GYNO-PEVARYL DEPOT VAGINAL SUPPOSITORY 150

PRODUCT NAME

GYNO-PEVARYLOVULES

GYNO-PEVARYL

DEPOT OVULES

DOSAGE FORMS AND STRENGTHS

150mg Ovules: 1 ovule contains 150.0 mg econazole nitrate

150mg Depot Ovules: 1 ovule contains 150 mg micronized econazole nitrate

Not all presentations may be available locally.

For excipients, see List of Excipients.

CLINICAL INFORMATION

Indications

GYNO-PEVARYLindicatedtreatmentvulvovaginalmycosesmycoticbalanitis .

Dosage and Administration

Dosage

Adult Females

150 mg Ovules: One ovule is inserted high into the vagina once daily at bedtime for three

consecutive days. This is best done in the reclining position. In sự kiện of relapse, or if the cultureexamination one week after treatment is positive, a second round of treatment should beundertaken .

150 mg Depot Ovules: One depot ovule is inserted high into the vagina in the morning and one in

the evening. This is best done in the reclining position .

Special Populations

Pediatrics (2 to 16 years old)

The safety and effectiveness in children has not been established .

Elderly (older than 65 years old)

Data are insufficient regarding the use of GYNO-PEVARYLin the elderly ( > 65 years old ) .

Contraindications

GYNO-PEVARYLis contraindicated in individuals who have shown hypersensitivity to any ofits ingredients .

Warnings and Precautions

For intravaginal use only. GYNO-PEVARYLis not for ophthalmic or oral use .The concurrent use of latex condoms or diaphragms with vaginal anti-infective preparations maydecrease the effectiveness of rubber contraceptive agents. Therefore products such as GYNO -PEVARYLshould not be used concurrently with a diaphragm or latex condom. Patients usingspermicidal contraceptives should consult their physician since any local vaginal treatment mayinactivate the spermicidal contraceptive .GYNO-PEVARYLshould not be used in conjunction with other internal or external treatmentof the genitalia .If marked irritation or sensitivity occurs, the treatment should be discontinued .Patients with sensitivity to imidazoles have also reported sensitivity to econazole nitrate .

Interactions

Econazole is a known inhibitor of CYP3A4 / 2C9. Due to the limited systemic availability after

vaginal application (see Pharmacokinetic Properties), clinically relevant interactions are unlikely

to occur, but have been reported with oral anticoagulants. In patients taking oral anticoagulants ,such as warfarin or acenocoumarol, caution should be exercised and the anticoagulant effectshould be monitored .

Pregnancy, Breast-feeding and Fertility

Pregnancy

Animal studies have shown reproductive toxicity (see Non-Clinical Information).

Because there is vaginal absorption, GYNO-PEVARYLshould not be used in the first trimesterof pregnancy unless the physician considers it essential to the welfare of the patient. GYNO -PEVARYLmay be used during the second and third trimester if the potential benefit to themother outweighs the possible risks to the fetus .

Breast-feeding

Following oral administration of econazole nitrate to lactating rats, econazole and / or metaboliteswere excreted in milk and were found in nursing pups. It is not known whether econazole nitrateis excreted in human milk .Caution should be exercised when using GYNO-PEVARYLif the patient is breast-feeding .

Fertility

Results of econazole animal reproduction studies showed no effects on fertility (see Non-Clinical

Information).

Effects on Ability to Drive and Use Machines

None known .

Adverse Reactions

Throughout this section, adverse reactions are presented. Adverse reactions are adverse eventsthat were considered to be reasonably associated with the use of econazole nitrate based on thecomprehensive assessment of the available adverse sự kiện information. A causal relationship witheconazole nitrate usually cannot be reliably established in individual cases. Further, becauseclinical trials are conducted under widely varying conditions, adverse reaction rates observed inthe clinical trials of a drug cannot be directly compared to rates in the clinical trials of anotherdrug and may not reflect the rates observed in clinical practice .

Clinical trial data

The safety of GYNO-PEVARYLVaginal Cream and Vaginal Ovules was evaluated in 3630patients who participated in 32 clinical trials. Adverse reactions reported for ≥ 1 % of patientstreated with either GYNO-PEVARYLVaginal Cream or Vaginal Ovules in these studies areshown in Table 1 .

Table 1. Adverse Reactions Reported by ≥1% of Patients Treated with GYNO-PEVARYL

in 32

Clinical Trials

System Organ Class

GYNO-PEVARYLAdverse Reaction( N = 3630 )

Skin and Subcutaneous Tissue Disorders

Skin burning sensationPruritusAdverse reactions that occurred in < 1 % of patients treated with either GYNO-PEVARYLVaginal Cream or Vaginal Ovules in the 32 clinical trials are listed in Table 2 .

Table 2. Adverse Reactions Reported by <1% of Patients Treated with GYNO-PEVARYL

in 32

Clinical Trials

System Organ Class

Adverse Reaction

Skin and Subcutaneous Tissue Disorders

Rash

Reproductive System and Breast Disorders

Vulvovaginal burning sensation

Postmarketing data

In addition to the adverse reactions reported during clinical studies and listed above, thefollowing adverse reactions have been reported during postmarketing experience ( Tables 3 and4 ). In each table, the frequencies are provided according to the following convention :Very common≥ 1/10Common≥ 1/100 and < 1/10Uncommon≥ 1 / 1000 and < 1/100Rare≥ 1/1000 0 and < 1/1000Very rare< 1/1000 0, including isolated reports .In Table 3, adverse reactions are presented by frequency category based on incidence in clinicaltrials or epidemiology studies, when known .

Table 3. Adverse Reactions Identified During Post-marketing Experience with GYNO-PEVARYL

by

Frequency Category Estimated from Clinical Trials or Epidemiologic Studies

System Organ Class

Frequency category

Preferred Term

Immune System Disorders

Not known

Hypersensitivity

Skin and Subcutaneous Tissue Disorders

Rare

Erythema

Not known

Angioedema, Urticaria, Contact dermatitis, Skin exfoliation

General Disorders and Administration Site

Conditions

Not known

Applicationsitepain ,Applicationsiteirritation ,Application site swelling

Overdose

Symptoms and signs

Adverse events associated with overdose or misuse of GYNO-PEVARYLare expected to be

consistent with adverse drug reactions already listed in Adverse Reactions.

Treatment

GYNO-PEVARYLis for topical application only. In the sự kiện of accidental ingestion, treatsymptomatically. If the product is accidentally applied to the eyes, wash with clean water orsaline and seek medical attention if symptoms persist .

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic Properties

Pharmacotherapeuticgroup :Antiinfectivesantiseptics ,excl .combinationswithcorticosteroids, imidazole derivatives, ATC code : G01A F05 .

Mechanism of action

Econazole nitrate acts by damaging fungal cell membranes, resulting in increased permeability .Sub-cellular membranes in the cytoplasm are damaged. The site of action is most probably theunsaturated fatty acid acyl moiety of membrane phospholipids .

Pharmacodynamic effects

Microbiology

A broad spectrum of antimycotic activity has been demonstrated against dermatophytes, yeastsand molds. A clinically relevant action against gram-positive bacteria has also been found .

Pharmacokinetic Properties

Absorption

Systemicabsorptioneconazoleextremelyaftervaginalapplication .Meanpeakplasma / serum concentrations of econazole and / or its metabolites were observed 1 to 2 days afterdose administration and were 65 ng / mL for the 150 mg Ovule. The percentage of appliedeconazole dose absorbed was found to be approximately 5 % for the 150 mg Ovule .

Distribution

Econazole and / or its metabolites in the systemic circulation are extensively bound ( > 98 % ) toserum proteins .

Metabolism

Econazole is extensively metabolized by oxidation, deamination and / or O-dealkylation .

Excretion

Econazole metabolites are eliminated in urine and feces .

NON-CLINICAL INFORMATION

Preclinical effects were observed only at exposures considered sufficiently in excess of themaximum human exposure, indicating little relevance to clinical use .Acute toxicity studies indicate a wide margin of safety with rodent oral LD50 values rangingfrom ˃ 160 – 463 mg / kg. In repeat dose toxicity studies, at high doses ( 50 mg / kg / day ) the liver wasidentified as a target organ with minimal toxicity and full recovery .Neither significant topical toxicity, phototoxicity, local dermal irritation, vaginal irritation norsensitization was noted. Only mild ocular irritation was noted with a cream formulation .

Carcinogenicity and Mutagenecity

No studies on the carcinogenic potential have been conducted due to the short course ofproposed clinical therapy and the absence of any significant potential of econazole to begenotoxic in a way that could lead to initiation or promotion of tumor formation .In various test systems either no or some limited gene-toxicity effects ( structural chromosomaldeviations ) have been shown. Based on an overall assessment of these data and the indicatedroute of administration including the resulting minimal systemic exposure to econazole, there islittle relevance for clinical use .

Reproductive Toxicology

Results of econazole reproduction studies showed no effects on teratogenicity .

Fertility

Results of econazole reproduction studies showed no effects on fertility .

Pregnancy

Low neonatal survival and fetal toxicity was associated only with maternal toxicity. In animalstudies, econazole nitrate has shown no teratogenic effects but was fetotoxic in rodents atmaternal subcutaneous doses of 20 mg / kg / day and at maternal oral doses of 10 mg / kg / day. Thesignificance of this in humans is unknown .

PHARMACEUTICAL INFORMATION

List of Excipients

150 mg Ovules: hard fat

150

mg

Depot

Ovules:

Polygel371 ,colloidalanhydroussilica ,hardfat ,stearylheptanoate / caprylate

Incompatibilities

None known .

Shelf Life

See “ expiry date ” ( month / year ) printed on outer pack .

Storage Conditions

150 mg Ovules: Do not store above 30°C

150 mg Depot Ovules: Do not store above 30°C

Keep out of reach of children .

Nature and Contents of Container

150 mg Ovules: blister packs (molded) of 3’s

150 mg Depot Ovules: blister packs (molded) of 2’s

Instructions for Use and Handling

Not applicable

BATCH RELEASER

Lusomedicamenta – Sociedade Tecnica Farmaceutica, S.A.Estrada Consiglieri Pedroso, 69 – BQueluz de Baixo2730 – 055 Barcarena, PortugalXian-Janssen Pharmaceutical LtdNo. 34, North Wanshou Road, 710043Xian, Shaanxi Province, Nước Trung Hoa

PRODUCT REGISTRANT

Johnson và Johnson Pte Ltd2 Science Park Drive# 07-13, Ascent

Singapore, Science Park 1

Nước Singapore 118222

DATE OF REVISION OF TEXT

28 August 2017 ( CCDS 17 March năm trước )

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