Pharmacology

Ketoconazole 2%
Broad spectrum antifungal agent

Mode of Action
Alters permeability of yeast & fungal cell membranes.
Inhibits ergosterol biosynthesis, major sterol of these cell membranes. Accumulation of 14 a-methylsterol.
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Pharmacology
14-a-demethylation step in ergosterol biosynthesis is cytochrome P450 dependent. Affects biosynthesis by inhibiting cytochrome P450 dependent 14-a-demethylase activity.

Accumulation of 14-a-methylsterols, & in ergosterol content of cell membrane, creates unstable condition leading to disturbed membrane function, compromised cell growth & viability.
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Pharmacology
At higher concentrations, there was accumulation of saturated fatty acid, an

affect that destabilizes structure &

permeability of fungal cell membrane.

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Pharmacology
Has dual action; fungistatic at low
concentrations which seems to be characteristic of all imidazoles & is related to inhibition of ergosterol biosynthesis & fungicidal at higher concentrations, which is by damage to cell membrane.
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Pharmacology
An MIC of 0.02 mcg/ml is sufficient to inhibit growth of Pityrosporum yeast. Also has action on 5-lipooxygenase, thus inhibits leukotriene B4 synthesis & thus suppresses inflammation more readily.
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Ketoconazole Shampoo
Studies showed no detectable absorption.
Plasma concentrations were consistently undetectable 3 to 12 hours after a single application & after upto 26 months of repeated (2 to 3 times weekly) application. High concentrations were detected in hair 72 hours after last application of shampoo.

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Ketoconazole Shampoo
High affinity for hair keratin. Levels in hair keratin were 5% or 20% of levels detected on hair shafts after single or

repeated application.
2% shampoo (twice weekly for 8 weeks). Exerts antifungal effect for some days after shampoo is washed out (substantivity).
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Ketoconazole Shampoo
Contraindications
Hypersensitivity

Experience with Ketoconazole

2% Ketoconazole shampoo, gave good or excellent improvement in 90% of treated patients compared with placebo 30%. 1% Ketoconazole shampoo gave a comparative response of 80%.
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Ketoconazole Shampoo
Experience with Ketoconazole
Better response was noted in male

compared to female patients, possibly

because men have less hair which allows better contact between affected scalp & shampoo
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Pharmacology
Zinc Pyrithione
Cytostatic agent (reduces rate of growth & multiplication of horny cells on scalp, thus causes decrease in no. of scales).

Bacteriostatic & fungistatic properties. sa

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Pharmacology
Mode of Action
1% Zinc pyrithione reduces flaking & itching caused by Dandruff (Antikeratolytic).
Inhibits anti-membrane transport via a direct or indirect effect on primary proton pump which energizes transport Site of action is intracellular rather than extracellular. Sales Training

Pharmacology
Mode of Action
Causes leakage of intracellular material. Effective at an MIC of 0.12-8 mcg/ml. Absorption is less than 1% of topical application. Adverse effects: peripheral neuritis with paraesthesia (abnormal sensation such as burning, pricking or tingling) & muscle weakness.
Sales Training Contraindications: Hypersensitivity.

SCALPE LOTION
Composition: Ketoconazole 2 % Zinc Pyrithione 1 % Cocomonoethanolamide - Conditioner Cocomonodiethanolamide- Conditioner Cocobetaine- Conditioner Ajidew - Moisturizer Amisoft Surfactant, Foams even in hard water Availability : Bottle of 60 ml
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Acetyl Coenzyme-A

Squalene Squalene epoxide Lanosterol Ketoconazole 14Demethyl lanosterol Episterol Ergosterol Fungal cell membrane synthesis

C-14 Demethylase

Zinc Pyrithione

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Fungal DNA synthesis

Rationale for Topical Ketoconazole Formulations

Oral treatment of these conditions cannot be justified for several reasons.
Dandruff & Seborrhoeic Dermatitis requires long term repetitive treatment. Risk of hepatotoxicity with longer duration of treatment (14 days), requires liver function monitoring.
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Rationale for Topical Ketoconazole Formulations

Causes rapid depression of serum testosterone about 25% of baseline at 4 hrs after ingestion. Gynaecomastia with therapeutic doses.

Higher or more frequent doses may

cause oligospermia & adrenal suppression.
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Rationale for Topical Ketoconazole Formulations

Dermatitis is associated with welldefined lesions which affect small areas of body.
Thus, localized skin disorders such as Dandruff & Seborrhoeic Dermatitis should not be treated systemically.

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Rationale for Scalpe Shampoo

Accumulation of flakes of scales & proliferation of P. ovale result in condition of Dandruff & Seborrhoeic Dermatitis. Social nuisance & unpleasant symptoms which include itching.

Clearing off accumulated flakes or preventing formation of excessive scales wont be sufficient treatment. Sales Training

Rationale for Scalpe Shampoo

This will not give even immediate relief to symptoms of itching as itching is primarily caused by P. ovale. So flakes are to be cleared.
More than this abnormal formation of flakes are to be prevented & the organism P. ovale has to be killed.
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Rationale for Scalpe Shampoo

Zinc pyrithione, being anti-keratolytic & cytostatic agent. Clears flakes of scales & prevents abnormal formation of scales. Ketoconazole 2% is mild fungistatic in low concentration & fungicidal at high concentration thus killing P. ovale effectively.
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Direction for Use

Moisten hair & scalp thoroughly with water. Apply sufficient shampoo to produce enough lather to wash scalp & hair.

Gently massage over entire area for approximately one minute.

Rinse thoroughly with warm water. Repeat leaving shampoo in scalp for additional 3 minutes.
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Direction for Use

Rinse with warm water, dry hair with

towel or warm air flow.

Shampoo twice a week for 4 weeks with at least 3 days between each shampooing followed by once weekly

as a maintenance therapy.
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Warnings & Precautions

For external use only. Avoid contact with eyes. If contact occurs, rinse thoroughly with water. Use of shampoo resulted in removal of curl from permanently waved hair.

No evidence of carcinogenesis, mutagenesis & impairment of fertility.

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Warnings & Precautions

Pregnancy & Lactation: Not contraindicated. Paediatric Use: Safety not established.

Contraindications
Hypersensitivity to Ketoconazole, Zinc Pyrothione or excipients.
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Adverse Reactions / Side Effects

Well tolerated. Rare instances, discolouration of hair. Increase in normal hair loss, irritation (< 1%), abnormal hair texture, mild dryness of skin, itching, oilyness/dryness of hair & scalp were noted.

Rarely peripheral neuritis can be seen with Zinc pyrithione.

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Overdosage
In accidental ingestion, supportive measures should be carried out. To avoid aspiration, neither emesis nor gastric lavage should be performed.

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Presentation
Plastic bottle of 60 ml in an attractive
carton.

A pack insert provides scientific

information as well as tips for layman on

obtaining maximum benefits

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Sales Training

Clinical Abstracts
A double-blind trial of 1% Ketoconazole shampoo versus placebo in the treatment of Dandruff
Application of the shampoo twice weekly gave good to exellent results in 74% of the patients versus 20% with placebo after 2 weeks. After 4 weeks results were 80% versus 23% respectively. Shampoo was well tolerated. Sales Training
Mycoses, 1992, Mar-Apr;35(3-4):103-5.

Clinical Abstracts
Successful treatment & prophylaxis of scalp Seborrhoeic Dermatitis & Dandruff with 2% Ketoconazole shampoo: results of a multicenter, double-blind placebocontrolled trial We conclude that Ketoconazole 2% shampoo is highly effective, not only in clearing scalp Seborrhoeic Dermatitis & Dandruff, but also in preventing relapse of the disease when used prophylactically once weekly.
Sales Brit. J.Training of Dermat; 1995, 132:441-445.

Clinical Abstracts
Treatment of Seborrhoeic dermatitis with Ketoconazole: II. Response of Seborrhoeic dermatitis of the face, scalp & trunk to topical Ketoconazole Face & scalp lesions, assessed by both patient & clinician showed significant improvement or complete clearance in the group treated with ketoconazole. Patients who had Seborrhoeic deramtitis of the chest or back & were treated with Ketoconazole also improved. There was no improvement with placebo. This study provides further evidence for the aetiological role of Pityrosporon yeasts in Seborrhoeic dermatitis & of the efficacy of topical ketoconazole in its treatment.
Brit. Sales Training J. of Dermat; 1987, 116, 217-221.

Clinical Abstracts
A comparative study of the fungicidal activity of Ketoconazole, Clotrimazole, Bifonazole, Econazole, Fenticonazole, Zinc Pyrithione & Selenium sulphide against Pityrosporum Ovale
In conclusion, Ketoconazole is the most potent antimycotic agent against P. ovale compared to other drugs tested. In animals, Ketoconazole was highly active. This is confirmed by the high clinical & mycological cure rates obtained in worldwide human clinical trials with Ketoconazole cream & shampoo for the treatment of Seborrhoeic dermatitis & Dandruff. Janseen Res. Foundation, Beerse, Belgium. Sales Training

Clinical Abstracts
The effects of a shampoo containing Zinc pyrithione on the control of Dandruff Several studies have demonstrated that ZPT containing shampoos are effective agents for the treatment of Dandruff.
Kligman et al, 1974, Futterer, 1981, Van Abbe et al., 1981

Originally formulated because of its antimicrobial properties, it has also been suggested that ZP may act as a cytostatic agent when used in Dandruff.
Priestely & Brown, 1980; Leyden, Mc Ginley & Kligman, 1976; Imokawa, Sales Training Shimizu & Okamoto, 1982, ImoKaula, Shimizu & Okamoto, 1982

Clinical Abstracts
The inhibitory effect of Zinc pyrithione on the epidermal proliferation of animal skins

It is suggested that the anti-dandruff effect

of Zinc pyrithione results primarily from its

action as an anti-biosynthetic agent rather than from its anti-yeast action.
Acta. Dermat. Venerol, 1982, 62(6):471-5.
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Clinical Abstracts
A randomized, double-blind, placebocontrolled trial of Ketoconazole 2% shampoo versus selenium sulfide 2.5% shampoo in the treatment of moderate to severe Dandruff

Conclusion: Both Ketoconazole 2% shampoo & Selenium sulfide 2.5% shampoo are effective in the treatment of moderate to severe Dandruff; however; Ketoconazole 2% shampoo appears to be better tolerated.
J. Am. Acad. Dermat. 1993, Dec.;26(6):1008-12. Sales Training

Clinical Abstracts
A Combination of 2% Ketoconazole plus 1% Zinc Pyrithione is more effective than 2% Ketoconazole alone in the treatment of Dandruff.
A randomised double blind comparison of two shampoos was carried out on 49 patients with moderate to severe dandruff (pityriasis sicca). Group A (n=23) used a shampoo containing 2% ketoconazole plus 1% zinc pyrithione whereas Group B (n=26) used a 2% ketoconazole shampoo. Scoring of dandruff was done on a 0-10 scale for each of the 6 regions of the scalp at 0,2 and 4 weeks. All patients shampooed twice a week for 4 weeks. Sales Training

Clinical Abstracts
A Combination of 2% Ketoconazole plus 1% Zinc Pyrithione is more effective than 2% Ketoconazole alone in the treatment of Dandruff. (Contd.)
Global assessment by the investigator showed good or excellent results in 74% in Group. A & 46% in Group B. A combination shampoo of 2% ketoconazole & 1% zinc pyrithione is more effective in the treatment of pityriasis sicca when compared to a shampoo containing 2% ketoconazole.
Vaishali Phadke, Ashish Pimpley, Uday Khopkar, S.L. Wadhwa, Paper presented at 28th National Conference IADVL, Jan. 27-30, 2000 Bangalore, Sales Training India.

Clinical Abstracts
Clinical Trial of Ketoconazole 2% + Zinc pyrithione 1% shampoo in management of seborrhoea capitis (pityriasis capitis).
To evaluate the efficacy of Ketoconazole 2% & Zinc Pyrithione 1% combination shampoo in Pityriasis Capitis we conducted the clinical trial in 30 patients. Male or female patients with moderate to severe scaling of the scalp for atleast 1-3 months were included in the study. The selected patients were advised to apply the shampoo twice weekly for 4 weeks & once weekly thereafter.
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Clinical Abstracts
Clinical Trial of Ketoconazole 2% + Zinc pyrithione 1% shampoo in management of seborrhoea capitis (pityriasis capitis).
Results were evaluated after appropriate statistical analysis. It was observed that there was a reduction in total loose & adherent dandruff score. The mean reduction was 31.3%, 92.8% & 98.5% at the end of 1st, 4th & 6th week respectively as compared to baseline. These results were statistically significant (p<0.05, Wilcoxin sign Rank Test). There was a reduction in other signs and symptoms like erythema and itching. Physicians global assessment demonstrated excellent to good results in 96.7% of the patients, whereas 96.7% of the patients accepted the shampoo as excellent or good treatment for dandruff. No adverse events were reported.
B. Narasimha Rao (Director B.N.R. Skin Hospitals), K.L. Vallabh Rao (Consulting Dermatologist, Hyderabad), Anish Desai (GM, Glenmark),
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SWOT analysis of the market

Strengths
Well established presence of company in dermatological segment.
A new combination shampoo in the market.

Medico-aesthetic approach to treating dandruff.

Well documented papers for Ketoconazole & ZPTO individually.

Slick packaging on the lines of OTC brands.

Strong association of brand name with the intended use.
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SWOT analysis of the market

Weakness
Lack of supportive data for combined action of Ketoconazole & ZPTO. Lack of initiative among shampoo users to approach doctors for dandruff related problems.

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SWOT analysis of the market

Opportunities
A huge market of OTC shampoo users & increasing number of sufferers. Few brands in the shampoo market especially for Dandruff & related problems.
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SWOT analysis of the market

Threats
Existing giants will retaliate.
New competition can emerge.

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Competition
Indirect : Nizral Ketoconazole (J & J) KZ Ketoconazole (H & H) Arcolane Ketoconazole (Galderma) Direct : Conaderm (Ranbaxi)
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Competition
Brand (Company) Selsun (Abbotts) Pack 60 ml 120 ml Selsun blue (Abbotts) 60 ml Nizral (Ethnor) 60 ml Ingredients Selenium sulfide 2.5% Selenium sulfide 2.5% Selenium sulfide 1% Ketoconazole 2% Ketoconazole 1%

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Competition
Brand (Company)
Ionax-T (Croslands) Alphosyl (Elder)

Pack
60 ml 20 gm

Ingredients
Salicylic Acid - 2%; Coal Tar - 4.25% Coal Tar extract - 5% v/w; Allantoin - 2% w/w

Salytar Ointment
(Shalaks)

15 gm
100 gm

Coal tar, Salicylic Acid & Sulphur Prepared Coal Tar 1%; Salicylic Acid - 3%

Salytar Scalp Solution

(Shalaks)

50 ml
100 ml
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Competition
Brand (Company)
Cetrilak Mild (Shalaks)

Pack
50 ml 100 ml 450 ml

Ingredients
Cetrimide - 5% w/v; Isopropyl alcohol - 10% w/v; Purified water - 100% v/v; Perfume - q.s.

Cetrilak Strong (Shalaks)

100 ml

Cetrimide - 20% w/v; Isopropyl alcohol - 10% v/v; Purified water - 100% v/v; perfume - q.s. Ketoconazole - 2% w/v
Selenium sulphide - 2.5% w/v

Danruff (Torrent)
Seldan (Mount Mettur)

30 ml
60 ml
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Competition
Brand (Company)
Seldruff Plus (Wings Pharma) Betnovate Scalp (Glaxo - Wellcome) Endruff (Nulife Pharma) Betadine AD (Win-Medicare)

Pack Ingredients
60 ml Selenium sulphide - 2.5% w/v; Clotrimazole - 1% w/v 20 ml Betamethasone valerate - 0.1% w/w 50 ml Cetrimide - 5% w/v; Calcium pantothenate 2% w/v 60 ml Povidone iodine - 4% w/v
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