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Ketoconazole (Topical)


VA CLASSIFICATION
Primary: DE102

Commonly used brand name(s): Nizoral A-D Shampoo; Nizoral Cream; Nizoral Shampoo.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antifungal (topical)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Tinea corporis {23} {25} (treatment) or
Tinea cruris {23} {25} (treatment) —Ketoconazole cream is indicated as a primary agent {07} in the topical treatment of tinea corporis (ringworm of the body) and tinea cruris (ringworm of the groin; jock itch) caused by Trichophyton rubrum , Trichophyton mentagrophytes , and Epidermophyton floccosum (Acrothesium floccosum) . {01} {06} {09} {13} {15} {18} {19} {21} {23} {25}

Tinea pedis {23} {25} (treatment)—Ketoconazole cream is indicated as a primary agent in the topical treatment of tinea pedis (athlete's foot). {18} {19} {23} {25}

Pityriasis versicolor {25} (treatment)—Ketoconazole cream and ketoconazole 2% shampoo are indicated as primary agents {07} in the topical treatment of pityriasis versicolor (tinea versicolor; “sun fungus”) caused by Malassezia furfur (Pityrosporon orbiculare) . {01} {06} {09} {13} {15} {17} {18} {19} {21} {23} {24} {25}

Candidiasis, cutaneous {23} {25} (treatment)—Ketoconazole cream is indicated as a primary agent {07} in the topical treatment of cutaneous candidiasis caused by Candida species. {06} {09} {15} {18} {19} {21} {23} {25}

Dermatitis, seborrheic (treatment) {23} {25} {26} or
Dermatitis, seborrheic (prophylaxis) {26}—Ketoconazole cream and [ketoconazole 2% shampoo] {26} are indicated in the treatment of seborrheic dermatitis. {09} {10} {13} {15} {18} {19} {21} {23} {25} {26} [Ketoconazole 2% shampoo] is indicated in the prophylaxis of seborrheic dermatitis. {26}

Dandruff (treatment) or
Dandruff (prophylaxis)—Ketoconazole shampoo 1% {27} and [ketoconazole shampoo 2%] {26} are indicated in the treatment and prophylaxis of the flaking, scaling, and itching associated with dandruff. {12} {14} {16} {20} {22} {26} {27}

[Paronychia (treatment)]1 {06}
[Tinea barbae (treatment)]1or {06}
[Tinea capitis (treatment)]1 {06}—Ketoconazole cream is used as a primary agent in the topical treatment of paronychia. {07} {13} Ketoconazole cream is used as a secondary agent {07} in the topical treatment of tinea barbae and tinea capitis. {06}

—Not all species or strains of a particular organism may be susceptible to ketoconazole.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Imidazoles {02}.
Molecular weight—
    531.44 {11}

Mechanism of action/Effect:

Fungistatic; may be fungicidal {25} and sporocidal {25}, depending on concentration; inhibits biosynthesis of ergosterol {25} or other sterols, damaging the fungal cell membrane and altering its permeability; as a result, loss of essential intracellular elements may occur; also inhibits biosynthesis of triglycerides and phospholipids by fungi; in addition, inhibits oxidative and peroxidative enzyme activity, resulting in intracellular buildup of toxic concentrations of hydrogen peroxide, which may contribute to deterioration of subcellular organelles and cellular necrosis. In the treatment of Candida albicans , inhibits transformation of blastospores into invasive mycelial form. {02}

Absorption:

Shampoo—Ketoconazole 2% shampoo was not detected in the plasma of 39 patients who shampooed 4 to 10 times a week for 6 months or in 33 patients who shampooed 2 or 3 times a week for 3 to 26 months (mean: 16 months). {24}

Cream—After a single topical application of ketoconazole cream to the chest, back, and arms of normal volunteers, systemic absorption of ketoconazole was not detected during the following 72-hour period, using a minimum detection level of 5 nanograms per mL in blood. {23}


Precautions to Consider

Cross-sensitivity and/or related problems

Persons sensitive to miconazole or other imidazoles may be sensitive to ketoconazole also. {13} {25}

Carcinogenicity

A long-term feeding study in Swiss albino mice and Wistar rats has shown no evidence of carcinogenicity. {01} {09} {15} {23} {24}

Mutagenicity

The dominant lethal mutation test in male and female mice, given single oral doses of ketoconazole as high as 80 mg per kg of body weight (mg/kg), has shown no mutations at any stage of germ cell development. The Ames Salmonella microsomal activator assay has also shown negative results. {01} {09} {15} {23} {24}

Pregnancy/Reproduction

Pregnancy—
Ketoconazole crosses the placenta. Adequate and well-controlled studies in humans have not been done. {23} {24}

Studies in rats, given oral doses of 80 mg/kg per day (10 times the maximum recommended human dose [MRHD]), have shown ketoconazole to be teratogenic, causing syndactyly and oligodactyly. {23} {24} However, these effects may be related to maternal toxicity, which was seen at this dose level. {23} {24}

FDA Pregnancy Category C. {01} {02} {09} {15} {23} {24}

Breast-feeding

It is not known whether ketoconazole cream {23}, applied topically on a regular basis, is absorbed systemically in sufficient amounts to be distributed into breast milk in detectable quantities. {09} {15} {23} However, no systemic absorption was detected following a single application of ketoconazole cream {23} to the chest, back, and arms of healthy volunteers. {23} In addition, ketoconazole shampoo was not detected in plasma after chronic shampooing. {24} Therefore, topical ketoconazole is unlikely to be distributed into breast milk in significant amounts or to cause adverse effects in the nursing infant. {07}

Pediatrics

No information is available on the relationship of age to the effects of this medicine in pediatric patients. Safety and efficacy have not been established {15} {23} {24}.


Geriatrics


No information is available on the relationship of age to the effects of this medicine in geriatric patients.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Sensitivity to topical ketoconazole{25}
Sensitivity to sulfites present in ketoconazole cream{23}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
For the cream or shampoo—Incidence less frequent
    
Itching, stinging, or irritation not present before therapy{23}{24}

For the cream—Incidence rare
    
Contact dermatitis{23} (skin rash)



Those indicating need for medical attention only if they continue or are bothersome
For the shampoo—Incidence less frequent
    
Dry skin{24}
    
dryness or oiliness of the hair and scalp{24}

For the shampoo—Incidence rare
    
Increase in normal hair loss{24}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
There has been no experience of overdose with ketoconazole cream {25}. Ingestion of ketoconazole shampoo may result in nausea and vomiting due to the detergent {26}.

To avoid aspiration—Gastric lavage or induced emesis should not be performed {24} {26}.

It has been reported that ketoconazole cannot be removed by hemodialysis {26}.

Specific treatment—Use general supportive measures and appropriate routine overdose management. {26}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ketoconazole (Topical) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to sulfites in ketoconazole cream or to topical ketoconazole

Pregnancy—Ketoconazole crosses the placenta; studies in animals found ketoconazole to be teratogenic

Proper use of this medication
» Avoiding contact with the eyes

For the cream form
Applying sufficient medication to cover affected and surrounding areas, and rubbing in gently

» Compliance with full course of therapy; fungal infections may require prolonged therapy

For the 1% shampoo form
Wetting hair and scalp with water

Applying adequate shampoo for lather and gently massaging in

Rinsing and repeating application

Rinsing thoroughly and drying hair

For the 2% shampoo form
Wetting hair and scalp with water

Applying shampoo to skin of affected area and wide margin surrounding area

Lathering and leaving in place for 5 minutes

Rinsing thoroughly and drying hair

» Proper dosing
Missed dose: Applying as soon as possible; not applying if almost time for next dose

» Proper storage

Precautions while using this medication
Checking with physician if skin condition becomes worse or if it does not improve within: 2 weeks for cutaneous candidiasis, pityriasis versicolor, tinea corporis, or tinea crucis; 4 weeks for seborrheic dermatitis; or 4 to 6 weeks for tinea pedis

For the cream form
» Using hygienic measures to cure infection and prevent reinfection

For tinea pedis
Carefully drying feet, especially between toes, after bathing

Not wearing socks made from wool or synthetic materials; wearing clean, cotton socks and changing them daily or more often if feet perspire excessively

Wearing sandals or well-ventilated shoes

Using a bland, absorbent powder or an antifungal powder between toes, on feet, and in socks and shoes liberally once or twice daily; using the powder between administration times for the cream

For tinea cruris
Not wearing underwear that is tight-fitting or made from synthetic materials; wearing loose-fitting cotton underwear instead

Using a bland, absorbent powder or an antifungal powder on the skin between administration times for the cream


Side/adverse effects
Signs of potential side effects, especially itching, stinging, or irritation not present before therapy (for cream and shampoo); contact dermatitis (for cream)


General Dosing Information
Prolonged {07} use of topical ketoconazole may rarely {07} lead to skin sensitization, resulting in hypersensitivity reactions with subsequent topical or systemic use of the medication. {04}

Tinea versicolor may cause hyper or hypopigmented patches on the body. Treatment of the infection may not result in normalization of the pigment for several months. {24}

For cream dosage form
To reduce the possibility of recurrence of infection, tinea corporis and tinea cruris should be treated for at least 2 {04} {05} {15} {23} to 4 weeks {25}. Candida and pityriasis versicolor should be treated for at least 2 {04} {05} {15} to 3 weeks {25}. Seborrheic dermatitis should be treated for at least 4 weeks or until clinical clearing occurs. {09} {15} {23} {25} Tinea pedis should be treated for approximately 4 {25} to 6 weeks. {18} {19} {23} {25}


Topical Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

KETOCONAZOLE CREAM

Usual adult and adolescent dose
Tinea corporis or
Tinea cruris or
Tinea pedis or
Pityriasis versicolor
Topical, to the affected {07} skin and surrounding areas, once a day. {01} {09} {13} {15} {18} {19} {21} {23} {25}

Candidiasis, cutaneous
Topical, to the affected skin and surrounding areas, once a day. {04} {09} {13} {21} {23} {25} More resistant cases may require twice a day treatment. {25}

Seborrheic dermatitis
Topical, to the affected skin and surrounding areas, two times a day. {09} {15} {13} {21} {23} {25}

[Paronychia]1 or
[Tinea barbae]1 or
[Tinea capitis]1
Topical, to the affected {07} skin and surrounding areas, two or three times a day. {04}


Usual pediatric dose
Safety and efficacy have not been established. {15} {23}

Strength(s) usually available
U.S.—


2% (Rx) [Nizoral Cream{23} (cetyl alcohol) (isopropyl myristate) (polysorbate 60) (polysorbate 80) (propylene glycol) (purified water) (sodium sulfite anhydrous) (sorbitan monostearate) (stearyl alcohol)]

Canada—


2% (Rx) [Nizoral Cream{25}]

Packaging and storage:
Store below 25 °C (77 °F) {23}, in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For external use only {25}.
   • Continue medicine for full time of treatment.


KETOCONAZOLE SHAMPOO

Usual adult and adolescent dose
Dandruff
1% shampoo—Topical, as a shampoo, every three or four days for up to 8 weeks, if needed, or as directed by physician. Prophylaxis: use only as needed to control dandruff. {27}

[Dermatitis, seborrheic]
2% shampoo—Topical, as a shampoo, twice a week for 2 to 4 weeks. Leave in place for 3 to 5 minutes before rinsing. Prophylaxis: once a week every 1 or 2 weeks. {26}

Pityriasis versicolor
2% shampoo—Topical, as a shampoo, to the affected skin and surrounding area(s), as a single application. {24} Leave in place for 5 minutes before rinsing. {24}


Usual pediatric dose
Safety and efficacy have not been established. {12} {16}

Strength(s) usually available
U.S.—


1% (OTC) [Nizoral A-D Shampoo{27} (sodium lauryl ether sulfate) (cocamide MEA) (sodium cocoyl sarcosinate) (glycol distearate) (acrylic acid polymer) (fragrance) (sodium chloride) (tetrasodium EDTA) (butylated hydroxytoluene) (quarternium-15) (polyquarternium-7) (sodium hydroxide) (hydrochloric acid) (FDC Blue No. 1)]


2% (Rx) [Nizoral Shampoo{24} (coconut fatty acid diethanolemide) (disodium monolauryl ether sulfosuccinate) (FDC Red No. 40) (hydrochloric acid) (imidurea) (laurimonium hydrolyzed animal collagen) (macrogol 120 methyl glucose dioleate) (perfume bouquet) (sodium chloride) (sodium hydroxide) (sodium lauryl ether sulfate) (purified water)]

Canada—


2% (Rx) [Nizoral Shampoo{26}]

Packaging and storage:
1% shampoo—Store between 2 and 30 °C (35 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing. {27}

2% shampoo—Store below 25 °C (77 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing. {24}

Auxiliary labeling:
   • For external use only.
   • Keep away from eyes. {24} {27}



Revised: 06/14/1999



References
  1. Nizoral cream package insert (Janssen—US), Rev 1/86, Rec 5/9/86.
  1. Ketoconazole (Systemic) monograph, USP DI 1987.
  1. Nizoral tablets package insert (Janssen—US), PDR 1987: 1032-3.
  1. Econazole (Topical) monograph, USP DI 1987.
  1. Ciclopirox (Topical) monograph, USP DI 1987.
  1. Indications Index review, 1986.
  1. Panel comments, Ketoconazole (Topical), 7/15/87.
  1. Open.
  1. Nizoral package insert (Janssen—US), Rev 2/88, Rec 4/89.
  1. Personal communications, Janssen (Canada), 6/28/89.
  1. Fleeger CA, editor. USAN 1993. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention Inc; 1992.
  1. Nizoral 2% shampoo package insert (Janssen—US), Rev 6/90, Rec 1/91.
  1. Nizoral 2% cream product monograph (Janssen—Canada), Rev 7/88, Rec 6/89.
  1. Nizoral 2% shampoo product monograph (Janssen—Canada), Rev 3/90, Rec 11/90.
  1. Nizoral 2% cream package insert (Janssen—US), PDR 1992: 1143.
  1. Panel comments: sent 5/18/92, due 6/8/92.
  1. Reviewer comment, 4/92.
  1. Nizoral cream communication from Janssen—US, 3/93.
  1. Nizoral cream package insert (Janssen—Canada), CPS 1992: 762-3.
  1. Nizoral shampoo package insert (Janssen—Canada), CPS 1992: 763.
  1. Nizoral cream package insert (Janssen—US), PDR 1993: 1171.
  1. Nizoral shampoo package insert (Janssen—US), PDR 1993: 1171.
  1. Nizoral cream (Janssen). In: PDR Physicians' desk reference. 52nd ed. 1998. Montvale, NJ: Medical Economics Company; 1998. p. 1305-6.
  1. Nizoral 2% shampoo package insert (Janssen—US), Rev 8/97, Rec 5/98.
  1. Nizoral cream (McNeil). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialities. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1127-8.
  1. Nizoral 2% shampoo (McNeil). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialities. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1128-9.
  1. Nizoral A-D 1% shampoo package insert (McNeil Consumer Products—US), Rec 5/3/99.
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