Gino Pletil

Miconazole Nitrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Gino Pletil (Miconazole Nitrate) reviews

1 INDICATIONS AND USAGE

• Gino Pletil Ointment is indicated for adjunctive treatment of diaper dermatitis when complicated by documented candidiasis (microscopic evidence of pseudohyphae and /or budding yeast) in immunocompetent pediatric patients 4 weeks and older. (1)
• Gino Pletil (Miconazole Nitrate) Ointment should not be used as a substitute for frequent diaper changes. (1)
• Gino Pletil (Miconazole Nitrate) Ointment should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance. (1)

1.1 Indication

Gino Pletil (Miconazole Nitrate) Ointment is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast), in immunocompetent pediatric patients 4 weeks and older. A positive fungal culture for Candida albicansis not adequate evidence of candidal infection since colonization with C. albicans can result in a positive culture. The presence of candidal infection should be established by microscopic evaluation prior to initiating treatment.

Gino Pletil (Miconazole Nitrate) should be used as part of a treatment regimen that includes measures directed at the underlying diaper dermatitis, including gentle cleansing of the diaper area and frequent diaper changes.

Gino Pletil (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes. Gino Pletil (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance.

1.2 Limitations of Use

The safety and efficacy of Gino Pletil (Miconazole Nitrate) have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term).

The safety and efficacy of Gino Pletil (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Gino Pletil (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

2 DOSAGE AND ADMINISTRATION

Gino Pletil (Miconazole Nitrate) is not for oral, ophthalmic, or intravaginal use.

Before applying Gino Pletil (Miconazole Nitrate), gently cleanse the skin with lukewarm water and pat dry with a soft towel. Avoid using any scented soaps, shampoos, or lotions on the diaper area.

Apply Gino Pletil (Miconazole Nitrate) to the affected area at each diaper change for 7 days. Continue treatment for the full 7 days, even if there is improvement. The safety of Gino Pletil (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use Gino Pletil (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.

Gently apply a thin layer of Gino Pletil (Miconazole Nitrate) to the diaper area with the fingertips. Do not rub Gino Pletil (Miconazole Nitrate) into the skin as this may cause additional irritation. Thoroughly wash hands after applying Gino Pletil (Miconazole Nitrate).

• Gino Pletil (Miconazole Nitrate) Ointment is for topical use only. Gino Pletil (Miconazole Nitrate) Ointment is not for oral, ophthalmic, or intravaginal use. (2)
• Gino Pletil (Miconazole Nitrate) Ointment should be applied as a thin layer to the affected area at each diaper change for 7 days. (2)
• Gino Pletil (Miconazole Nitrate) Ointment should be used as part of a treatment regimen that includes gentle cleansing of the diaper area and frequent diaper changes. (2)

3 DOSAGE FORMS AND STRENGTHS

White ointment containing 0.25% Gino Pletil (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum.

• Ointment with 0.25% Gino Pletil (Miconazole Nitrate) nitrate, 15% zinc oxide, and 81.35% white petrolatum. (3)

4 CONTRAINDICATIONS

None

• None

5 WARNINGS AND PRECAUTIONS

If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider.

The safety and efficacy of Gino Pletil (Miconazole Nitrate) have not been evaluated in incontinent adult patients. Gino Pletil (Miconazole Nitrate) should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

• If irritation occurs or if the disease worsens, discontinue use of the medication, and contact the health care provider. (5)

6 ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Prestium Pharma, Inc. at 1-866-897-5002 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rate 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 clinical practice.

A total of 835 infants and young children were evaluated in the clinical development program. Of 418 subjects in the Gino Pletil group, 58 (14%) reported one or more adverse events. Of 417 subjects in the zinc oxide/white petrolatum control group, 85 (20%) reported one or more adverse events. Adverse events that occurred at a rate of ≥ 1% for subjects who were treated with Gino Pletil (Miconazole Nitrate) were approximately the same in type and frequency as for subjects who were treated with zinc oxide/white petrolatum ointment.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of Gino Pletil (Miconazole Nitrate).

GASTROINTESTINAL DISORDERS: vomiting

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: burning sensation, condition aggravated, inflammation, pain

INJURY, POISONING AND PROCEDURAL COMPLICATIONS: accidental exposure

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: blister, dermatitis contact, diaper dermatitis, dry skin, erythema, pruritus, rash, skin exfoliation

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

Drug-drug interaction studies were not conducted. Women who take a warfarin anticoagulant and use a Gino Pletil (Miconazole Nitrate) intravaginal cream or suppository may be at risk for developing an increased prothrombin time, international normalized ratio (INR), and bleeding. The potential for this interaction between warfarin and Gino Pletil (Miconazole Nitrate) is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Gino Pletil in pregnant women. Therefore, Gino Pletil (Miconazole Nitrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Gino Pletil (Miconazole Nitrate) nitrate administration has been shown to result in prolonged gestation and decreased numbers of live young in rats and in increased number of resorptions and decreased number of live young in rabbits at oral doses of 100 mg/kg/day and 80 mg/kg/day, which are 28 and 45 times the maximum possible topical exposure of caregivers, respectively, assuming 100% absorption.

8.3 Nursing Mothers

Safety and efficacy of Gino Pletil (Miconazole Nitrate) have not been established in nursing mothers. It is not known if the active components of Gino Pletil (Miconazole Nitrate) may be present in milk.

8.4 Pediatric Use

Efficacy was not demonstrated in infants less than 4 weeks of age. Safety and efficacy have not been established in very-low-birth-weight infants.

Gino Pletil should not be used to prevent diaper dermatitis.

The safety of Gino Pletil (Miconazole Nitrate) when used for longer than 7 days is not known. Do not use more than 7 days.

8.5 Geriatric Use

Safety and efficacy in a geriatric population have not been evaluated.

11 DESCRIPTION

Gino Pletil (Miconazole Nitrate) contains the synthetic antifungal agent, Gino Pletil (Miconazole Nitrate) nitrate (0.25%) USP, zinc oxide (15%) USP, and white petrolatum (81.35%) USP.

The chemical name of Gino Pletil (Miconazole Nitrate) nitrate is 1-[2, 4-dichloro-ß-{(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate with empirical formula C₁₈H₁₄Cl₄N₂O-HNO₃ and molecular weight of 479.15. The structural formula of Gino Pletil (Miconazole Nitrate) nitrate is as follows:

The zinc oxide has an empirical formula of ZnO and a molecular weight of 81.39.

The white petrolatum, which is obtained from petroleum and is wholly or nearly decolorized, is a purified mixture of semisolid saturated hydrocarbons having the general chemical formula C_nH_2n+2. The hydrocarbons consist mainly of branched and unbranched chains. White petrolatum contains butylated hydroxytoluene (BHT) as stabilizer.

Each gram of Gino Pletil (Miconazole Nitrate) contains 2.5 mg of Gino Pletil (Miconazole Nitrate) nitrate USP, 150 mg of zinc oxide USP, and 813.5 mg of white petrolatum USP containing butylated hydroxytoluene, trihydroxystearin, and Chemoderm^® 1001/B fragrance.¹

Gino Pletil (Miconazole Nitrate) is a smooth, uniform, white ointment.

Structural formula of Gino Pletil (Miconazole Nitrate) nitrate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The Gino Pletil component of Gino Pletil (Miconazole Nitrate) is an antifungal agent. The mechanism of action of white petrolatum and zinc oxide for the adjunctive treatment of diaper dermatitis is unknown.

12.2 Pharmacodynamics

The human pharmacodynamics of Gino Pletil (Miconazole Nitrate) is unknown.

12.3 Pharmacokinetics

The topical absorption of Gino Pletil from Gino Pletil (Miconazole Nitrate) was studied in immunocompetent male and female infants and children (n=17) with diaper dermatitis complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) ranging in age from 1 month to 21 months. After multiple daily applications to the affected area at every diaper change (approximately 5-12 times per day) for 7 days, the plasma concentrations of Gino Pletil (Miconazole Nitrate) were below the lower limit of quantitation (LOQ) of 0.5 ng/mL in 15 out of 17 (88%) subjects. In the other 2 remaining subjects, the plasma concentrations of Gino Pletil (Miconazole Nitrate) were 0.57 and 0.58 ng/mL, respectively at a single timepoint (4 hours after the last application) on Day 7.

12.4 Microbiology

The Gino Pletil (Miconazole Nitrate) nitrate component in this product has been shown to have in vitro activity against Candida albicans, an organism that is associated with diaper dermatitis. The activity of Gino Pletil (Miconazole Nitrate) nitrate against C. albicans is based on the inhibition of the ergosterol biosynthesis in the cell membrane. The accumulation of ergosterol precursors and toxic peroxides results in cytolysis of the cell. In vitro minimal inhibitory concentration (MIC) test results for C. albicans isolates obtained from treatment failures in Clinical Study 1 (see Clinical Studies (14)) does not appear to indicate that resistance to Gino Pletil (Miconazole Nitrate) nitrate was the reason for treatment failure. The clinical significance of the in vitro activity of Gino Pletil (Miconazole Nitrate) nitrate against C. albicans in the setting of diaper dermatitis is unclear.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Gino Pletil (Miconazole Nitrate) in animals has not been evaluated.

Gino Pletil (Miconazole Nitrate) nitrate was negative in a bacterial reverse mutation test, a chromosome aberration test in mice, and micronucleus assays in mice and rats.

Gino Pletil (Miconazole Nitrate) nitrate had no adverse effect on fertility in a study in rats at oral doses of up to 320 mg/kg/day, which is 89 times the maximum possible topical exposure of caregivers, assuming 100% absorption.

14 CLINICAL STUDIES

Study 1 was a double-blind, multicenter study in which Gino Pletil (Miconazole Nitrate) was compared to the zinc oxide and white petrolatum combination treatment and included 236 infants and toddlers with diaper dermatitis, complicated by candidiasis as documented by KOH tests that demonstrated psuedohyphae and/or budding yeasts. Study medication was applied at every diaper change for 7 days.

The primary endpoint was “Overall Cure” and required that subjects be both clinically cured (total resolution of all signs and symptoms of infection) and microbiologically cured (eradication of candidiasis). Primary efficacy was assessed 1 week following the end of treatment, at Day 14.

Study results are shown in the following table.

Overall Cure at Day 14
	Gino Pletil (Miconazole Nitrate) n=112	Zinc Oxide/White Petrolatum n=124
	26 (23%)	12 (10%)

Two additional studies provided supportive evidence of the clinical efficacy of Gino Pletil (Miconazole Nitrate) in infants and toddlers with diaper dermatitis, some of whom cultured positive for C. albicans. However, candidal infection was not documented in the culture-positive subjects, as microscopic testing (e.g. KOH) was not done. Therefore, the positive culture results may have reflected colonization rather than infection.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Gino Pletil is a smooth, uniform, white ointment supplied in an aluminum tube, as follows:

50g (NDC 40076-002-50)

16.2 Storage Conditions

Store at controlled room temperature between 20°C and 25°C (68°F and 77°F); with excursions permitted between 15°C and 30°C (59°F and 86°F).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Patients using Gino Pletil (Miconazole Nitrate) should be informed about the following information:

• Gino Pletil (Miconazole Nitrate) is to be used only for diaper dermatitis that is complicated by documented candidiasis (i.e. documented by microscopic testing).
• Gino Pletil (Miconazole Nitrate) should not be used as a substitute for frequent diaper changes.
• Gino Pletil (Miconazole Nitrate) should not be used to prevent diaper dermatitis.
• Gino Pletil (Miconazole Nitrate) should not be used long term.
• Gino Pletil (Miconazole Nitrate) should be used only as directed by the health care provider.
• Gino Pletil (Miconazole Nitrate) is for external use only. It is not for oral, ophthalmic, or intravaginal use.
• Gently cleanse the diaper area with lukewarm water or a very mild soap and pat the area dry with a soft towel before applying Gino Pletil (Miconazole Nitrate).
• Gently apply Gino Pletil (Miconazole Nitrate) to the diaper area with the fingertips after each diaper change. Do not rub Gino Pletil (Miconazole Nitrate) into the skin as this may cause additional irritation.
• Thoroughly wash hands after applying Gino Pletil (Miconazole Nitrate).
• Treatment should be continued for 7 days, even if there is improvement. Do not use Gino Pletil (Miconazole Nitrate) for longer than 7 days. If symptoms have not improved by day 7, see your health care provider.
• Gino Pletil (Miconazole Nitrate) should not be used on children for whom it is not prescribed.

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of Prestium Pharma, Inc.

Revised Oct 2013 VSN:3PI

FDA-Approved Patient Labeling

Gino Pletil (Miconazole Nitrate)^® (Vu-sion) Ointment

(0.25% Gino Pletil (Miconazole Nitrate) nitrate, 15% zinc oxide and 81.35% white petrolatum)

IMPORTANT: For Skin Use Only. Do not use in the mouth, eyes, or vagina.

Read the Patient Information that comes with Gino Pletil (Miconazole Nitrate) before you use it on your child. This leaflet does not take the place of talking to your health care provider about your child’s medical condition or treatment. If you have any questions or if you are not sure about any of the information on Gino Pletil (Miconazole Nitrate), ask your health care provider, or pharmacist.

What is Gino Pletil (Miconazole Nitrate)?

Gino Pletil (Miconazole Nitrate) is a prescription skin medicine used to treat diaper rash that also has a yeast infection in children who are at least 4 weeks old and who have a normal immune system. Gino Pletil (Miconazole Nitrate) contains medicines that will help treat the yeast infection and the diaper rash, but you must also change your child’s diapers very often so that your child is not wearing a wet or soiled diaper. Even if you use Gino Pletil (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry. You should use water or a very mild cleanser to clean your child’s diaper area. Gino Pletil (Miconazole Nitrate) is not to be used to prevent diaper rash or to be used for more than 7 days.

Your health care provider will need to do a special test to tell if your child’s diaper rash also has a yeast infection. Do not use Gino Pletil (Miconazole Nitrate) on your child’s diaper rash unless your health care provider tells you that there is also a yeast infection.

Who should not use Gino Pletil (Miconazole Nitrate)?

Gino Pletil (Miconazole Nitrate) is not for treatment of all cases of diaper rash. Gino Pletil (Miconazole Nitrate) is only for diaper rash that also has a yeast infection. Most cases of diaper rash do not need the yeast medicine that is in Gino Pletil (Miconazole Nitrate) because most cases of diaper rash do not also have a yeast infection.

Do not use Gino Pletil (Miconazole Nitrate) on any other children or other family member.

Do not use Gino Pletil (Miconazole Nitrate) on your child’s diaper rash if they are allergic to anything in it. See the end of this leaflet for a list of ingredients in Gino Pletil (Miconazole Nitrate).

Do not use on infants less than 4 weeks of age.

Do not use in infants or children who do not have a normal immune system.

How should I use Gino Pletil (Miconazole Nitrate) on my child?

Gino Pletil (Miconazole Nitrate) is applied to the skin on your child’s diaper area at each diaper change for 7 days.

Apply Gino Pletil (Miconazole Nitrate) for the full 7 days even if the diaper rash starts to go away. Call your child’s health care provider if the diaper rash gets worse or does not go away with 7 days of treatment with Gino Pletil (Miconazole Nitrate). Gino Pletil (Miconazole Nitrate) should not be used for more than 7 days.

To apply Gino Pletil (Miconazole Nitrate):

• Gently, clean the skin on your child’s diaper area with warm ( not hot ) water. You may also use a very mild soap. Pat the area dry with a soft towel.
• Use your fingertips and gently apply a thin layer of Gino Pletil (Miconazole Nitrate) to your child’s diaper area at each diaper change. Do not rub Gino Pletil (Miconazole Nitrate) into your child’s skin. Rubbing the skin can cause more irritation.
• Wash your hands after applying Gino Pletil (Miconazole Nitrate) on your child.

Gino Pletil (Miconazole Nitrate) is for skin use only.

Call your child’s health care provider or poison control center right away if any Gino Pletil (Miconazole Nitrate) is swallowed. Call your child’s health care provider if Gino Pletil (Miconazole Nitrate) gets in the eye.

Keep out of reach of children.

What other steps will help diaper rash go away?

• Check your child’s diaper often. Change the diaper at the first sign of wetness.
• Clean your child’s diaper area after each diaper change. Gently wipe the diaper area from the front to back using warm ( not hot )water. You may also use a mild soap. Rinse the diaper area well. Pat dry with a soft towel.
• Keep the diaper area open to air when possible.
• Even if you use Gino Pletil (Miconazole Nitrate), diaper rash will not go away if you do not keep your child’s diaper area clean and dry.

What are the possible side effects of Gino Pletil (Miconazole Nitrate)?

Gino Pletil (Miconazole Nitrate) may cause irritation. You should call your child’s health care provider if irritation appears or if the diaper rash gets worse.

How should I store Gino Pletil (Miconazole Nitrate)?

• Keep Gino Pletil (Miconazole Nitrate) out of the reach of children to avoid the risk of accidental ingestion.
• Store Gino Pletil (Miconazole Nitrate) at room temperature between 68°F to 77°F (20°C to 25°C).

General information about Gino Pletil (Miconazole Nitrate)

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use Gino Pletil (Miconazole Nitrate) for a condition for which it was not prescribed. Do not give Gino Pletil (Miconazole Nitrate) to other children or family members, even if they have the same symptoms your child has. It may harm them.

This leaflet summarizes the most important information about Gino Pletil (Miconazole Nitrate). If you would like more information, talk to your child’s health care provider. You can ask your child’s health care provider or pharmacist for information about Gino Pletil (Miconazole Nitrate) that is written for healthcare professionals.

Side effects may be reported to Prestium Pharma, Inc. at 1-866-897-5002 or the FDA at 1-800-FDA-1088.

What are the ingredients in Gino Pletil (Miconazole Nitrate)?

Active Ingredients: Gino Pletil (Miconazole Nitrate) nitrate, zinc oxide, and white petrolatum

Inactive Ingredients: trihydroxystearin, butylated hydroxyltoluene (BHT), and Chemoderm^® 1001/B fragrance

This Patient Information leaflet has been approved by the U.S. Food and Drug Administration.

The Patient Information leaflet was last revised: October 2013

Manufactured for:

Prestium Pharma, Inc.

Newtown, PA 18940

Manufactured by:

GlaxoSmithKline

Mississauga, ON, Canada

Made in Canada

© 2013 Delcor Asset Corporation, an affiliate of

Prestium Pharma, Inc.

Revised Oct 2013

VSN:3PIL

Principal Display Panel

NDC 40076-002-50

Gino Pletil (Miconazole Nitrate)^®

(miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP)

Ointment

50 grams

R_x only

Principal Display Panel NDC 40076-002-50 Vusion® (miconazole nitrate 0.25% USP, zinc oxide 15% USP, white petrolatum 81.35% USP) Ointment 50 grams Rx only

Tinidazole:

• Warning: potential risk for carcinogenicity
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• Patient counseling information
• Gino Pletil (Tinidazole) reviews

WARNING: POTENTIAL RISK FOR CARCINOGENICITY

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent ( 13.1). Although such data have not been reported for Gino Pletil (Tinidazole), the two drugs are structurally related and have similar biologic effects. Its use should be reserved for the conditions described in INDICATIONS AND USAGE ( 1).

WARNING: POTENTIAL RISK FOR CARCINOGENICITY

See full prescribing information for complete boxed warning.

Carcinogenicity has been seen in mice and rats treated chronically with metronidazole, another nitroimidazole agent ( 13.1). Although such data have not been reported for Gino Pletil (Tinidazole), the two drugs are structurally related and have similar biologic effects. Use should be limited to approved indications only.

Indications and Usage, Bacterial Vaginosis ( 1.4) 5/2007

Dosage and Administration, Bacterial Vaginosis ( 2.6) 5/2007

1 INDICATIONS AND USAGE

Gino Pletil is a nitroimidazole antimicrobial indicated for:

• Trichomoniasis ( 1.1)
• Giardiasis: in patients age 3 and older ( 1.2)
• Amebiasis: in patients age 3 and older ( 1.3)
• Bacterial Vaginosis: in non-pregnant, adult women ( 1.4, 8.1)

1.1 Trichomoniasis

Gino Pletil (Tinidazole) is indicated for the treatment of trichomoniasis caused by Trichomonas vaginalis. The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection .

1.2 Giardiasis

Gino Pletil is indicated for the treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) in both adults and pediatric patients older than three years of age .

1.3 Amebiasis

Gino Pletil (Tinidazole) is indicated for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in both adults and pediatric patients older than three years of age. It is not indicated in the treatment of asymptomatic cyst passage .

1.4 Bacterial Vaginosis

Gino Pletil (Tinidazole) is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women .

Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Gino Pletil (Tinidazole) and other antibacterial drugs, Gino Pletil (Tinidazole) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

• Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners with the same dose and at the same time
• Giardiasis: Adults: a single 2 g dose taken with food. Pediatric patients older than three years of age: a single dose of 50 mg/kg (up to 2 g) with food ( 2.4)
• Amebiasis, Intestinal: Adults: 2 g per day for 3 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3 days with food ( 2.5). Amebic liver abscess: Adults: 2 g per day for 3-5 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3-5 days with food ( 2.5)
• Bacterial vaginosis: Non-pregnant, adult women: 2 g once daily for 2 days taken with food, or 1 g once daily for 5 days taken with food ( 2.6)

2.1 Dosing Instructions

It is advisable to take Gino Pletil (Tinidazole) with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of Gino Pletil (Tinidazole) .

Alcoholic beverages should be avoided when taking Gino Pletil (Tinidazole) and for 3 days afterwards .

2.2 Compounding of the Oral Suspension

For those unable to swallow tablets, Gino Pletil tablets may be crushed in artificial cherry syrup to be taken with food.

Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration.

2.3 Trichomoniasis

The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time.

2.4 Giardiasis

The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg with food.

2.5 Amebiasis

Intestinal: The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food.

Amebic Liver Abscess: The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days.

2.6 Bacterial Vaginosis

The recommended dose in non-pregnant females is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of Gino Pletil (Tinidazole) in pregnant patients has not been studied for bacterial vaginosis.

3 DOSAGE FORMS AND STRENGTHS

• 500 mg tablets are pink, oval, scored tablets, with TM debossed on one side and 500 on the other

4 CONTRAINDICATIONS

The use of Gino Pletil (Tinidazole) is contraindicated:

• In patients with a previous history of hypersensitivity to Gino Pletil (Tinidazole) or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome .
• During first trimester of pregnancy .
• In nursing mothers: Interruption of breast-feeding is recommended during Gino Pletil (Tinidazole) therapy and for 3 days following the last dose .

• Prior history of hypersensitivity to Gino Pletil (Tinidazole) or other nitroimidazole derivatives ( 4, 6.1, 6.2)
• First trimester of pregnancy ( 4, 8.1)
• Nursing mothers, unless breast-feeding is interrupted during Gino Pletil (Tinidazole) therapy and for 3 days following the last dose ( 4, 8.3)

5 WARNINGS AND PRECAUTIONS

• Seizures and neuropathy have been reported. Discontinue Gino Pletil if abnormal neurologic signs develop ( 5.1)
• Vaginal candidiasis may develop with Gino Pletil (Tinidazole) and require treatment with an antifungal agent ( 5.2)
• Use Gino Pletil (Tinidazole) with caution in patients with blood dyscrasias. Gino Pletil (Tinidazole) may produce transient leukopenia and neutropenia ( 5.3, 7.3)

5.1 Neurological Adverse Reactions

Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with Gino Pletil (Tinidazole). The appearance of abnormal neurologic signs demands the prompt discontinuation of Gino Pletil (Tinidazole) therapy.

5.2 Vaginal Candidiasis

The use of Gino Pletil may result in Candida vaginitis. In a clinical study of 235 women who received Gino Pletil (Tinidazole) for bacterial vaginosis, a vaginal fungal infection developed in 11 (4.7%) of all study subjects .

5.3 Blood Dyscrasia

Gino Pletil (Tinidazole) should be used with caution in patients with evidence of or history of blood dyscrasia .

5.4 Drug Resistance

Prescribing Gino Pletil (Tinidazole) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS

Most common adverse reactions for a single 2 g dose of Gino Pletil (incidence >1%) are metallic/bitter taste, nausea, weakness/fatigue/malaise, dyspepsia/cramps/epigastric discomfort, vomiting, anorexia, headache, dizziness and constipation ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at 1-855-778-0177or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Studies 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.

Among 3669 patients treated with a single 2 g dose of Gino Pletil (Tinidazole), in both controlled and uncontrolled trichomoniasis and giardiasis clinical studies, adverse reactions were reported by 11.0% of patients. For multi-day dosing in controlled and uncontrolled amebiasis studies, adverse reactions were reported by 13.8% of 1765 patients. Common (≥ 1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in Table 1 below are pooled from studies with variable designs and safety evaluations.)

Other adverse reactions reported with Gino Pletil (Tinidazole) include:

Central Nervous System: Two serious adverse reactions reported include convulsions and transient peripheral neuropathy including numbness and paresthesia . Other CNS reports include vertigo, ataxia, giddiness, insomnia, drowsiness.

Gastrointestinal: tongue discoloration, stomatitis, diarrhea

Hypersensitivity: urticaria, pruritis, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema

Renal: darkened urine

Cardiovascular: palpitations

Hematopoietic: transient neutropenia, transient leukopenia

Other: Candida overgrowth, increased vaginal discharge, oral candidiasis, hepatic abnormalities including raised transaminase level, arthralgias, myalgias, and arthritis.

	2 g single dose	Multi-day dose
GI: Metallic/bitter taste	3.7%	6.3%
Nausea	3.2%	4.5%
Anorexia	1.5%	2.5%
Dyspepsia/cramps/epigastric discomfort	1.8%	1.4%
Vomiting	1.5%	0.9%
Constipation	0.4%	1.4%
CNS: Weakness/fatigue/malaise	2.1%	1.1%
Dizziness	1.1%	0.5%
Other: Headache	1.3%	0.7%
Total patients with adverse reactions	11.0% (403/3669)	13.8% (244/1765)

Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia.

Adverse Reactions in Pediatric Patients: In pooled pediatric studies, adverse reactions reported in pediatric patients taking Gino Pletil (Tinidazole) were similar in nature and frequency to adult findings including nausea, vomiting, diarrhea, taste change, anorexia, and abdominal pain.

Bacterial vaginosis: The most common adverse reactions in treated patients (incidence >2%), which were not identified in the trichomoniasis, giardiasis and amebiasis studies, are gastrointestinal: decreased appetite, and flatulence; renal: urinary tract infection, painful urination, and urine abnormality; and other reactions including pelvic pain, vulvo-vaginal discomfort, vaginal odor, menorrhagia, and upper respiratory tract infection .

6.2 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of Gino Pletil (Tinidazole). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Severe acute hypersensitivity reactions have been reported on initial or subsequent exposure to Gino Pletil (Tinidazole). Hypersensitivity reactions may include urticaria, pruritis, angioedema, Stevens-Johnson syndrome and erythema multiforme.

7 DRUG INTERACTIONS

Although not specifically identified in studies with Gino Pletil, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole. Therefore, these drug interactions may occur with Gino Pletil (Tinidazole).

The following drug interactions were reported for metronidazole, a chemically-related nitroimidazole and may therefore occur with Gino Pletil (Tinidazole):

• Warfarin and other oral coumarin anticoagulants: Anticoagulant dosage may need adjustment during and up to 8 days after Gino Pletil (Tinidazole) therapy ( 7.1)
• Alcohol-containing beverages/preparations: Avoid during and up to 3 days after Gino Pletil (Tinidazole) therapy ( 7.1)
• Lithium: Monitor serum lithium concentrations ( 7.1)
• Cyclosporine, tacrolimus: Monitor for toxicities of these immunosuppressive drugs ( 7.1)
• Fluorouracil: Monitor for fluorouracil-associated toxicities ( 7.1)
• Phenytoin, fosphenytoin: Adjustment of anticonvulsant and/or Gino Pletil (Tinidazole) dose(s) may be needed ( 7.1, 7.2)
• CYP3A4 inducers/inhibitors: Monitor for decreased Gino Pletil (Tinidazole) effect or increased adverse reactions ( 7.2)

7.1 Potential Effects of Gino Pletil (Tinidazole) on Other Drugs

Warfarin and Other Oral Coumarin Anticoagulants: As with metronidazole, Gino Pletil (Tinidazole) may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The dosage of oral anticoagulants may need to be adjusted during Gino Pletil (Tinidazole) co-administration and up to 8 days after discontinuation.

Alcohols, Disulfiram: Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during Gino Pletil (Tinidazole) therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with Gino Pletil (Tinidazole), Gino Pletil (Tinidazole) should not be given to patients who have taken disulfiram within the last two weeks.

Lithium: Metronidazole has been reported to elevate serum lithium levels. It is not known if Gino Pletil (Tinidazole) shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and Gino Pletil (Tinidazole) treatment to detect potential lithium intoxication.

Phenytoin, Fosphenytoin: Concomitant administration of oral metronidazole and intravenous phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. Metronidazole did not significantly affect the pharmacokinetics of orally-administered phenytoin.

Cyclosporine, Tacrolimus: There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During Gino Pletil (Tinidazole) co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities.

Fluorouracil: Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of Gino Pletil (Tinidazole) and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities.

7.2 Potential Effects of Other Drugs on Gino Pletil

CYP3A4 Inducers and Inhibitors: Simultaneous administration of Gino Pletil (Tinidazole) with drugs that induce liver microsomal enzymes, i.e., CYP3A4 inducers such as phenobarbital, rifampin, phenytoin, and fosphenytoin (a pro-drug of phenytoin), may accelerate the elimination of Gino Pletil (Tinidazole), decreasing the plasma level of Gino Pletil (Tinidazole). Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole, may prolong the half-life and decrease the plasma clearance of Gino Pletil (Tinidazole), increasing the plasma concentrations of Gino Pletil (Tinidazole).

Cholestyramine: Cholestyramine was shown to decrease the oral bioavailability of metronidazole by 21%. Thus, it is advisable to separate dosing of cholestyramine and Gino Pletil (Tinidazole) to minimize any potential effect on the oral bioavailability of Gino Pletil (Tinidazole).

Oxytetracycline: Oxytetracycline was reported to antagonize the therapeutic effect of metronidazole.

7.3 Laboratory Test Interactions

Gino Pletil (Tinidazole), like 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 hexokinase glucose. 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 dinucleotide (NAD ⁺↔ NADH). Potential interference is due to the similarity of absorbance peaks of NADH and Gino Pletil (Tinidazole).

Gino Pletil (Tinidazole), like metronidazole, may produce transient leukopenia and neutropenia; however, no persistent hematological abnormalities attributable to Gino Pletil (Tinidazole) have been observed in clinical studies. Total and differential leukocyte counts are recommended if re-treatment is necessary.

8 USE IN SPECIFIC POPULATIONS

• Pediatric Use: Data on Gino Pletil use in children is limited to treatment of giardiasis and amebiasis in patients age 3 and older ( 8.4)
• Hemodialysis patients: If Gino Pletil (Tinidazole) is administered the same day and prior to hemodialysis, administer an additional ½ dose after end of hemodialysis ( 8.6, 12.3)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 5/2007

8.1 Pregnancy

Teratogenic effects: Pregnancy Category C

The use of Gino Pletil (Tinidazole) in pregnant patients has not been studied. Since Gino Pletil (Tinidazole) crosses the placental barrier and enters fetal circulation it should not be administered to pregnant patients in the first trimester.

Embryo-fetal developmental toxicity studies in pregnant mice indicated no embryo-fetal toxicity or malformations at the highest dose level of 2,500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based upon body surface area conversions). In a study with pregnant rats a slightly higher incidence of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5-fold the highest human therapeutic dose based upon body surface area conversions). No biologically relevant neonatal developmental effects were observed in rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions). Although there is some evidence of mutagenic potential and animal reproduction studies are not always predictive of human response, the use of Gino Pletil (Tinidazole) after the first trimester of pregnancy requires that the potential benefits of the drug be weighed against the possible risks to both the mother and the fetus.

8.3 Nursing Mothers

Gino Pletil is excreted in breast milk in concentrations similar to those seen in serum. Gino Pletil (Tinidazole) can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during Gino Pletil (Tinidazole) therapy and for 3 days following the last dose.

8.4 Pediatric Use

Other than for use in the treatment of giardiasis and amebiasis in pediatric patients older than three years of age, safety and effectiveness of Gino Pletil (Tinidazole) in pediatric patients have not been established.

Pediatric Administration: For those unable to swallow tablets, Gino Pletil (Tinidazole) tablets may be crushed in artificial cherry syrup, to be taken with food .

8.5 Geriatric Use

Clinical studies of Gino Pletil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Because the pharmacokinetics of Gino Pletil (Tinidazole) in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from those in healthy subjects, no dose adjustments are necessary in these patients.

Patients undergoing hemodialysis: If Gino Pletil (Tinidazole) is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of Gino Pletil (Tinidazole) equivalent to one-half of the recommended dose be administered after the end of the hemodialysis .

8.7 Hepatic Impairment

There are no data on Gino Pletil (Tinidazole) pharmacokinetics in patients with impaired hepatic function. Reduced elimination of metronidazole, a chemically-related nitroimidazole, has been reported in this population. Usual recommended doses of Gino Pletil (Tinidazole) should be administered cautiously in patients with hepatic dysfunction .

10 OVERDOSAGE

There are no reported overdoses with Gino Pletil (Tinidazole) in humans.

Treatment of Overdosage: There is no specific antidote for the treatment of overdosage with Gino Pletil (Tinidazole); therefore, treatment should be symptomatic and supportive. Gastric lavage may be helpful. Hemodialysis can be considered because approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session.

11 DESCRIPTION

Gino Pletil (Tinidazole) is a synthetic antiprotozoal and antibacterial agent. It is 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has the following chemical structure:

Gino Pletil (Tinidazole) pink oral tablets contain 500 mg of Gino Pletil (Tinidazole). Inactive ingredients include croscarmellose sodium, FD&C Red 40 lake, FD&C Yellow 6 lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized corn starch, titanium dioxide, and triacetin.

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gino Pletil is an antiprotozoal, antibacterial agent. .

12.3 Pharmacokinetics

Absorption: After oral administration, Gino Pletil (Tinidazole) is rapidly and completely absorbed. A bioavailability study of Gino Pletil (Tinidazole) tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of Gino Pletil (Tinidazole) following an overnight fast. Oral administration of four 500 mg tablets of Gino Pletil (Tinidazole) under fasted conditions produced a mean peak plasma concentration (C _max) of 47.7 (±7.5) µg/mL with a mean time to peak concentration (T _max) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC, 0-∞) of 901.6 (± 126.5) µg/hr/mL at 72 hours. The elimination half-life (T _1/2) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 µg/mL at 24 hours, 3.8 µg/mL at 48 hours and 0.8 µg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ - 3 days of multi-day dosing.

Administration of Gino Pletil (Tinidazole) tablets with food resulted in a delay in T _max of approximately 2 hours and a decline in C _max of approximately 10% _, compared to fasted conditions. However, administration of Gino Pletil (Tinidazole) with food did not affect AUC or T _1/2 in this study.

In healthy volunteers, administration of crushed Gino Pletil (Tinidazole) tablets in artificial cherry syrup, [prepared as described in Dosage and Administration ( 2.2) ] after an overnight fast had no effect on any pharmacokinetic parameter as compared to tablets swallowed whole under fasted conditions.

Distribution: Gino Pletil (Tinidazole) is distributed into virtually all tissues and body fluids and also crosses the blood-brain barrier. The apparent volume of distribution is about 50 liters. Plasma protein binding of Gino Pletil (Tinidazole) is 12%. Gino Pletil (Tinidazole) crosses the placental barrier and is secreted in breast milk.

Metabolism: Gino Pletil (Tinidazole) is significantly metabolized in humans prior to excretion. Gino Pletil (Tinidazole) is partly metabolized by oxidation, hydroxylation, and conjugation. Gino Pletil (Tinidazole) is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite.

Gino Pletil (Tinidazole) is biotransformed mainly by CYP3A4. In an in vitro metabolic drug interaction study, Gino Pletil (Tinidazole) concentrations of up to 75 µg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.

The potential of Gino Pletil (Tinidazole) to induce the metabolism of other drugs has not been evaluated.

Elimination: The plasma half-life of Gino Pletil (Tinidazole) is approximately 12-14 hours. Gino Pletil (Tinidazole) is excreted by the liver and the kidneys. Gino Pletil (Tinidazole) is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces.

Patients with impaired renal function: The pharmacokinetics of Gino Pletil (Tinidazole) in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of Gino Pletil (Tinidazole) is significantly increased; the half-life is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session . The pharmacokinetics of Gino Pletil (Tinidazole) in patients undergoing routine continuous peritoneal dialysis have not been investigated.

Patients with impaired hepatic function: There are no data on Gino Pletil (Tinidazole) pharmacokinetics in patients with impaired hepatic function. Reduction of metabolic elimination of metronidazole, a chemically-related nitroimidazole, in patients with hepatic dysfunction has been reported in several studies .

12.4 Microbiology

Mechanism of Action: Gino Pletil (Tinidazole) is an antiprotozoal, antibacterial agent. The nitro- group of Gino Pletil (Tinidazole) is reduced by cell extracts of Trichomonas. The free nitro- radical generated as a result of this reduction may be responsible for the antiprotozoal activity. Chemically reduced Gino Pletil (Tinidazole) was shown to release nitrites and cause damage to purified bacterial DNA in vitro. Additionally, the drug caused DNA base changes in bacterial cells and DNA strand breakage in mammalian cells. The mechanism by which Gino Pletil (Tinidazole) exhibits activity against Giardia and Entamoeba species is not known.

Antibacterial: Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis ; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or Mycoplasma hominis, has not been defined. The following in vitro data are available, but their clinical significance is unknown. Gino Pletil (Tinidazole) is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

• Bacteroides spp.
• Gardnerella vaginalis
• Prevotella spp.

Gino Pletil (Tinidazole) does not appear to have activity against most strains of vaginal lactobacilli.

Antiprotozoal: Gino Pletil (Tinidazole) demonstrates activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis; Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica.

For protozoal parasites, standardized susceptibility tests do not exist for use in clinical microbiology laboratories.

Drug Resistance: The development of resistance to Gino Pletil (Tinidazole) by G. duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis has not been examined.

Cross-resistance: Approximately 38% of T. vaginalis isolates exhibiting reduced susceptibility to metronidazole also show reduced susceptibility to Gino Pletil (Tinidazole) in vitro. The clinical significance of such an effect is not known.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Gino Pletil (Tinidazole) and other antibacterial drugs, Gino Pletil (Tinidazole) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole, a chemically-related nitroimidazole, has been reported to be carcinogenic in mice and rats but not hamsters. In several studies metronidazole showed evidence of pulmonary, hepatic, and lymphatic tumorigenesis in mice and mammary and hepatic tumors in female rats. Gino Pletil carcinogenicity studies in rats, mice or hamsters have not been reported.

Gino Pletil (Tinidazole) was mutagenic in the TA 100, S. typhimurium tester strain both with and without the metabolic activation system and was negative for mutagenicity in the TA 98 strain. Mutagenicity results were mixed (positive and negative) in the TA 1535, 1537, and 1538 strains. Gino Pletil (Tinidazole) was also mutagenic in a tester strain of Klebsiella pneumonia. Gino Pletil (Tinidazole) was negative for mutagenicity in a mammalian cell culture system utilizing Chinese hamster lung V79 cells (HGPRT test system) and negative for genotoxicity in the Chinese hamster ovary (CHO) sister chromatid exchange assay. Gino Pletil (Tinidazole) was positive for in vivo genotoxicity in the mouse micronucleus assay.

In a 60-day fertility study, Gino Pletil (Tinidazole) reduced fertility and produced testicular histopathology in male rats at a 600 mg/kg/day dose level (approximately 3-fold the highest human therapeutic dose based upon body surface area conversions). Spermatogenic effects resulted from 300 and 600 mg/kg/day dose levels. The no observed adverse reaction level for testicular and spermatogenic effects was 100 mg/kg/day (approximately 0.5-fold the highest human therapeutic dose based upon body surface area conversions). This effect is characteristic of agents in the 5-nitroimidazole class.

13.2 Animal Toxicology and/or Pharmacology

In acute studies with mice and rats, the LD ₅₀ for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD ₅₀ was > 2,000 mg/kg for both oral and intraperitoneal administration.

A repeated-dose toxicology study has been performed in beagle dogs using oral dosing of Gino Pletil (Tinidazole) at 100 mg/kg/day, 300 mg/kg/day, and 1000 mg/kg/day for 28-days. On Day 18 of the study, the highest dose was lowered to 600 mg/kg/day due to severe clinical symptoms. The two compound-related effects observed in the dogs treated with Gino Pletil (Tinidazole) were increased atrophy of the thymus in both sexes at the middle and high doses, and atrophy of the prostate at all doses in the males. A no-adverse-effect level (NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL identified for males because of minimal atrophy of the prostate at 100 mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC comparisons).

14 CLINICAL STUDIES

14.1 Trichomoniasis

Gino Pletil (2 g single oral dose) use in trichomoniasis has been well documented in 34 published reports from the world literature involving over 2,800 patients treated with Gino Pletil (Tinidazole). In four published, blinded, randomized, comparative studies of the 2 g Gino Pletil (Tinidazole) single oral dose where efficacy was assessed by culture at time points post-treatment ranging from one week to one month, reported cure rates ranged from 92% (37/40) to 100% (65/65) (n=172 total subjects). In four published, blinded, randomized, comparative studies where efficacy was assessed by wet mount between 7-14 days post-treatment, reported cure rates ranged from 80% (8/10) to 100% (16/16) (n=116 total subjects). In these studies, Gino Pletil (Tinidazole) was superior to placebo and comparable to other anti-trichomonal drugs. The single oral 2 g Gino Pletil (Tinidazole) dose was also assessed in four open-label trials in men (one comparative to metronidazole and 3 single-arm studies). Parasitological evaluation of the urine was performed both pre- and post-treatment and reported cure rates ranged from 83% (25/30) to 100% (80/80) (n=142 total subjects).

14.2 Giardiasis

Gino Pletil (Tinidazole) (2 g single dose) use in giardiasis has been documented in 19 published reports from the world literature involving over 1,600 patients (adults and pediatric patients). In eight controlled studies involving a total of 619 subjects of whom 299 were given the 2 g × 1 day (50 mg/kg × 1 day in pediatric patients) oral dose of Gino Pletil (Tinidazole), reported cure rates ranged from 80% (40/50) to 100% (15/15). In three of these trials where the comparator was 2 to 3 days of various doses of metronidazole, reported cure rates for metronidazole were 76% (19/25) to 93% (14/15). Data comparing a single 2 g dose of Gino Pletil (Tinidazole) to usually recommended 5-7 days of metronidazole are limited.

14.3 Intestinal Amebiasis

Gino Pletil use in intestinal amebiasis has been documented in 26 published reports from the world literature involving over 1,400 patients. Most reports utilized Gino Pletil (Tinidazole) 2 g/day × 3 days. In four published, randomized, controlled studies (1 investigator single-blind, 3 open-label) of the 2 g/day × 3 days oral dose of Gino Pletil (Tinidazole), reported cure rates after 3 days of therapy among a total of 220 subjects ranged from 86% (25/29) to 93% (25/27).

14.4 Amebic Liver Abscess

Gino Pletil (Tinidazole) use in amebic liver abscess has been documented in 18 published reports from the world literature involving over 470 patients. Most reports utilized Gino Pletil (Tinidazole) 2 g/day × 2-5 days. In seven published, randomized, controlled studies (1 double-blind, 1 single-blind, 5 open-label) of the 2 g/day × 2-5 days oral dose of Gino Pletil (Tinidazole) accompanied by aspiration of the liver abscess when clinically necessary, reported cure rates among 133 subjects ranged from 81% (17/21) to 100% (16/16). Four of these studies utilized at least 3 days of Gino Pletil (Tinidazole).

14.5 Bacterial Vaginosis

A randomized, double-blind, placebo-controlled clinical trial in 235 non-pregnant women was conducted to evaluate the efficacy of Gino Pletil (Tinidazole) for the treatment of bacterial vaginosis. A clinical diagnosis of bacterial vaginosis was based on Amsel's criteria and defined by the presence of an abnormal homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains ≥20% clue cells on microscopic examination. Clinical cure required a return to normal vaginal discharge and resolution of all Amsel's criteria. A microbiologic diagnosis of bacterial vaginosis was based on Gram stain of the vaginal smear demonstrating (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells, with quantification of these bacterial morphotypes to determine the Nugent score, where a score ≥4 was required for study inclusion and a score of 0-3 considered a microbiologic cure. Therapeutic cure was a composite endpoint, consisting of both a clinical cure and microbiologic cure. In patients with all four Amsel's criteria and with a baseline Nugent score ≥4, Gino Pletil (Tinidazole) oral tablets given as either 2 g once daily for 2 days or 1 g once daily for 5 days demonstrated superior efficacy over placebo tablets as measured by therapeutic cure, clinical cure, and a microbiologic cure.

Outcome	Gino Pletil (Tinidazole) 1 g × 5 days (n=76)	Gino Pletil (Tinidazole) 2 g × 2 days (n=73)	Placebo (n=78)
	% Cure	% Cure	% Cure
Therapeutic Cure Difference 2 97.5% CI 3	36.8 31.7 (16.8, 46.6)	27.4 22.3 (8.0, 36.6)	5.1
Clinical Cure Difference 2 97.5% CI 3	51.3 39.8 (23.3, 56.3)	35.6 24.1 (7.8, 40.3)	11.5
Nugent Score Cure Difference 2 97.5% CI 3	38.2 33.1 (18.1, 48.0)	27.4 22.3 (8.0, 36.6)	5.1

¹Modified Intent-to-Treat defined as all patients randomized with a baseline

Nugent score of at least 4

²Difference in cure rates (Tindamax-placebo)

³CI: confidence interval

p-values for both Gino Pletil (Tinidazole) regimens vs. placebo for therapeutic, clinical and

Nugent score cure rates for both 2 and 5 days <0.001

The therapeutic cure rates reported in this clinical study conducted with Gino Pletil (Tinidazole) were based on resolution of 4 out of 4 Amsel's criteria and a Nugent score of <4. The cure rates for previous clinical studies with other products approved for bacterial vaginosis were based on resolution of either 2 or 3 out of 4 Amsel's criteria. At the time of approval for other products for bacterial vaginosis, there was no requirement for a Nugent score on Gram stain, resulting in higher reported rates of cure for bacterial vaginosis for those products than for those reported here for Gino Pletil (Tinidazole).

17 PATIENT COUNSELING INFORMATION

17.1 Administration of Drug

Patients should be told to take Gino Pletil with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of Gino Pletil (Tinidazole).

17.2 Alcohol Avoidance

Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Gino Pletil (Tinidazole) therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

17.3 Drug Resistance

Patients should be counseled that antibacterial drugs including Gino Pletil (Tinidazole) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Gino Pletil (Tinidazole) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Gino Pletil (Tinidazole) or other antibacterial drugs in the future.

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