

35 mg/L

inflamed meninges

43 mg/L

(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.

Page 19 of 31

HAEMODIALYSIS

During haemodialysis, 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.

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-nitroimidazole-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 I.V. 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.

i.v.

i.v.

4350

3650

1170

1260

p.o.

i.p.

i.v.

i.v.

5000

5000

1575

1575

Page 20 of 31

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, 1000, 1500, 3000 or 5000 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 1500 and

5000 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 initial 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 1000 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 1000 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

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

Page 21 of 31

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 2500 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

Page 22 of 31

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 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 CF

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 consistant

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.

Page 23 of 31

BIBLIOGRAPHY

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.

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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 Monograph -

FLAGYL® (metronidazole). ODAN Laboratories Ltd. Date of

revision: January 29, 2018, control number 209684.

Page 27 of 31

CONSUMER INFORMATION

Pr

MAR-METRONIDAZOLE

(Metronidazole Capsules)

Manufacturer`s Standard

500 mg Capsules

This leaflet is published and designed specifically

for Consumers. This leaflet is a summary and will

not tell you everything about MAR-

METRONIDAZOLE. Contact your doctor or

pharmacist if you have any questions about the

drug.

What the medication is used for:

Antibacterial drugs like MAR-METRONIDAZOLE

treat only bacterial infections. They do not treat viral

infections such as the common cold. Although you

feel

better

early

treatment,

MAR-

METRONIDAZOLE

should

used

exactly

directed.

Misuse

overuse

MAR-

METRONIDAZOLE

could

lead

growth

bacteria

that

will

killed

MAR-

METRONIDAZOLE

(resistance).

This

means

that

MAR-METRONIDAZOLE may not work for you in

the future. Do not share your medicine.

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:

MAR-METRONIDAZOLE works by killing bacteria

and parasites that cause infections in your body.

When it should not be used:

Do not take MAR-METRONIDAZOLE and tell your

doctor if:

You are allergic (hypersensitive) to

metronidazole, nitroimidazoles (e.g. tinidazole) or

any of the ingredients in MAR-

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 MAR-METRONIDAZOLE if any of the

above applies to you. If you are not sure, talk to your

doctor or pharmacist before taking MAR-

METRONIDAZOLE.

What the medicinal ingredients are:

MAR-METRONIDAZOLE contains a medicine called

metronidazole.

What the nonmedicinal ingredients are:

Oral Capsules:

Silicon dioxide, D&C Red No. 33, D&C Yellow

No.10, FD&C Blue No. 1, FD&C Green No. 3,

gelatin, lactose monohydrate, magnesium stearate,

sodium lauryl sulfate, titanium dioxide and black ink.

What dosage forms it comes in:

MAR-METRONIDAZOLE is available as:

Oral capsules containing 500 mg metronidazole.

BEFORE you use MAR-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

IMPORTANT: PLEASE READ

WARNINGS AND PRECAUTIONS

ABOUT THIS MEDICATION

Page 28 of 31

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 MAR-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 MAR-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 forsection.

Avoid alcohol during MAR-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.

MAR-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 MAR-

METRONIDAZOLE can affect the way some other

medicines work. Also, some other medicines can

affect the way MAR-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

(Coumadin

Lithium;

Phenobarbital;

Phenytoin (Dilantin

5-fluorouracil (or 5-FU);

Busulfan (Myleran

Cyclosporin (Neoral

Disulfiram

Vecuronium

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

before taking MAR-METRONIDAZOLE.

Do not drink any alcohol while you are taking MAR-

METRONIDAZOLE and for at least 1 day after

finishing your course. Drinking alcohol while using

MAR-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.

IMPORTANT: PLEASE READ

INTERACTIONS WITH THIS MEDICATION

Page 29 of 31

The 250 mg strength is not marketed by Marcan

Pharmaceuticals Inc.

Usual adult dose:

TREATMENT OF TRICHOMONIASIS

Oral Administration:

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: One 250 mg tablet twice a day, morning

and night for 10 consecutive days.

Men: One 250 mg tablet 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 – Three 250 mg tablets three

times daily for 5 to 7 days.

Amebic abscesses of the liver – Two to three 250 mg

tablets 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:

One 250 mg tablet 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 orally twice a day for 7 days.

Concurrent treatment of sexual partners is not usually

indicated.

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

MAR-METRONIDAZOLE capsules.

Oral Administration:

500 mg every 8 hours. Treatment for seven days

should be satisfactory for most patients.

Overdose:

Missed Dose:

forget

take

MAR-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.

Like all medicines, MAR-METRONIDAZOLE can

cause side effects, although not everybody gets them.

These side effects may include:

Unpleasant taste in the mouth

Furred tongue or 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

IMPORTANT: PLEASE READ

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.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

PROPER USE OF THIS MEDICATION

Page 30 of 31

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

unexpected side effects while taking MAR-

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

Keep MAR-METRONIDAZOLE in a safe place where

children cannot reach or see it.

MAR-METRONIDAZOLE (metronidazole) oral

capsules should be stored between 15 and 30° C.

IMPORTANT: PLEASE READ

HOW TO STORE IT

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

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 eyes

Mental problems such

as feeling confused and

seeing or hearing

things that are not

there (hallucinations)

Numbness, tingling,

pain, or a feeling of

weakness, in the arms

or legs

Page 31 of 31

This document plus the full product monograph,

prepared for health professionals can be found by

contacting Marcan Pharmaceuticals Inc. or by

calling toll free number +1-855-627-2261.

This leaflet was prepared by Marcan Pharmaceuticals

Inc., 2 Gurdwara Road, Suite #112, Ottawa, ON, K2E

1A2, Canada.

Flagyl

is a registered trade-mark of Aventis Pharma S.A.,

France

Coumadin

is a registered trade-mark of Bristol-Myers Squibb

Pharma Company

Neoral

is a registered trade-mark of Novartis AG

Dilantin

is a registered trade-mark of Warner-Lambert

Company LLC

Myleran

is a registered trade-mark of Aspen Global

Incorporated.

Last Prepared: August 06, 2019

IMPORTANT: PLEASE READ

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected side effects associated

with the use of health products to the Canada Vigilance

Program by one of the following:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html)

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.

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