Gnostol

Gnostol is indicated in the prophylaxis and treatment of infections in which anaerobic bacteria have been identified or are suspected to be the cause.

Gnostol is active against a wide range of pathogenic micro-organisms notably species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and Gardnerella vaginalis.

It is also active against Trichomonas, Entamoeba histolytica, Giardia lamblia and Balantidium coli.

Gnostol is indicated in adults and children for the following indications:

1. The prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic streptococci.

2. The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, and post-operative wound infections from which pathogenic anaerobes have been isolated.

3. Urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male.

4. Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginosis or Gardnerella vaginitis).

5. All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers).

6. Giardiasis.

7. Acute ulcerative gingivitis.

8. Anaerobically-infected leg ulcers and pressure sores.

9. Acute dental infections (e.g. acute pericoronitis and acute apical infections).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

1. Treatment of infections in which anaerobic bacteria have been identified or are suspected as pathogens, particularly Bacteroides fragilis and other species of Bacteroides and including other species for which metronidazole is bactericidal, such as Fusobacteria, Eubacteria, Clostridia and anaerobic cocci.

Gnostol has been used successfully in: septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, peritonitis and post-operative wound infection from which one or more of these anaerobes have been isolated.

2. Prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic Streptococci.

VANDAZOLE (metronidazole vaginal gel) is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in non-pregnant women.

Gnostol is indicated for the treatment of bacterial vaginosis in females 12 years of age and older.

For oral administration.

Gnostol tablets should be swallowed, without chewing, with half a glassful of water during or after meals.

Prophylaxis against anaerobic infection:

Chiefly in the context of abdominal (especially colorectal) and gynaecological surgery.

Adults: 400 mg 8 hourly during 24 hours immediately preceding operation followed by postoperative intravenous or rectal administration until the patient is able to take tablets.

Children < 12 years: 20-30mg/kg as a single dose given 1-2 hours before surgery

Newborns with a gestation age < 40 weeks: 10mg/kg body weight as a single dose before operation

Anaerobic infections:

The duration of a course of Gnostol treatment is about 7 days but it will depend upon the seriousness of the patient's condition as assessed clinically and bacteriologically.

Treatment of established anaerobic infection:

Adults: 800 mg followed by 400 mg 8 hourly.

Children > 8 weeks to 12 years of age: The usual daily dose is 20-30 mg/kg/day as a single dose or divided into 7.5 mg/kg every 8 hours. The daily dose may be increased to 40 mg/kg, depending on the severity of the infection. Duration of treatment is usually 7 days.

Children < 8 weeks of age: 15 mg/kg as a single dose daily or divided into 7.5 mg/kg every 12 hours.

In newborns with a gestation age <40 weeks, accumulation of Gnostol can occur during the first week of life, therefore the concentrations of Gnostol in serum should preferable be monitored after a few days therapy.

Prophylaxis against postoperative infections caused by anaerobic bacteria: Children < 12 years: 20-30 mg/kg as a single dose given 1-2 hours before surgery Newborns with a gestation age <40 weeks: 10 mg/kg body weight as a single dose before operation

Protozoal and other infections:

Urogenital trichomoniasis:

Where re-infection is likely, in adults the consort should receive a similar course of treatment concurrently

Adults and adolescents: 2000 mg as a single dose or 200 mg 3 times daily for 7 days or 400 mg twice daily for 5-7 days

Children 1-10 years: 40 mg/kg orally as a single dose or 15 - 30 mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000 mg/dose

Bacterial vaginosis:

Adults and children over 10 years: 400mg twice daily for 5-7 days or 2000mg as a single dose for 1 day

Amoebiasis:

a) Invasive intestinal disease in susceptible subject:

Adults, elderly and children over 10 years: 800mg three times daily for 5 days.

Children (7-10 years): 400 mg three times daily for 5 days.

Children (3-7 years): 200 mg four times daily for 5 days.

Children (1-3 years): 200 mg three times daily for 5 days.

b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis:

Adults, elderly and children over 10 years: 400mg three times daily for 5-10 days.

Children (7-10 years): 200 mg three times daily for 5-10 days.

Children (3-7 years): 100 mg four times daily for 5-10 days.

Children (1-3 years): 100 mg three times daily for 5-10 days.

c) Amoebic liver abscess, also forms of extra-intestinal amoebiasis:

Adults, elderly and children over 10 years: 400mg three times daily for 5 days.

Children (7-10 years): 200 mg three times daily for 5 days.

Children (3-7 years): 100 mg four times daily for 5 days.

Children (1-3 years): 100 mg three times daily for 5 days.

d) Symptomless cyst passers:

Adults, elderly and children over 10 years: 400-800mg three times daily for 5-10 days.

Children (7-10 years): 200-400 mg three times daily for 5-10 days.

Children (3-7 years): 100-200 mg four times daily for 5-10 days.

Children (1-3 years): 100-200 mg three times daily for 5-10 days.

Alternatively, 35 to 50 mg/kg daily in 3 divided doses for 5 to 10 days, not to exceed 2400 mg/day

Giardiasis:

Adults, elderly and children over > 10 years: 2000 mg once daily for 3 days, or 400 mg three times daily for 5 days, or 500 mg twice daily for 7 to 10 days

Children 7 to 10 years: 1000 mg once daily for 3 days

Children 3 to 7 years: 600 to 800 mg once daily for 3 days

Children 1 to 3 years: 500 mg once daily for 3 days

Alternatively, as expressed in mg per kg of body weight:

15-40 mg/kg/day divided in 2-3 doses.

Eradication of Helicobacter pylori in paediatric patients:

As a part of a combination therapy, 20 mg/kg/day not to exceed 500 mg twice daily for 7-14 days. Official guidelines should be consulted before initiating therapy

Acute ulcerative gingivitis:

Adults, elderly and children over 10 years: 200 mg three times daily for 3 days.

Children (7-10 years): 100 mg three times daily for 3 days.

Children (3-7 years): 100 mg twice daily for 3 days.

Children (1-3 years): 50 mg three times daily for 3 days.

Acute dental infections:

Adults, elderly and children over 10 years: 200 mg three times daily for 3-7 days.

Leg ulcers and pressure sores:

Adults, elderly and children over 10 years: 400 mg three times daily for 7 days

Children and infants weighing less than 10 kg should receive proportionally smaller dosages.

Elderly: Gnostol is well tolerated by the elderly but a pharmacokinetic study suggests cautious use of high dosage regimens in this age group.

Route of administration: Rectal

1. Treatment of Anaerobic Infections:

Adults and children over 10 years: 1 gram suppository inserted into the rectum eight hourly for three days. Oral medication with 400 mg three times daily should be substituted as soon as this becomes feasible. If rectal medication must be continued for more than three days, the suppositories should be inserted at 12 hourly intervals.

Children (5 -10 years): As for adults but with 500 mg suppositories and oral medication with 7.5 mg/kg bodyweight three times daily.

Infants and children under 5 years: As for children of 5-10 years but with appropriate reduction in dosage of suppositories (one half of a 500 mg suppository for 1 to 5 years and one quarter of a 500 mg suppository for under 1 year).

2. Prevention of Anaerobic Infections:

In appendectomy and post-operative medication for elective colonic surgery.

Adults and children over 10 years: 1 gram suppository inserted into the rectum two hours before surgery and repeated at eight hourly intervals until oral medication (200 to 400 mg three times daily) can be given to complete a seven day course.

If rectal medication is necessary after the third post-operative day, the frequency of administration should be reduced to 12 hourly.

Children (5-10 years): 500 mg suppositories administered as for adults until oral medication (3.7 to 7.5 mg/kg bodyweight three times daily) becomes possible.

The recommended dose is one applicator full of VANDAZOLE (metronidazole vaginal gel) , (approximately 5 grams of gel containing approximately 37.5 mg of metronidazole) administered intravaginally once a day for 5 days. For once a day dosing, VANDAZOLE should be administered at bedtime.

Not for ophthalmic, dermal, or oral use.

A single-dose, pre-filled disposable applicator (which delivers approximately 5 g of gel containing 65 mg of metronidazole) administered once intravaginally. Gnostol should be administered at bedtime.

Gnostol is not for ophthalmic, dermal or oral use.

Known hypersensitivity to nitroimidazoles, Gnostol or any of the excipients.

Known hypersensitivity to nitroimidazoles, metronidazole or any of the excipients.

Hypersensitivity

The use of VANDAZOLE (metronidazole vaginal gel) is contraindicated in patients with a history of hypersensitivity to metronidazole, other nitroimidazole derivatives, or parabens. Reported reactions include urticaria; erythematous rash; Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains.

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer VANDAZOLE (metronidazole vaginal gel) to patients who have taken disulfiram within the last two weeks.

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue alcohol consumption during and for at least three days after therapy with VANDAZOLE (metronidazole vaginal gel).

Hypersensitivity

Gnostol is contraindicated in persons who have shown hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives.

Use Of Disulfiram

Psychotic reactions have been reported with co-administration disulfiram and oral metronidazole. Do not administer concurrently with or within 2 weeks of disulfiram.

Concomitant Alcohol

Disulfiram-like reactions to alcohol have been reported with co-administration of oral metronidazole; do not consume ethanol or propylene glycol, during and for at least 24 hours following treatment.

Regular clinical and laboratory monitoring (especially leukocyte count) are advised if administration of Gnostol for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions, such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).

Gnostol should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.

The elimination half-life of Gnostol remains unchanged in the presence of renal failure. The dosage of Gnostol therefore needs no reduction. Such patients however retain the metabolites of Gnostol. The clinical significance of this is not known at present.

In patients undergoing haemodialysis, Gnostol and metabolites are efficiently removed during an eight hour period of dialysis. Gnostol should therefore be re-administered immediately after haemodialysis.

No routine adjustment in the dosage of Gnostol need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

Gnostol is mainly metabolised by hepatic oxidation. Substantial impairment of Gnostol clearance may occur in the presence of advanced hepatic insufficiency.

Significant cummulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of Gnostol may contribute to the symptoms of the encephalopathy. Gnostol should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Patients should be warned that Gnostol may darken urine.

Due to inadequate evidence on the mutagenicity risk in humans , the use of Gnostol for longer treatment than usually required should be carefully considered.

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 Gnostol for systemic use. In this population, Gnostol should therefore 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 Gnostol.

There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

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

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Gnostol for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions, such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures).

Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.

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, metronidazole should therefore 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 metronidazole.

There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

The elimination half-life of metronidazole remains unchanged in the presence of renal failure. The dosage of metronidazole therefore needs no reduction. Such patients however retain the metabolites of metronidazole. The clinical significance of this is not known at present.

In patients undergoing haemodialysis metronidazole and metabolites are efficiently removed during an eight hour period of dialysis. Metronidazole should therefore be re-administered immediately after haemodialysis.

No routine adjustment in the dosage of Gnostol need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Gnostol should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Patients should be warned that metronidazole may darken urine.

Due to inadequate evidence on the mutagenicity risk in humans , the use of Gnostol for longer treatment than usually required should be carefully considered.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Central and Peripheral Nervous System Effects

Use of oral or intravenous metronidazole is associated with convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or parethesia of an extremity. VANDAZOLE (metronidazole vaginal gel) should be administered with caution to patients with central nervous system diseases. Discontinue VANDAZOLE (metronidazole vaginal gel) promptly if a patient develops abnormal neurologic signs.

Carcinogenicity in Animals

Metronidazole has been shown to be carcinogenic in mice and rats. Unnecessary use of metronidazole should be avoided. Use of VANDAZOLE (metronidazole vaginal gel) should be reserved for the treatment of bacterial vaginosis

Interference with Laboratory Tests

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminostransferase (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. Consider postponing chemistry laboratory tests to after treatment with VANDAZOLE (metronidazole vaginal gel).

Patient Counseling Information

Interaction with Alcohol

Instruct the patient not to consume alcoholic beverages and preparations containing ethanol or propylene glycol during and for at least 3 days after treatment with VANDAZOLE.

Drug Interactions

Instruct the patient not to use VANDAZOLE (metronidazole vaginal gel) if disulfiram had been used within the last two weeks , and to inform their healthcare provider if they are taking oral anticoagulants, or lithium.

Vaginal Intercourse and Use with Vaginal Products

Instruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) during treatment with VANDAZOLE (metronidazole vaginal gel).

Fungal Vaginal Infections

Inform the patient that vaginal fungal infections can occur following use of VANDAZOLE (metronidazole vaginal gel) and may require treatment with an antifungal drug.

Human Milk Feeding

Advise women that they may consider discontinuing milk feeding or pump and discard their milk during treatment and for 24 hours after the last dose of VANDAZOLE (metronidazole vaginal gel).

Accidental Exposure to the Eye

Inform the patient that VANDAZOLE (metronidazole 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 and consult a healthcare provider.

Vaginal Irritation

Inform the patient to discontinue use and consult a healthcare provider if vaginal irritation occurs with use of VANDAZOLE (metronidazole vaginal gel).

Administration of Drug

Instruct the patient that VANDAZOLE (metronidazole vaginal gel, 0.75%) is supplied with 5 vaginal applicators. For once daily dosing, one applicator should be used per dose. See DIRECTIONS FOR USE for complete instructions on how to use the product and the vaginal applicator.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity after chronic oral administration in mice and rats. Pulmonary tumors and lymphomas were reported in several oral mouse studies in which mice were dosed at 75 mg/kg and above (about 5 times the clinical human dose based on body surface area comparison). Malignant liver tumors were reported in male mice dosed at doses equivalent to a human dose of 41 mg/kg/day (33 times the recommended clinical dose based on body surface area comparisons). Chronic oral dosing of metronidazole in rats at doses above 150 mg/kg (about 20 times the clinical human dose based on body surface area comparison) has resulted in mammary and hepatic tumors. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although no life-time studies were performed to evaluate the carcinogenic potential of VANDAZOLE (metronidazole vaginal gel, 0.75%), published data have shown that intravaginal administration of metronidazole to Wistar rats for 5 days, at doses 26 times the recommended human dose based on body surface area comparisons, has resulted in an increased frequency of micronuclei in rat vaginal mucosal cells.

Metronidazole has shown mutagenic activity in a number of in vitro assay systems. In addition, a dose dependent increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosome aberrations has been reported in one study of patients with Crohn's disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in a second study, no increase in chromosome aberrations was reported in patients with Crohn's disease who were treated with metronidazole for 8 months.

Fertility studies have been performed in mice up to six times the recommended human oral dose (based on mg/m²) and have revealed no evidence of impaired fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category B

VANDAZOLE (metronidazole vaginal gel) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women.

There are published data from case-control studies, cohort studies, and two meta-analyses that include more than 5000 pregnant women who used metronidazole systemically during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of systemic antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following systemic metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Oral reproductive toxicity studies have been performed in mice at doses up to six times the recommended human dose based on body surface area comparisons and have revealed no evidence of impaired fertility or harm to the fetus. However, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed.

Animal studies have shown that metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Because animal reproduction studies are not always predictive of human response, and because metronidazole crosses the placental barrier and is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Caution should be exercised when VANDAZOLE is administered to a nursing woman. Following oral metronidazole administration, concentrations of metronidazole in human milk are similar to concentrations in plasma. Since some metronidazole is systemically absorbed following vaginal administration of metronidazole, excretion in human milk is possible.

Because of the potential for tumorigenicity shown for metronidazole in animal studies, a decision should be made whether to discontinue nursing or to discontinue VANDAZOLE (metronidazole vaginal gel) , taking into account the importance of the therapy to the mother. A nursing mother may choose to pump and discard her milk for the duration of VANDAZOLE (metronidazole vaginal gel) therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

Pediatric Use

The safety and efficacy of VANDAZOLE (metronidazole vaginal gel) in the treatment of bacterial vaginosis in post-menarchal females have been established on the extrapolation of clinical trial data from adult women. The safety and efficacy of VANDAZOLE (metronidazole vaginal gel) in premenarchal females have not been established.

Geriatric Use

Clinical studies with VANDAZOLE (metronidazole vaginal gel) did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Other reported clinical experience in using metronidazole gel, 1% has not identified differences in responses between elderly and younger patients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Central And Peripheral Nervous System Effects

Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral or intravenous metronidazole. Gnostol should be administered with caution to patients with central nervous system diseases. Discontinue promptly if abnormal neurologic signs develop.

Carcinogenicity In Animals

Metronidazole has been shown to be carcinogenic at high doses administered orally in mice and rats. Unnecessary use of metronidazole should be avoided. Use of Gnostol should be reserved for the treatment of bacterial vaginosis.

Drug/Laboratory Test Interactions

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Interaction With Alcohol

Instruct the patient not to consume alcoholic beverages and preparations containing ethanol or propylene glycol during and for at least 24 hours after treatment with Gnostol.

Drug Interactions

Instruct the patient not to use Gnostol if disulfiram had been used within the last two weeks , and to inform their healthcare provider if they are taking oral anticoagulants, or lithium.

Vaginal Intercourse And Use With Vaginal Products

Instruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) following the single administration of Gnostol.

Lactation

Advise women not to breastfeed during treatment with Gnostol and to discontinue breastfeeding for 2 days after treatment with Gnostol. Also advise a nursing mother that she may choose to pump and discard her milk during treatment with Gnostol and for 2 days after the therapy with Gnostol and, feed her infant stored human milk or formula.

Vaginal Irritation

Inform the patient to discontinue use and consult a healthcare provider if vaginal irritation occurs with use of Gnostol.

Administration Of Drug

Instruct the patient that Gnostol is supplied as a single dose in a pre-filled applicator. See Instructions for Use for complete instructions on how to use the product and the vaginal applicator.

Nonclinical Toxicology

Carcinogenesis Mutagenesis, Impairment Of Fertility

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Pulmonary tumors were reported in several mouse studies in which mice were dosed orally at 75 mg/kg and above (about 6 or more times the maximum recommended human dose based on mg/m²). Malignant lymphoma was reported at 66 mg/kg and above (about 5 or more times the maximum recommended human dose based on mg/m²). These tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). All these effects were statistically significant.

There were statistically significant increases in the incidence of mammary tumors, among female rats administered metronidazole at 270 mg/kg and above (about 40 times the maximum human dose based on mg/m²). Hepatic adenomas and carcinomas were observed in rats administered 300 mg/kg (about 45 times the maximum human dose based on mg/m²).

Two lifetime oral tumorigenicity studies in hamsters have been performed and reported to be negative at doses up to 80 mg/kg (about 10 times the maximum human dose based on mg/m²).

Carcinogenesis studies have not been conducted with Gnostol.

Although metronidazole has shown in vitro mutagenic activity in bacterial reverse mutation tests, it was negative in in vitro mammalian mutation systems including CHO/HGPRT and CH V79 lung cell assays. Metronidazole was not clastogenic in vitro chromosome aberration tests in CHO cells up to 5000 μg/mL but was positive in human and monkey peripheral blood lymphocytes at 0.1 μg/mL.

In general, numerous micronucleus studies in rats and mice have failed to demonstrate a potential for genetic damage up to single oral doses 3000 mg/kg in mice (about 225 times the maximum human dose based on mg/m²). However, a dose dependent increase in the frequency of micronuclei was observed in CFW mice after intraperitoneal injections of up to 160 mg/kg (about 12 times the maximum human dose based on mg/m²). Â Fertility studies have been performed in mice orally dosed up to 500 mg/kg (about 37 times the maximum human dose based on mg/m²) revealed no evidence of impaired fertility.

While no effects on fertility were observed in female rats dosed intraperitoneally at doses up to 1000 mg/kg (about 300 times the maximum human dose based on mg/m²), studies in male rats resulted in effects on testes and sperm production at oral doses of 100 mg/kg and above (about 30 times the maximum human dose based on mg/m²).

Use In Specific Populations

Pregnancy

Risk Summary

There are no data available on the use of Gnostol in pregnant women. Metronidazole usage in pregnancy has been associated with certain congenital anomalies (see Data). In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally, during organogenesis to pregnant rats and rabbits at up to 60 times and 30 times the recommended human dose based on body surface area comparison, respectfully(see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Blood levels following Gnostol vaginal administration are lower than those achieved with oral metronidazole. Following a single intravaginal 5 g dose of Gnostol, mean maximum concentration (Cmax) and total exposure (AUC0-∞) are approximately 2% and 4%, respectively, of those following a single oral 500 mg dose of metronidazole tablets. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly.

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero; however, these findings were not confirmed.

In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy.

Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Animal Data

No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rabbits at up to 200 mg/kg (about 60 times the maximum human dose based on body surface area comparison). Similarly, no fetotoxic or teratogenic effects were observed in five studies in rats where dosing was administered orally in the diet or by gastric intubation at doses up to 200 mg/kg (about 30 times the maximum human dose based on body surface area comparison).

As well, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at doses up to 100 mg/kg (about 7 times the maximum human dose based on body surface area comparison). However, some intrauterine deaths were observed in Swiss Webster mice administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1 times the maximum human dose based on body surface area comparison). The relationship of these intraperitoneal findings in mice to the vaginal use of Gnostol is unknown.

Lactation

Risk Summary

There is no information on the presence of metronidazole in human milk, or the effects on the breast-fed child, or the effects on milk production following intravaginal administration of Gnostol. Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to plasma concentrations (see Data). Since some metronidazole is systemically absorbed following vaginal administration of Gnostol, excretion in human milk following topical use is possible.

Because of the potential risk for tumorigenicity shown in animal studies with metronidazole, breastfeeding is not recommended during treatment with Gnostol and for 2 days (based on half-life) after Gnostol therapy ends (see Clinical Considerations).

Clinical Considerations

A nursing mother may choose to pump and discard her milk during Gnostol therapy and for 2 days after Gnostol therapy ends, and feed her infant stored human milk or formula.

Data

In a study of nursing mothers receiving oral metronidazole 600 (n=11) or 1200 (n=4) mg daily, mean maternal plasma concentrations were 5.0 and 12.5 mcg/mL, respectively, within 2 hours following administration; the milk: maternal plasma ratio was approximately 1.

Pediatric Use

The safety and effectiveness of Gnostol have been established in pediatric subjects between the ages of 12 and less than 18 years old. Use of Gnostol in this age group is supported by evidence from a multicenter, open-label safety and tolerability study in 60 pediatric subjects with bacterial vaginosis and, evidence from adequate and well-controlled studies in adult women,

The safety and effectiveness of Gnostol in pediatric subjects below the age of 12 years have not been established.

Geriatric Use

Clinical studies with Gnostol did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects.

Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.

Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.

The frequency of adverse events listed below is defined using the following convention:

Very common (>1/10); common (>1/100 to < 1/10); uncommon (>1/1,000 to < 1/100); rare (>1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Serious adverse reactions occur rarely with standard recommended regimens. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia, and pancytopenia

Not known: leucopenia.

Immune system disorders:

Rare: anaphylaxis,

Not known: angioedema, urticaria, fever.

Metabolism and nutrition disorders:

Not known: anorexia.

Psychiatric disorders:

Very rare: Psychotic disorders, including Confusion and hallucinations.

Not known: depressed mood

Nervous system disorders:

Very rare:

- Encephalopathy (eg. confusion, fever, headache, hallucinations, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (eg. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve on discontinuation of the drug.

- Drowsiness, dizziness, convulsions, headaches

Not known:

- during intensive and/or prolonged Gnostol therapy, peripheral sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.

- Aseptic meningitis

Eye disorders:

Very rare: vision disorders such as diplopia and myopia, which, in most cases, is transient.

Not known: optic neuropathy/neuritis

Ear and labyrinth disorders:

Not known: hearing impaired/hearing loss (including sensorineural), tinnitus

Gastrointestinal disorders:

Not known: Taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.

Hepatobiliary disorders:

Very rare:

- increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis which is reversible on drug withdrawal.

- Cases of Liver failure requiring liver transplant have been reported in patients treated with Gnostol in combination with other antibiotic drugs

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pustular eruptions, pruritis, flushing

Not known: erythema multiforme, Steven-Johnson syndrome or toxic epidermal necrolysis, fixed drug eruption.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and urinary disorders:

Very rare: darkening of urine (due to Gnostol metabolite).

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The frequency of adverse events listed below is defined using the following convention:

very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Serious adverse reactions occur rarely with standard recommended regimens. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia

Not known: leucopenia.

Immune system disorders:

Rare: anaphylaxis

Not known: angiodema, urticaria , fever.

Metabolism and nutrition disorders:

Not known: anorexia.

Psychiatric disorders:

Very rare: psychotic disorders, including confusion and hallucinations.

Not known: depressed mood

Nervous system disorders:

Very rare:

- encephalopathy (eg. confusion, fever, headache, hallucinations, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (eg. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve on discontinuation of the drug.

- drowsiness, dizziness, convulsions, headaches

Not known:

- during intensive and/or prolonged metronidazole therapy, peripheral sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.

- aseptic meningitis

Eye disorders:

Very rare: vision disorders such as diplopia and myopia, which, in most cases, is transient.

Not Known: optic neuropathy/neuritis

Ear and labyrinth disorders

Not known: hearing impaired/hearing loss (including sensorineural), tinnitus

Gastrointestinal disorders:

Not known: taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.

Hepatobiliary disorders:

Very rare:

- increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis which is reversible on drug withdrawal.

- cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pustular eruptions, pruritis, flushing

Not known: erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis, fixed drug eruption

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and urinary disorders:

Very rare: darkening of urine (due to metronidazole metabolite).

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to VANDAZOLE compared to another formulation of vaginal metronidazole in 220 women in a single trial. The population was non-pregnant females (age range 18 to 72 years, the mean was 33 years +/- 11 years) with bacterial vaginosis. The racial demographic of those enrolled was 71 (32%) of White, 143 (65%) of Black, 3 (1%) of Hispanic, 2 (1%) of Asian, and 1 (0%) of other. Patients administered an applicator full of VANDAZOLE (metronidazole vaginal gel) intravaginally once daily at bedtime for 5 days.

There were no deaths or serious adverse reactions related to drug therapy in the clinical trial. VANDAZOLE (metronidazole vaginal gel) was discontinued in 5 patients (2.3%) due to adverse reactions.

The incidence of all adverse reactions in VANDAZOLE (metronidazole vaginal gel) -treated patients was 42% (92/220). Adverse reactions occurring in ≥ 1% of patients were: fungal infection* (12%), headache (7%), pruritus (6%), abdominal pain (5%), nausea (3%), dysmenorrhea (3%), pharyngitis (2%), rash (1%), infection (1%), diarrhea (1%), breast pain (1%), and metrorrhagia (1%).

* Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with VANDAZOLE (metronidazole vaginal gel). Approximately 10% of patients treated with VANDAZOLE (metronidazole vaginal gel) developed Candida vaginitis during or immediately after therapy.

Additional uncommon events, reported by < 1% of those women treated with VANDAZOLE (metronidazole vaginal gel) included:

General: allergic reaction, back pain, flu syndrome, mucous membrane disorder, pain

Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, gingivitis, vomiting

Nervous System: depression, dizziness, insomnia

Respiratory System: asthma, rhinitis

Skin and Appendages: acne, sweating, urticaria

Urogenital System: breast enlargement, dysuria, female lactation, labial edema, leucorrhea, menorrhagia, pyleonephritis, salpingitis, urinary frequency, urinary tract infection, vaginitis, vulvovaginal disorder

Other Metronidazole Formulations

Other Vaginal Formulations

Other reactions that have been reported in association with the use of other formulations of metronidazole vaginal gel include: unusual taste and decreased appetite.

Topical (Dermal) Formulations

Other reactions that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse reactions exceeded an incidence of 2% of patients.

Oral and Parenteral Formulations

The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole:

Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.

Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages.

Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis.

Hematopoietic: Reversible neutropenia, reversible thrombocytopenia.

Hypersensitivity Reactions: Urticaria; erythematous rash; Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains.

Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience

Clinical Trial Experience In Adult Subjects

The safety of Gnostol was evaluated in a randomized, double-blind, vehicle-controlled study in subjects with bacterial vaginosis. A total of 321 non-pregnant females with a mean age of 33.4 years (range 18 to 67 years) received Gnostol. Subjects were primarily Black/African American (58.3%) or White (39.3%). Subjects administered a single dose of Gnostol at bedtime on the first day of the study.

There were no deaths or serious adverse reactions in this trial. Adverse reactions were reported by 19.0% of subjects treated with Gnostol versus 16.1% of subjects treated with Vehicle Gel.

Adverse reactions occurring in ≥1% of subjects receiving Gnostol were: vulvovaginal candidiasis (5.6%), headache (2.2%), vulvovaginal pruritus (1.6%), nausea (1.6%), diarrhea (1.2%), and dysmenorrhea (1.2%). No subjects discontinued treatment due to adverse reactions.

Clinical Trial Experience In Pediatric Subjects

The safety of Gnostol was evaluated in a multicenter, open-label study evaluating the safety and tolerability of Gnostol in 60 pediatric subjects between the ages of 12 and less than 18 years old all of whom were treated with a single dose of Gnostol administered once at bedtime intravaginally. Most subjects in this study were either Black/African-American, non-Hispanic (47%) or Hispanic (35%)

Safety in pediatric female subjects aged 12 to less than 18 years old was comparable to adult women. No deaths occurred and no subjects discontinued treatment due to adverse reactions. Adverse reactions occurring in ≥ 1% of pediatric subjects included: vulvovaginal discomfort (2%).

Other Metronidazole Formulations

Other Vaginal Formulations

Other reactions that have been reported in association with the use of other formulations of metronidazole vaginal gel include: unusual taste and decreased appetite.

Topical (Dermal) Formulations

Other reactions that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse reactions exceeded an incidence of 2% of patients.

Oral And Parenteral Formulations

The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole:

Cardiovascular

Flattening of the T-wave may be seen in electrocardiographic tracings.

Nervous System

The most serious adverse reactions reported in patients treated with oral metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

Gastrointestinal

Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages.

Genitourinary

Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis.

Hematopoietic

Reversible neutropenia, reversible thrombocytopenia.

Hypersensitivity Reactions

Urticaria; erythematous rash; Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains.

Renal

Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

Single oral doses of Gnostol, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no specific antidote for Gnostol overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

Single oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no specific antidote for metronidazole overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects.

There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied Gnostol could be absorbed in sufficient amounts to produce systemic effects.

Pharmacotherapeutic group: Antibacterials for systemic use, ATC code: J01X D01

Gnostol is active against a wide range of pathogenic micro-organisms notably species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and Gardnerella vaginalis. It is also active against Trichomonas, Entamoeba histolytica, Giardia lamblia and Balantidium coli.

Pharmacotherapeutic code: Antibacterials for systemic use, ATC code: J01X D01.

Metronidazole has antiprotozoal and antibacterial actions and is effective against Trichomonas vaginalis and other protozoa including Entamoeba histolytica and Giardia lamblia and against anaerobic bacteria.

Gnostol is rapidly and almost completely absorbed on administration of Gnostol tablets; peak plasma concentrations occur after 20 min to 3 hours.

The half-life of Gnostol is 8.5 ± 2.9 hours. Gnostol can be used in chronic renal failure; it is rapidly removed from the plasma by dialysis. Gnostol is excreted in milk but the intake of a suckling infant of a mother receiving normal dosage would be considerably less than the therapeutic dosage for infants.

Metronidazole is readily absorbed from the rectal mucosa and widely distributed in body tissues. Maximum concentrations occur in the serum after about 1 hour and traces are detected after 24 hours.

At least half the dose is excreted in the urine as metronidazole and its metabolites, including an acid oxidation product, a hydroxy derivative and glucoronide. Metronidazole diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum.

Following a single, intravaginal 5 g dose of Gnostol (equivalent to 65 mg of metronidazole) to 20 healthy female subjects, a mean maximum serum metronidazole concentration (Cmax) of 239 ng/mL was observed (range: 114 to 428 ng/mL). The average time to achieve this Cmax was 7.3 hours (range: 4 to 18 hours). This Cmax is approximately 2% of the mean maximum serum concentration reported in healthy subjects administered a single, oral 500 mg dose of metronidazole tablets (mean Cmax = 12,785 ng/mL).

The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of Gnostol (equivalent to 65 mg of metronidazole), was 5,434 ng•hr/mL (range: 1382 to 12744 ng•hr/mL). This AUC0-∞ is approximately 4% of the reported AUC of metronidazole following a single oral 500 mg dose of metronidazole (approximately 125,000 ng•hr/mL).

Not applicable.

Not applicable

No special requirements.

No special requirements