Anti fungal agents

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ANTIFUNGAL AGENTS

By: Mrs. Kalaivani Sathish M. PharmAssistant Professor,

PIMS - PANIPAT

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• Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites.

• Complex organisms in comparison to bacteria .• Have nucleus and well defined nuclear membrane, and

chromosomes.• Have rigid cell wall composed of chitin (bacterial cell

wall is composed of peptidoglycan)• Fungal cell membrane contains ergosterol , human cell

mebmrane is composed of cholesterol• Antibacterial agents are not effective against fungi.• Fungal infections are also called as mycoses

ANTIFUNGAL AGENTSIntroduction

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ANTIFUNGAL AGENTS

• Systemic fungal infections are a major cause of death in patients whose immune system is compromised– cancer or its chemotherapy,– organ transplantation– HIV-1 infection.

• Superficial infections of the skin and other soft tissue structures.

• Antifungal agents target– distinctive components of the fungal cell membrane– others alter cell wall synthesis– nucleic acid synthesis

Introduction

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• Superficial : Affect skin – mucous membrane– Tinea versicolor– Dermatophytes : affect keratin layer of skin, hair, nail.

e.g.tinea pedis, ring worm infection– Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail

infections.• Deep Infections :– Affect internal organs as : lung ,heart , brain leading to

pneumonia , endocarditis , meningitis.

ANTIFUNGAL AGENTSTypes of Fungal Infections

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• Disrupt fungal cell membrane– Polyenes – amphotericin, Nystatin– Azoles

• Imidazole – Ketoconazole, Miconazole, Clotrimazole• Triazole – Fluconazole, Itraconazole

– Allylamines - Terbinafin– Echinocandins - Capsofungin

• Inhibit mitosis - Gresiofulvin• Inhibit DNA synthesis - Flucytosine• Miscellaneous– Tolnaftate– Cyclopirox

ANTIFUNGAL AGENTSMechanism of action of Antifungal agents

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Membrane function Amphotericin B

Cell Wall SynthesisCapsofungin

Nucleic acid synthesisFlucytosine

Ergosterol synthesisAzolesLanosterol synthesis

Terbinafine

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• Antifungal agent with the broadest spectrum of activity• Produced by Streptomyces nodosus. • Natural, Amphoteric polyene macrolide – – Amphoteric = can react as an acid as well as a base– polyene = many double bonds – macrolide = containing a large lactone ring

• Heptaene macrolide - large lactone ring with multiple ketone and hydroxyl group)

• Drug of choice for the vast majority of life-threatening systemic fungal infections

• Interacts with ergosterols, forms pores that increase membrane permeability and allow leakage of intracellular ions & macromolecules from fungal cell ( cell death ).

ANTIFUNGAL AGENTSAmphotericin B

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• Broad range of pathogenic fungi• Protozoa, Leishmania braziliensis and

Naegleria fowleri• No antibacterial activity• Amphotericin A & B are antifungal antibiotics.• Amphotericin A is not used clinically.

ANTIFUNGAL AGENTSAmphotericin B

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Mechanism of action of

Amphotericin

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• Poorly absorbed orally, useful for fungal infection of gastrointestinal tract.

• For systemic infections given as slow I/V infusion.• Locally used in corneal ulcers, arthritis and candidial

bladder irrigation• Highly protein bound - > 90%• Penetration through BBB is poor but increases in inflamed

meninges.• Excreted slowly via kidneys, traces found in urine for

months after cessation of drugs.• Half life 15 days

ANTIFUNGAL AGENTSAmphotericin - ADME

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Amphotericin ADME

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1. Slow IV infusion for systemic fungal disease.2. Intrathecal for fungal CNS infections.3. Topical drops & direct subconjunctival

injection for Mycotic corneal ulcers & keratitis.

4. Local injection into the joints in fungal arthritis.

5. Bladder irrigation in Candiduria.

ANTIFUNGAL AGENTSRoutes of Administration

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• Packaged in a lipid- associated delivery system which acts as a reservoir

• Large doses can be administered – 5 times • Reduces binding to human cell membrane • Clinically have more efficacy , less nephrotoxicity• More expensive

ANTIFUNGAL AGENTSAmphotericin – Liposomal Preparations

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Liposomal preparations of Amphotericin

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• Usual dose is 0.5–0.6 mg/kg, administered in 5% glucose over 4 hours

• Candida esophagitis, Rapidly progressive mucormycosis or invasive aspergillosis .

• Coccidioides meningitis: Intrathecal infusion ; started with twice weekly schedule , increased to thrice weekly and continued on twice-weekly schedule.

• Treatment of cryptococcal meningitis, Severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis, penicilliosis marneffei, invasive aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis, and trichosporonosis.

• Given once weekly to prevent relapse in patients with AIDS who have been treated successfully for cryptococcosis or histoplasmosis.

ANTIFUNGAL AGENTSAmphotericin B - Therapeutic Uses and Dosage

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• Major acute reaction to intravenous is fever and chills, which typically end spontaneously in ~30 minutes and often abate with subsequent infusions.

• Tachypnea and modest hypotension may occur, but true bronchospasm or anaphylaxis is rare.

• Hypotension and hypoxia in preexisting cardiac or lung disease • Prophylactic use of IV glucocorticoids decreases reaction• Transient azotemia occurs in 80% of patients• Kidney function may be affected if other nephrotoxic agents like

aminoglycoside are used concurrently. • Administration of 1 L of NS IV prior to amphotericin B administration

is recommended for adults who can tolerate the Na+ load. • Azotemia occurs less frequently with lipid preparations of

amphotericin, and saline loading is not needed.

ANTIFUNGAL AGENTSAmphotericin B - Adverse effects

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• Hypochromic, normocytic anemia is usual and reverses slowly following cessation of therapy.

• It is due decreased production of erythropoietin and often responds to erythropoietin.

• Headache, nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common.

• Arachnoiditis, manifested by fever and headache, can occur with intrathecal injection; it may be decreased by intrathecal administration of 10–15 mg of hydrocortisone.

• Local injections of amphotericin B into a joint or peritoneal dialysate fluid commonly produce irritation and pain.


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Immediate reactions ( Infusion –related toxicity ).• Fever, muscle spasm, vomiting ,headache, hypotension. • Can be avoided by :– Slowing the infusion– Decreasing the daily dose – Premedication with antipyretics, antihistamincs or corticosteroids.– test dose.

Slower Reactions:• Most serious is renal toxicity (nearly in all patients ).• Hypokalemia• Hypomagnesaemia• Impaired liver functions• Anemia, Thrombocytopenia


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• Synthetic, water soluble, fluorinated pyrimidine analog• Often used in combination with amphotericin B and

Itraconazole• Spectrum of antigungal activity is considerably less than

that of amphotericin B. • Amphotericin B increases cell permeability , allowing more

5-FC to penetrate the cell, they are synergistic• Fungistatic• Has useful activity against Candida and Cryptococcus.• Acts by inhibiting synthesis of fungal DNA

ANTIFUNGAL AGENTSFlucytosine

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• Absorbed rapidly and well from the GI tract, widely distributed

• Minimally bound to plasma proteins. • Penetrates well into CSF.• Mainly excreted unchanged through kidney• Half life drug normally is 3–6 hours but may reach 200

hours in renal failure. • Dose modification is necessary in renal dysfunction

plasma concentrations should be measured periodically• Flucytosine is cleared by hemodialysis and peritoneal

dialysis

ANTIFUNGAL AGENTSFlucytosine - ADME

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• Given orally at 100 mg/kg/day, in 4 divided doses and is used predominantly in combination with amphotericin B.

• Severe deep fungal infections as in meningitis• Cryptococcal meningitis: begin with amphotericin B plus

flucytosine and change to fluconazole after the patient has improved.

• There is the risk of amphotericin induecd azotemia and flucytocine dose has to be reduced in this situation otherwise the combination will cause bone marrow suppression or colitis

ANTIFUNGAL AGENTSFlucytosine – Uses

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• Hematologic : Leukopenia, thrombocytopenia, bone marrow depression

• Allergic: Rash, nausea, vomiting, diarrhea, and enterocolitis

• Hepatic: Elevation in hepatic transaminases but this reverses when therapy is stopped.

• Toxicity is more frequent in patients with AIDS or azotemia.

• Alopecia

ANTIFUNGAL AGENTSFlucytosine – Adverse effects

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• Bacterial origin. • Isolated from Streptomyces noursei in 1950

by Elizabeth Lee Hazen and Rachel Fuller Brown,.

• Polyene macrolide ,similar in structure & mechanism to amphotericin B.

• Too toxic for systemic use.• Used only topically - available as creams,

ointment , suppositories & other preparations.

• Not significantly absorbed from skin, mucous membrane, GIT so little significant toxicity.

ANTIFUNGAL AGENTSNystatin/Nysfungin

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• Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract.

• Oral suspension of 100,000 U/ml 4 times a day and tablets 500,000 U are used to decrease GIT colonization with Candida

• Vaginal candidiasis - pessaries used for 2 weeks• Can be used in combination with antibacterial

agents & corticosteroids• In Cutaneous infection available in cream, ointment

or powder form and applied 2-3 times a day

ANTIFUNGAL AGENTSNystatin/Nysfungin – Clinical uses

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• Bivalent chemical group composed of five-membered organic rings

• Broad spectrum of activity - Antibacterial, antiprotozoal, anthelminthic and antifungal.

• Group of synthetic fungistatic agents • Classification: according to the number of nitrogen atoms

attached to the ring– Imidazoles (2 nitrogen atoms): Ketoconazole,

Miconazole, Econazole, Clotrimazole, Bifonazole– Triazoles (3 nitrogen atoms): Itraconazole, Fluconazol,

Vorionazole → systemic treatment

ANTIFUNGAL AGENTSAzole Antifungals

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• Cryptococci, Blastomyces, Histoplasma capsulatum, Coccidioides , Paracoccidioides brasiliensis, and dermatophytes.

• Aspergillus spp., Scedosporium, apiospermum (Pseudallescheria boydii), Fusarium, and Sporothrix schenckii are intermediate in susceptibility.

• C. krusei and the agents of mucormycosis are resistant.

ANTIFUNGAL AGENTSAzole - antifungal activity

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• Inhibit the fungal cytochrome P450 enzyme• Responsible for converting lanosterol to

ergosterol ( the main sterol in fungal cell membrane ).

ANTIFUNGAL AGENTSAzole Antifungals- Mechanism of Action

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• Contain 2 Nitrogen atoms attached to the ring• Reduce the formation of ergosterol in the cell

membrae which become permeable to cellular constituents.

• They lack selectivity, and also inhibits human gonadal and steroid synthesis leading to decreased testosterone and cortisol production

• Ketoconazole, • miconazole, • clotrimazole, • isoconazole ,• Tioconazole

ANTIFUNGAL AGENTSAzole Antifungals- Imidazoles

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Mechanism of action

Ketoconazole

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• Well absorbed orally as acidic environment favors its dissolution.

• Bioavailability is impaired with food.• Cola drinks improve its absorption in patients with

achlorhydria.• Metabolized extensively in liver and inactive products

appear in the feces.• Moderate hepatic dysfunction has no effect on drug

concentration. • 84 % is bound to plasma proteins.• Half life increases with dose• It does not enter CSF.

ANTIFUNGAL AGENTSImidazole – Ketoconazole- ADME

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• Inhibits adrenal and gonadal steroids which leads to menstrual irregularities, loss of libido, impotency and gynaecomastia in males.

• Efficacy is poor in immunosuppressed patients and in meningitis.

• Hepatotoxic - rare but may prove fatal.• Dose dependant nausea, anorexia ,vomiting• Hair loss• Fluid retention and hypertension. • Not used in Pregnancy, lactation ,hepatic dysfunction

ANTIFUNGAL AGENTSImidazole – Ketoconazole – Adverse Effects

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Decrease in the ergosterol in the

fungal membraneBy ketoconazle

reduces the fungicidal

action of amphotericin

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Used topically or systematic (oral route only ) to treat 1. Oral & vaginal candidiasis.2. Dermatophytosis.3. Systemic mycoses & mucocutaneous candidiasis.

ANTIFUNGAL AGENTSImidazole – Ketoconazole – Clinical uses

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Ketoconazole is not useful for

fungal infections of UT

as level of parent drug in urine is

very low

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• Bioavailability is low by taking orally.• Used topically.• Absorption less than 0.5 % from intact skin, 3-10 %

from vagina• Activity in vagina remains for 3 days.• Stigma, erythema, edema, vesication, pruritus,

urticaria mild vaginal burning sensation may occour.• Cure dermatophytes, cutaneous candidiasis and

vulvovaginal candidiasis

ANTIFUNGAL AGENTSImidazole – Clotrimazole

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• Damage the fungal cell membrane by inhibiting enzyme desmethylase

• They are selective • Penetrate to CNS• Resistant to degradation• Cause less endocrine disturbance.• Fluconazole,• itraconazole,• voriconazole

ANTIFUNGAL AGENTSAzole Antifungals- Triazoles

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• It is a synthetic triazole, new drug• Lacks endocrine side effects of ketoconazole.• Broad spectrum activity• Administered orally as well as I/V. • Food increases its absorption• Metabolized in liver to active metabolite• Highly lipid soluble ,well distributed to bone, sputum,

adipose tissues.• Can not cross BBB

ANTIFUNGAL AGENTSAzole antifungals – Itraconazole

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• Food increases its absorption• Metabolized in liver extensively• It is highly lipid soluble and well distributed to

bone, sputum and adipose tissue. • Highly bound to plasma protein• Half life is 30-40 hours• Does not penetrate CSF adequately • The capsule is better absorbed with food, but the

oral solution is better absorbed in the fasting state

ANTIFUNGAL AGENTSItraconazole- ADME

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ANTIFUNGAL AGENTSAzole antifungals – Itraconazole - Therapeutic Uses• Available as a capsule and solutions for oral or intravenous

administration• Oral solution is 60% more bioavailable than the capsules• IV only in serious infections.• Dose – Cap 200 to 400 mg/day

• doses exceeding 200 mg/day are given in 2 divided doses • Loading dose: 200 mg 3 times daily can be given for the first 3

days• The only agent with significant activity against aspergillus species• It can safely be administered prophylactically in patients receiving

bone marrow transplants

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• Dermatophytoses and onychomycosis.• Onychomycosis - 200 mg daily after food for 3 months• For deep mycoses, loading dose of 200 mg three times

daily for 3 days. Thereafter, two 100-mg capsules are given twice daily with food.

• Histoplasmosis : AIDS-associated histoplasmosis maintainance therapy - 200 mg once daily

• It easily penetrate CSF and is a drug of choice in cryptococcal meningitis and coccido mycosis

• Cryptococcosis: 400 mg daily for 8 weeks in meningitis, In AIDS 200 mg for life.

ANTIFUNGAL AGENTSAzole antifungals – Itraconazole - Therapeutic Uses

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• Itraconazole solution - for oropharyngeal and esophageal candidiasis.

• Taken fasting in a dose of 100 mg once daily and swished vigorously in the mouth before swallowing to optimize topical effect.

• 100 mg of the solution twice a day for 2–4 weeks.• Candidiasis: 200 mg on 1st day then 100 mg daily for 2 weeks.• Not effective in aspergillosis.• Used orally in dermatophytosis & vulvo-vaginal candidiasis.

ANTIFUNGAL AGENTSAzole antifungals – Itraconazole - Therapeutic Uses

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• Interact with many drugs• Interactions can cause serious toxicity• Fatal cardiac arrhythmias.• Congestive heart failure in patients with impaired

ventricular function.• Hepatic failure and death. If symptoms of hepatotoxicity

occur, the drug should be discontinued and liver function assessed.

• Anaphylaxis and severe rash have rarely occurred.

ANTIFUNGAL AGENTSItraconazole – Adverse Effects

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• Relative to capsules, the oral solution of itraconazole more frequently causes diarrhea, abdominal cramps, anorexia, and nausea.

• Intravenous itraconazole has all the adverse effects of capsules but generally is well tolerated.

• Chemical phlebitis: dedicated catheter port is required,

• Infusion durations >1 hour are recommended. • Intravenous formulation is contraindicated in patients

with a creatinine clearance <30 mL/min.


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• The adverse effects are related to dose and duration of use• In the absence of interacting drugs, itraconazole capsules

are well tolerated at 200 mg daily. • GI distress occurs with use of 300 mg/day or more• In patients receiving 50–400 mg/day, nausea and vomiting,

hypertriglyceridemia, hypokalemia, elevated serum aminotransferases, and rash occurred in few patients

• Doses of 300 mg twice daily have led to adrenal insufficiency, lower limb edema, hypertension, and rhabdomyolysis

• Doses above 400 mg/day are not recommended for long-term use


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• It is fluorinated bistriazole.• The widest therapeutic index of the azoles.• Excellent bioavailability by oral route.• Bioavailability not altered by food or gastric acidity• Not hepatotoxic• It can safely be administered prophylactically in patients

receiving bone marrow transplants.• Maximum excretion by kidney• Half life is 25-30 hours.

ANTIFUNGAL AGENTSFluconazole - ADME

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• Fluconazole is almost completely absorbed from the GI tract irrespective of food or gastric acidity.

• Concentration in plasma is same by oral or I/v route.

• Only 10% of drug in circulation is protein bound. • Readily diffuses into body fluids, including

breast milk, sputum, saliva, and CSF.

ANTIFUNGAL AGENTSFluconazole - ADME

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• Tablets for oral administration• Powder for oral suspension• Intravenous solutions containing 2 mg/mL.• Dosage is 50–800 mg once daily for oral or

intravenous administration. • Children are treated with 3–6 mg/kg once

daily

ANTIFUNGAL AGENTSFluconazole - Dosage

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• Candidiasis - 200 mg on the first day and then 100 mg daily for at least 2 weeks, in oropharyngeal candidiasis.

• single dose of 150 mg is effective in uncomplicated vaginal candidiasis.

• 400 mg daily in deep candidiasis in allogeneic bone marrow transplant recipients

• Systemic fungal infections– 400-800 mg q24h– > 800 mg q24h in unstable patient

• Maintenance for cryptococcal meningitis - 400 mg/day, for the initial 8 weeks in the treatment in AIDS after the patient has been stabilized with intravenous amphotericin B.

ANTIFUNGAL AGENTSFluconazole - Uses

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• Nausea and vomiting at doses >200 mg/day• Headache, skin rash, abdominal pain, and diarrhea • Reversible alopecia may occur with prolonged

therapy • Rare deaths due to hepatic failure or Stevens-

Johnson syndrome have occurred. • Highly teratogenic: Associated with skeletal and

cardiac deformities in infants born to women taking high doses during pregnancy and should be avoided during pregnancy

ANTIFUNGAL AGENTSFluconazole – Adverse effects

• Fungistatic in vitro for various species of dermatophytes.

• Inhibits fungal mitosis

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ANTIFUNGAL AGENTSGriseofulvin

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• Entirely local action, no systemic absorption• Micronized and ultramicronized powders are used to

facilitate dissolution• Half life in plasma of ~1 day. • Deposited in keratin precursor cells and persists in keratin

to provide prolonged resistance to fungi.• The new growth of hair or nails is the first to become free

of disease.• As the fungus-containing keratin is shed, it is replaced by

normal tissue. • Griseofulvin is detectable in the stratum corneum within 4–

8 hours of oral administration. • Sweat and transepidermal fluid loss play important roles in

drug transfer to the stratum corneum. • Only a very small fraction of the drug is present in body

fluids and tissues.

ANTIFUNGAL AGENTSGriseofulvin - ADME

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• Mycotic infections of the hair (tinea capitis) • Tinea of the hands and beard• “Athlete’s foot” or epidermophytosis

involving the skin and nails• Not effective in treatment of subcutaneous or

deep mycoses

ANTIFUNGAL AGENTSGriseofulvin - Uses

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• 5–15 mg/kg for children • 0.5–1 g for adults in 4 divided doses• Severe infections: 1.5–2 g daily for short periods • Best results are obtained• Treatment must be continued until infected tissue is

replaced by normal hair, skin, or nails, which requires 1 month for scalp and hair ringworm, 6–9 months for fingernails, and at least a year for toenails.

ANTIFUNGAL AGENTSGriseofulvin - Dosage

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• Headache, GI symptoms (e.g., nausea, vomiting, diarrhea, heartburn, flatulence), and rash.

• More serious reactions include hepatotoxicity, serum sickness reaction, angioedema, and hematologic effects (e.g., leukopenia, neutropenia, punctate basophilia, and monocytosis).

• Blood should be checked weekly during treatment.• Estrogen-like effects have been observed in

children.

ANTIFUNGAL AGENTSGriseofulvin – adverse effects

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• Topical treatment is useful in superficial fungal infections confined to the stratum corneum, squamous mucosa, or cornea, including dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and fungal keratitis.

• Unsuccessful for mycoses of the nails (onychomycosis) and hair (tinea capitis)

• No place in subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis.

• Efficacy of topical agents depends not only on the type of lesion and the mechanism of drug action, but also on the viscosity, hydrophobicity, and acidity of the formulation.

ANTIFUNGAL AGENTSTopical Antifungal Agents

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• Regardless of formulation, penetration of topical drugs into hyperkeratotic lesions often is poor.

• Removal of thick, infected keratin may be a useful adjunct to therapy.

• Preferred formulations are– Creams – Solutions– Powders, whether applied by shake containers or

aerosols, largely are used for the feet and moist lesions of the groin and other intertriginous areas


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1. Topical azole derivatives2. Nystatin& Amphotericin3. Terbinafine4. Tolnaftate5. Naftifine6. Griseofulvin


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• Used in superficial fungal infections:– Dermatophytosis ( ring worm)– Candidiasis– Fungal keratitis.

• Not effective in mycoses of the nails & hair or subcutaneous mycoses.

• Preferred formulation for cutaneous application is cream or solution.


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• Indications for topical use include – tinea corporis– tinea pedis– tinea cruris– tinea versicolor– cutaneous candidiasis.

• Agents for topical use should be selected based on cost and availability.

• They are applied twice daily for 3–6 weeks. • Preparations for cutaneous use are effective for

ANTIFUNGAL AGENTSTopical Antifungal Agents - Azoles

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• Creams, suppositories, and tablets for vaginal candidiasis• 5 gm, Used once daily for 1–7 days, preferably at bedtime to

facilitate retention.• Three vaginal formulations—

– clotrimazole tablets, – miconazole suppositories, – Terconazole cream

• Come in both low- and high-dose preparations. • Shorter duration of therapy is recommended for the higher

doses. • The action is local and only little is absorbed• Most common side effect is vaginal burning or itching. • A male sexual partner may experience mild penile irritation.

ANTIFUNGAL AGENTSTopical Antifungal Agents – Vaginal Applications

Health & Medicine

Anti fungal agents