Consumer medicine information

Zidoval Vaginal Gel

Metronidazole

BRAND INFORMATION

Brand name

Zidoval Vaginal gel

Active ingredient

Metronidazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zidoval Vaginal Gel.

What is in this leaflet

This leaflet answers some common questions about Zidoval Vaginal Gel. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Zidoval against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Zidoval is used for

Zidoval Vaginal Gel contains an active ingredient, metronidazole. Metronidazole is an antibacterial agent.

Zidoval is used to treat infection of the vagina (bacterial vaginosis) caused by certain bacteria. It is not suitable for all types of vaginal infections. By applying Zidoval directly into the vagina, metronidazole can kill the bacteria at the site of the infection.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

Before you use Zidoval

When you must not use it

Do not use Zidoval if you have an allergy to:

  • any medicine containing metronidazole
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not give Zidoval to a child under the age of 12 years.

Safety and effectiveness in children younger than 12 years have not been established.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • a disease of the blood, liver, kidneys or central nervous system
  • Cockayne syndrome, also called Neill-Dingwall syndrome.

Tell your doctor if you are pregnant or breast-feeding.

Your doctor can discuss with you the risks and benefits of using Zidoval whilst pregnant or breastfeeding.

Tell your doctor if you have, or think you may have vaginal thrush (candidiasis).

The symptoms of vaginal thrush may become more noticeable when you use Zidoval gel and you may need another treatment from your doctor for this.

Tell your doctor if:

  • you are having your period or are about to start your period
  • you have taken disulfiram (Antabuse) in the past 2 weeks.

Disulfiram is used to help people who have a drinking problem. If Zidoval and disulfiram are taken close together, serious unwanted effects may occur.

If you have not told your doctor about any of the above, tell them before you start using Zidoval.

Taking other medicines

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

Some medicines and Zidoval may interfere with each other. These include:

  • medicine to prevent blood clotting (e.g. warfarin)
  • lithium
  • cyclosporin
  • 5-fluorouracil
  • carmustine (BCNU) or cyclophosphamide.

These medicines may be affected by Zidoval or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

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.

How to use Zidoval

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions in this leaflet, ask your doctor or pharmacist for help.

How much to use

Each dose consists of one applicator filled with 5 g of Zidoval gel.

How to use it

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 Vaginal Gel 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 this 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.

When to use it

Use Zidoval at bedtime.

Vaginal medicines can leak out of the vagina during treatment. Using Zidoval at bedtime will help reduce leakage. Using Zidoval at the same time each day will also help you remember when to use it.

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

How long to use it

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 of treatment even if your symptoms start to clear up within a few days.

If you forget to use it

If you forget to have a dose of Zidoval gel, use it as soon as you remember and continue with your treatment as before.

If, by the time you remember, it is time to have your next dose, do not double-up on your treatment. Have your original missed dose and continue your treatment as usual.

Never have more than one dose of the gel a day to make up for missed doses.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

If you use too much (overdose)

Telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have accidentally swallowed Zidoval Vaginal Gel or may have used too much of it. Do this even if there are no signs of discomfort or poisoning.

You may need medical attention.

While you are using Zidoval

Things you must do

If you are about to be started on any new medicine remind your doctor and pharmacist that you are using Zidoval.

Tell any other doctors and pharmacists who treat you that you are using this medicine.

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

It may affect other medicines used during surgery.

As with all vaginal infections avoid sexual intercourse during the infection and whilst you are using Zidoval gel.

If you become pregnant while using this medicine, tell your doctor immediately.

If you are about to have any blood tests tell your doctor that you are using this medicine.

It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

It is important that your doctor check your progress after you finish using Zidoval. This is to make sure that the infection has cleared up.

Things you must not do

Do not use Zidoval to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine or change the dose without checking with your doctor.

Zidoval is for vaginal use only. Do not use it in any other way.

Things to be careful of

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Zidoval.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • abnormal vaginal discharge
  • itching, burning or swelling in or around the vagina
  • a feeling of increased pressure in the pelvic area
  • stomach cramp or pain
  • feeling sick or vomiting
  • unusual taste
  • diarrhoea (loose stools)
  • reduced appetite
  • stomach bloating (gas)
  • feeling thirsty, dry mouth
  • headache
  • dizziness
  • feeling depressed
  • skin itch or rash
  • feeling tired
  • darkened urine.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using Zidoval Vaginal Gel

Storage

Keep your tube of Zidoval gel and the vaginal applicators together in their box until it is time to use them.

Keep your pack of Zidoval in a cool dry place where the temperature stays below 25°C.

Exposure to extreme heat or cold can spoil the gel.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Zidoval is a colourless to straw-coloured gel, contained in an aluminium tube.

Each tube contains 40g of Zidoval Vaginal Gel.

Ingredients

Each 5 g of Zidoval Vaginal Gel (one full applicator) contains 37.5 mg of metronidazole as the active ingredient.

Other ingredients:

  • carbomer 974P
  • propylene glycol
  • methyl hydroxybenzoate
  • propyl hydroxybenzoate
  • disodium edetate
  • sodium hydroxide
  • purified water

Supplier

Zidoval is supplied by:

iNova Pharmaceutical (Australia) Pty. Limited
ABN: 13 617 871 539
Level 10, 12 Help St
Chatswood, NSW 2067
Telephone: 1800 630 056

AUST R 73743

This leaflet was prepared in November 2017.

BRAND INFORMATION

Brand name

Zidoval Vaginal gel

Active ingredient

Metronidazole

Schedule

S4

 

1 Name of Medicine

Metronidazole.

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:

CAS number.

443-48-1.

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.

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 Cmax = 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.

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.

4.3 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.

4.8 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.

4.2 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.

4.7 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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes