Consumer medicine information

Zidoval Vaginal Gel

Metronidazole

BRAND INFORMATION

Brand name

Zidoval

Active ingredient

Metronidazole

Schedule

SUMMARY CMI

Zidoval^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Zidoval?

Zidoval contains the active ingredient metronidazole. Zidoval is used to treat vaginal infections (bacterial vaginosis) caused by certain bacteria.

For more information, see Section 1. Why am I using Zidoval? in the full CMI.

2. What should I know before I use Zidoval?

Do not use if you have ever had an allergic reaction to metronidazole or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Zidoval? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zidoval and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Zidoval?

Use one applicator filled with Zidoval gel. Apply at bedtime
Follow the instructions provided in the package insert on how to apply your dose of Zidoval.

More instructions can be found in Section 4. How do I use Zidoval? in the full CMI.

5. What should I know while using Zidoval?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Zidoval. Tell your doctor immediately if you become pregnant whilst using Zidoval. If you are about to have a blood test, tell your doctor you are using Zidoval. Avoid sexual intercourse while you have a vaginal infection and when using Zidoval. After completing a course of Zidoval, see your doctor to confirm that the infection has cleared up.
Things you should not do	Zidoval is for vaginal use only. Do not use it any other way.
Driving or using machines	Whilst Zidoval is not expected to affect your ability to drive or operate machinery, be careful with these activities until you know how Zidoval how affects you.
Drinking alcohol	Discuss with your doctor whether you may drink alcohol during treatment with Zidoval. Drinking alcohol when using Zidoval may make you feel dizzy or sick.
Looking after your medicine	Store Zidoval in a cool dry place below 25°C.

For more information, see Section 5. What should I know while using Zidoval? in the full CMI.

6. Are there any side effects?

Common side effects include nausea and vomiting, upset stomach or pain, vaginal discharge, vaginal or vulval irritation, yeast infection, pelvic discomfort, unpleasant taste or feeling on the tongue, decreased appetite, dizziness, headache. Serious side effects include allergic reaction, darkened urine, yellowing of the skin or eyes and seizures.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Zidoval^®

Active ingredient: Metronidazole

Consumer Medicine Information (CMI)

This leaflet provides important information about using Zidoval. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Zidoval.

Where to find information in this leaflet:

1. Why am I using Zidoval?
2. What should I know before I use Zidoval?
3. What if I am taking other medicines?
4. How do I use Zidoval?
5. What should I know while using Zidoval?
6. Are there any side effects?
7. Product details

1. Why am I using Zidoval?

Zidoval contains the active ingredient metronidazole. Zidoval is an antibacterial agent used to kill certain bacteria.

Zidoval is used to treat vaginal infections (bacterial vaginosis) caused by certain bacteria.

It is not suitable for all types of vaginal infections. By applying Zidoval directly into the vagina, it can kill the bacteria at the site of the infection.

2. What should I know before I use Zidoval?

Warnings

Do not use Zidoval if:

you are allergic to metronidazole, other nitroimidazole derivatives or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine
the packaging is torn or shows signs of tampering.

Check with your doctor if you:

have any allergies to any other medicines, foods, preservatives or dyes
have any other medical conditions including a disease of the blood, liver, kidneys, or central nervous system
have a condition called Cockayne syndrome, also called Neill-Dingwall syndrome
have, or think you have vaginal thrush (candidiasis). The symptoms of vaginal thrush may become more noticeable when you use Zidoval, and you may need another treatment from your doctor for this.
take any medicines for any other condition
are having your period or are about to start your period. Your doctor may wait until your period is finished before commencing treatment.
have taken disulfiram (Antabuse) in the past 2 weeks. Disulfiram is used to help people who have a drinking problem. If disulfiram and Zidoval are taken closely together, serious unwanted effects may occur.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Talk with your doctor if you are pregnant or breastfeeding.

Metronidazole crosses the placenta and may harm your unborn baby.

Your doctor can discuss with you benefits and risks of taking Zidoval while you are pregnant or breastfeeding.

Use in Children

Do not give Zidoval to a child under 12 years of age. Safety and effectiveness of Zidoval have not been established in this age group.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interfere with Zidoval and affect how it works including:

medicines to prevent blood clotting (e.g., warfarin)
lithium
cyclosporin
5-fluorouracil
carmustine (BCNU) or cyclophosphamide
disulfiram.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Zidoval.

4. How do I use Zidoval?

How much to use

Each dose consists of one applicator filled with 5 g of Zidoval gel.
Apply Zidoval for 5 days in a row or for as long as your doctor tells you.

To help prevent reinfection, always complete the full course even if your symptoms start to clear up within a few days.

When to use Zidoval

Use Zidoval at bedtime

Vaginal medicines can leak out of the vagina during treatment. Using Zidoval at bedtime will help reduce leakage.

Wear a panty liner or sanitary napkin during treatment to help keep Zidoval from getting onto your clothes. Do not use tampons as they may soak up the medicine and stop you receiving the full dose.

How to apply Zidoval

Your box of Zidoval contains a tube of vaginal gel and five single use vaginal applicators.

To ensure maximum hygiene always:

wash your hands before opening the tube or touching the applicator
use a new applicator for each dose
dispose of the used applicator in the rubbish bin.

Opening the tube

Before using Zidoval for the first time, puncture the metal seal on the tube. To do this, unscrew the cap from the tube and pierce the seal using the pointed tip of the cap.

Filling the applicator

Step 1:

Remove an applicator from its wrapper. Unscrew the cap from the tube and screw the open end of the applicator onto the tube.

Step 2:

Squeeze the tube slowly from the bottom to fill the applicator with gel. The plunger will move as the applicator fills and will stop moving when the applicator contains the correct amount of gel.

Step 3:

Unscrew the applicator and replace the cap on the tube.

Inserting the applicator

Hold the filled applicator by its barrel and gently insert it into your vagina as far as it will comfortably go.

You may find it easiest to do whilst lying on your back with your knees bent. Otherwise choose any position you find comfortable.

Applying the gel

Slowly press the plunger to deposit the gel into your vagina. Continue pressing until the plunger stops. This will ensure you have released the correct amount of gel. Remove the applicator from the vagina and put it in the rubbish bin.

If you forget to use Zidoval

Zidoval should be used regularly at the same time each day. If you miss your dose at the usual time, use it as soon as you remember and continue with your treatment as before.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much Zidoval

If you think that you have used too much Zidoval, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Zidoval?

Things you should do

Call your doctor straight away if you:

become pregnant while using this medicine.

Remind any doctor, dentist, or pharmacist you visit that you are using Zidoval.

If you going to have surgery, tell the surgeon or anaesthetist that you are using Zidoval.

If you are about to have a blood test, tell you doctor that you are using Zidoval. It may interfere with the results of some tests.

Avoid sexual intercourse during the infection and whilst you are using Zidoval.

Zidoval contains ingredients that may cause burning or irritation of the eye. If you accidentally get Zidoval in your eye, rinse the eye immediately with plenty of cool tap water.

After you have finished your course of Zidoval, see your doctor to check your progress. This is to ensure that the infection has cleared up.

Things you should not do

Zidoval is for vaginal use only. Do not use it in any other way.
Do not give your medicine to anyone else, even if they have the same condition as you.
Do not stop using Zidoval or change the dose with checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Zidoval affects you.

Whilst Zidoval is not expected to affect your ability to drive or use machinery, caution is appropriate.

Tell your doctor if you drink alcohol.

Drinking alcohol during treatment with Zidoval may make you feel dizzy or sick.

Looking after your medicine

Follow the instructions on the carton on how to take care of your medicine properly.

Store Zidoval below 25°C in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
nausea and vomiting decreased appetite stomach upset or pain diarrhoea vaginal discharge vaginal or vulval irritation yeast infection pelvic discomfort unpleasant taste or feeling on the tongue skin itch or rash dizziness headache.	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
allergic reaction darkened urine yellowing of the skin or eyes seizures.	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice this serious side effect.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Zidoval contains

Active ingredient
(main ingredient)

Metronidazole

Other ingredients
(inactive ingredients)

Carbomer 974P

Propylene glycol

Methyl hydroxybenzoate

Propyl hydroxybenzoate

Disodium edetate

Sodium hydroxide

Purified water

Potential allergens

Methyl hydroxybenzoate

Propyl hydroxybenzoate

Do not take this medicine if you are allergic to any of these ingredients.

What Zidoval looks like

Zidoval is a colourless to straw-coloured gel contained in an aluminium tube. Each 5 g of Zidoval vaginal gel (one full applicator) contains 37.5 mg of metronidazole as the active ingredient.

Registration number: AUST R 73743.

Who distributes Zidoval

iNova Pharmaceuticals (Australia) Pty Limited
ABN: 13 617 871 539
Level 10, 12 Help Street
Chatswood NSW 2067
Tel: 1800 630 056

This leaflet was prepared in November 2022.

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Zidoval

Active ingredient

Metronidazole

Schedule

1 Name of Medicine

Metronidazole.

2 Qualitative and Quantitative Composition

Metronidazole 0.75% w/w.
Each 5 g applicator of vaginal gel contains approximately 37.5 mg of metronidazole.

Excipients with known effect.

Methyl hydroxybenzoate 0.08% w/w.
Propyl hydroxybenzoate 0.02% w/w.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vaginal gel.
Zidoval Vaginal Gel is a nonsterile gelled, colourless to straw-coloured transparent, slightly hazy single-phase purified water solution, containing metronidazole at a concentration of 7.5 mg/g (0.75% w/w). The gel is formulated at the normal vaginal pH of 4.0.

4 Clinical Particulars

4.1 Therapeutic Indications

Zidoval Vaginal Gel 0.75% is indicated in the treatment of symptomatic bacterial vaginosis (formerly referred to as Haemophilus vaginalis vaginitis, Gardnerella vaginalis vaginitis, nonspecific vaginitis, Corynebacterium vaginale vaginitis or anaerobic vaginosis).

Note.

For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of at least three of the following four criteria: a) a vaginal discharge pH of greater than 4.5; b) a vaginal discharge emitting a "fishy" amine odour when mixed with a 10% KOH solution; c) a vaginal discharge containing clue cells on wet mount microscopy examination; d) a gram stain consistent with a diagnosis of bacterial vaginosis (Lactobacillus morphotype absent or markedly decreased, Gardnerella morphotype predominant flora, white blood cells absent or few, Mobiluncus morphotype may or may not be present).
A diagnosis of bacterial vaginosis requires that other pathogens which may be associated with genital infection, such as Trichomonas vaginalis, Candida albicans, Chlamydia trachomatis and Neisseria gonorrhoeae, should be ruled out by appropriate laboratory means.

4.2 Dose and Method of Administration

The recommended dose is one applicator full of Zidoval Vaginal Gel (approximately 5 g containing approximately 37.5 mg of metronidazole) intravaginally once a day, at bedtime, for 5 days.

4.3 Contraindications

Zidoval Vaginal Gel is contraindicated for patients with a prior history of hypersensitivity to metronidazole, hydroxybenzoates, other ingredients of the formulation or other nitroimidazole derivatives.

4.4 Special Warnings and Precautions for Use

Identified precautions.

General.

Approximately 6 to 10% of patients treated with Zidoval Vaginal Gel developed symptomatic Candida vaginitis during or immediately after therapy. This may be due to known or previously unrecognised vulvovaginal candidiasis may present with more prominent symptoms during therapy. Zidoval Vaginal Gel contains ingredients that may cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.

Convulsive seizures and peripheral neuropathy.

Some patients treated with oral or intravenous metronidazole have been reported to have convulsive seizures or peripheral neuropathy, the latter characterised mainly by numbness or paraesthesia of an extremity. While the occurrence of serious neurological symptoms with Zidoval Vaginal Gel is unlikely, the appearance of abnormal neurological signs should prompt discontinuation of therapy. Zidoval Vaginal Gel should be administered with caution to patients with central nervous system diseases.

Cockayne syndrome.

Cases of severe hepatotoxicity or 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, metronidazole should therefore be used after careful benefit-risk assessment and 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 medicine should be discontinued.
Patients with Cockayne syndrome should be advised to immediately report symptoms of potential liver injury to their physician and stop taking metronidazole.

Haematologic effects.

Some patients treated with oral metronidazole have been observed to have a mild transient leukopenia. Zidoval Vaginal Gel should be administered with caution to patients with evidence of or a history of blood dyscrasia.

Use in hepatic impairment.

Patients with severe hepatic disease metabolise metronidazole slowly. This may result in the accumulation of metronidazole and its metabolites in the plasma. Zidoval Vaginal Gel should be administered with caution in patients with evidence of hepatic dysfunction. However, a total treatment course of 187.5 mg is unlikely to lead to excessive serum levels.

Use in renal impairment.

In patients with renal failure, there is no accumulation of metronidazole however hydroxy and acid metabolites are retained. Haemodialysis removes metronidazole and these metabolites.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of Zidoval Vaginal Gel in children have not been established.

Effects on laboratory tests.

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation reduction of nicotinamide adenine dinucleotides (NAD+NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Zidoval Vaginal Gel therapy results in markedly lower serum levels of metronidazole when compared to oral metronidazole therapy. Although these lower serum levels are less likely to result in the interactions that have been observed with oral metronidazole, the possibility of these interactions cannot be excluded.

Alcohol.

Concurrent usage of oral metronidazole and alcohol may result in a disulfiram-like reaction. Despite the relatively low serum levels of metronidazole produced following administration of Zidoval Vaginal Gel, the possibility of a disulfiram-like reaction to alcohol while on Zidoval therapy cannot be excluded. Patients should be cautioned about drinking alcohol while being treated with Zidoval Vaginal Gel.

Carmustine (BCNU) or cyclophosphamide.

Metronidazole should be used with caution in patients receiving these drugs.

Coumarin anticoagulants.

Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. Zidoval Vaginal Gel should be administered with caution in patients on this type of anticoagulant therapy.

Cyclosporin and 5-fluorouracil.

Oral metronidazole has been shown to increase the plasma concentrations of cyclosporin and 5-fluorouracil. Although vaginal administration of metronidazole results in markedly lower plasma metronidazole concentrations when compared to oral metronidazole, the possibility of these interactions cannot be ruled out.

Disulfiram.

Concurrent usage of oral metronidazole and disulfiram has been reported to cause psychotic reactions in alcoholic patients. Zidoval Vaginal Gel should not be administered to patients who have taken disulfiram within the past 2 weeks.

Lithium.

Short-term oral metronidazole therapy in patients stabilised on relatively high doses of lithium has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B2)
The potential adverse effects of Zidoval Vaginal Gel on pregnancy have not been determined. Metronidazole crosses the placental barrier and enters the foetal circulation rapidly. Metronidazole blood levels are significantly lower after administration of Zidoval Vaginal Gel than those achieved with oral metronidazole.
A substantial amount of data is available regarding the effects of human exposure to metronidazole in pregnancy over more than 30 years. A review of literature reports in 1469 women treated with metronidazole during pregnancy, 206 during the first trimester, concluded that the incidence of abortions, perinatal death and malformations, or of icterus neonatorum was not increased. A decade later, another literature review was published on 2139 women (254 treated with metronidazole during first trimester, 521 during second trimester, 554 during third trimester and 880 at an unspecified time during pregnancy) concluded that metronidazole was safe during pregnancy.
In 7 retrospective studies in UK and USA, the effect of metronidazole use was examined in 1776 pregnancies; in 246 pregnancies the drug was used during first trimester. Dosage regimens varied; oral dose of 250-750 mg/day for 7-10 days either alone or in combination with 500 mg vaginal suppository. No evidence of increase in the incidence of any particular abnormality was seen in these studies. Collectively, these studies led to the conclusion that metronidazole was safe to use during pregnancy, including during the first trimester.
In two prescription event studies, 2327 women who had a prescription for metronidazole filled at any time during pregnancy did not show an increase in the incidence of malformations in babies born to them.
A meta-analysis of 7 studies (1336 patients exposed; 154,163 patients with no exposure to the drug) showed no evidence of increased risk of malformation from the use of metronidazole during pregnancy. A similar analysis from 5 studies (2524 patients exposed and 196,927 not exposed to drug) showed no relationship between metronidazole use during pregnancy and birth defects.
In a prospective follow-up of 34 cases exposed to metronidazole during pregnancy, metronidazole was not considered to cause birth defects. Twenty five cases had received the drug during first trimester, seven during the second and one during the third trimester and date of exposure for one was not known.
Although no conclusive evidence of foetotoxicity or teratogenicity has been observed in animal studies with other forms of metronidazole, and clinical experience to date with the use of metronidazole in pregnant women has revealed no evidence of a foetotoxic or teratogenic effect of the drug, there are no adequate and well controlled studies of therapy with Zidoval Vaginal Gel in pregnant women.
Intravenous and oral formulations of metronidazole are not recommended to be given in the first trimester of pregnancy because it crosses the placenta and enters the foetal circulation rapidly. Although it has not been shown to be teratogenic in either human or animal studies, such a possibility cannot be excluded. Metronidazole vaginal gel should be used in pregnancy if no other treatment option is considered appropriate.
After oral administration, metronidazole has been shown to be secreted in breast milk in concentrations similar to those found in plasma. Metronidazole plasma levels are significantly lower after administration of Zidoval Vaginal Gel than those achieved with oral metronidazole. Since the potential adverse effects of metronidazole on postnatal development have not been determined, thus a decision should be made, whether to discontinue breastfeeding or treatment with Zidoval Vaginal Gel, taking into account the importance of the treatment to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

In four randomised placebo or active controlled pivotal clinical trials, adverse events reported by the investigator as probably or possibly related to treatment and with an incidence of 1% or greater are presented in Table 1 below. A dash represents an incidence of less than 1%.

Postmarketing data.

The listing below includes all spontaneous adverse events, reported worldwide during the period of August 1992 to December 1997, and is presented at frequency of: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1000; very rare < 1/10,000.

Application site disorder.

Very rare: application site reaction.

Body as a whole.

Very rare: allergic reaction.

Central and peripheral nervous system disorders.

Very rare: dizziness, headache, paraesthesia.

Gastrointestinal system disorders.

Very rare: abdominal pain, diarrhoea, nausea.

Reproductive disorders, female.

Very rare: leukorrhoea, vaginitis, vulvar disorder.

Skin and appendages disorder.

Very rare: pruritus genital, rash, urticaria.

Special senses other, disorder.

Very rare: taste perversion.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no human experience with overdosage of Zidoval Vaginal Gel.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zidoval Vaginal Gel is an intravaginal dosage form of the synthetic antibacterial agent, metronidazole. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antibacterial agent.
Metronidazole is effective against a wide range of obligate anaerobes. It is not effective against aerobes or facultative anaerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimum inhibitory concentration. The antibacterial activity results from the disruption of DNA and the inhibition of nucleic acid synthesis.
The aetiology of bacterial vaginosis is unclear and changes in vaginal flora which accompany bacterial vaginosis are probably its manifestation rather than its cause. Monitoring changes in vaginal flora by Gram stain slides of vaginal discharge smears may supplement diagnosis and assessment of treatment efficacy by standard clinical criteria.
Metronidazole has been shown to have in vivo and clinical activity against:
Obligate anaerobic gram negative bacilli including Bacteroides species (B. fragilis, B. distasonis, B. ocatus, B. thetaiotaomicron, B. vulgaris) and Fusobacterium species.
Anaerobic gram positive bacilli including Clostridium species and susceptible strains of Eubacterium.
Anaerobic gram positive cocci including Peptostreptococcus species.
Treatment success in bacterial vaginosis may be accompanied by a decrease in (but not elimination of) organisms such as Gardnerella vaginalis and Bacteroides species. This may also be accompanied by an increase in Lactobacillus species in the vagina.

Clinical trials.

Four randomised, double blind, controlled clinical studies demonstrated the effectiveness and safety of Zidoval Vaginal Gel in the treatment of bacterial vaginosis. The bases for clinical diagnosis of bacterial vaginosis in these studies were the presence of ≥ 20% clue cells in vaginal discharge and 2 of the following 3 clinical criteria: i) homogenous vaginal discharge; ii) a vaginal discharge with a pH ≥ 4.7; iii) a vaginal discharge emitting a positive amine odour test. In addition, Gram stains were also used to confirm accuracy of diagnosis in these studies. Patients were considered as treatment success if all 3 clinical criteria were absent and clue cells, if present, must be < 20%.
In a randomised, double blind, placebo controlled clinical trial, Zidoval Vaginal Gel (5 g) given intravaginally twice daily for five days for treatment of bacterial vaginosis (assessed by Amsel Criteria) achieved treatment success (81%; n = 43) at 12 to 16 days post-therapy that was statistically significantly greater than the placebo (11%; n = 35). At follow up visit (28 to 32 days post-therapy), treatment success for Zidoval Vaginal Gel (76%; n = 38) remained statistically significantly greater than the placebo (6%; n = 34). Results of Gram stain scores agreed with clinical diagnosis overall in 90% cases at all visits combined.
In a randomised, investigator blinded, parallel clinical trial, Zidoval Vaginal Gel (5 g) given intravaginally twice daily for five days for treatment of bacterial vaginosis achieved comparable treatment successes (86%, n = 37, at 2 weeks post initiation of therapy; 71%, n = 34, at 4 weeks post initiation of therapy) to oral 500 mg metronidazole tablets given twice daily for 7 days (84%, n = 44, at 2 weeks post initiation of therapy; 68%, n = 41, at 4 weeks post initiation of therapy). Clinical and Gram stain diagnoses were in agreement 90% of the time.
In a randomised, double blind clinical trial, Zidoval Vaginal Gel (5 g) given intravaginally twice daily for five days for treatment of bacterial vaginosis achieved comparable (p = 0.333) treatment success (79%, n = 103) at 12 to 16 days post-therapy to Sultrin (sulfathiazole, sulfacetamide, sulfabenzamide) cream given twice daily intravaginally for 5 days (71%, n = 113). At follow up visit (28 to 32 days post-therapy), treatment success for Zidoval Vaginal Gel (66%, n = 96) was statistically significantly greater (p = 0.018) than Sultrin (47%, n = 109). Results of Gram stain scores agreed with clinical diagnosis overall in 89% cases in Zidoval group and in 87% in Sultrin group.
In a randomised, investigator blind clinical trial, the efficacy of Zidoval Vaginal Gel (5 g) given intravaginally twice daily versus once daily for five days for treatment of bacterial vaginosis was compared. At visit 2 (7 to 12 days post-therapy) and visit 3 (28 to 35 days post-therapy) respectively, 77% (n = 199) and 58% (n = 180) of patients were considered treatment success in the once daily dosing group. For the twice daily dosing regimen, corresponding treatment success rates were 80% (n = 196) and 61% (n = 178), respectively. Difference between treatment groups was not statistically significant. Gram stain scores and clinical diagnosis correlated in 83% cases.

5.2 Pharmacokinetic Properties

Healthy volunteers.

Following a single, intravaginal 5 g dose of Zidoval Vaginal Gel 0.75% (equivalent to 37.5 mg of metronidazole) administered to 12 healthy volunteers, a mean maximum serum metronidazole concentration of 237 nanogram/mL was achieved (range: 152 to 368 nanogram/mL). This is approximately 2% of the mean maximum serum metronidazole concentration achieved in the same subjects administered a single, oral 500 mg dose of metronidazole (mean C_max = 12,785 nanogram/mL, range: 10,013 to 17,400 nanogram/mL). These peak concentrations were obtained between 6 to 12 hours after dosing with Zidoval Vaginal Gel and 1 to 3 hours after dosing with oral metronidazole. The extent of exposure (area under the curve (AUC)) of metronidazole, when administered as a single intravaginal 5 g dose of Zidoval Vaginal Gel, was approximately 4% (4977 nanogram.hr/mL) of the AUC of a single oral 500 mg dose of metronidazole (approximately 13,3395 nanogram.hr/mL). Dose adjusted comparisons of AUCs indicated that the absorption of metronidazole administered vaginally was approximately half that of an equivalent oral dosage on a milligram per milligram comparison basis.

Patients with bacterial vaginosis.

Following administration of 5 g doses of Zidoval Vaginal Gel twice daily for 5 days to 4 patients with bacterial vaginosis, mean maximum serum metronidazole concentrations of 214 nanogram/mL on day 1 and 294 nanogram/mL (range: 228 to 349 nanogram/mL) on day 5 (steady-state) were achieved. Steady-state metronidazole serum concentrations following oral dosages of 400 to 500 mg twice daily have been reported to range from 6000 to 20,000 nanogram/mL.

5.3 Preclinical Safety Data

Genotoxicity.

Although metronidazole has shown mutagenic activity in several in vitro systems, including bacteria, there is no conclusive evidence of genotoxicity in mammals. While the results of genotoxicity and, mutagenicity assays of metronidazole in rodent-based systems and in vitro are equivocal, the human use of metronidazole as a therapeutic agent since 1960 shows no conclusive evidence of human genotoxicity and mutagenicity at therapeutic levels of metronidazole.

Carcinogenicity.

Chronic oral administration of metronidazole showed increased tumour incidence in rats and mice. The results of rodent tests are not always indicative of human risk, in part, due to metabolic and digestive differences. While the results of carcinogenicity assays of metronidazole in rodent-based systems and in vitro are equivocal, the human use of metronidazole as a therapeutic agent since 1960 shows no conclusive evidence of human carcinogenicity at therapeutic levels of metronidazole. Retrospective studies in women treated systemically with metronidazole have revealed no increased incidence of tumour formation compared to the untreated population.

6 Pharmaceutical Particulars

6.1 List of Excipients

Contains carbomer 974P, disodium edetate, methyl hydroxybenzoate, propyl hydroxybenzoate and propylene glycol.
Zidoval Vaginal Gel does not contain mineral oil.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze.

6.5 Nature and Contents of Container

Tube packaged with 5 disposable applicators.
Each 5 g of Zidoval Vaginal Gel 0.75% contains 37.5 mg of metronidazole.
Pack sizes: 9 g^#, 40 g.
^# Not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Metronidazole is 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical formula of C₆H₉N₃O₃, a molecular weight of 171.16.

Chemical structure.

It has the following structure:

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