Candibiotic

Uses

Prophylaxis and treatment of seasonal & perennial allergic rhinitis including hay fever & non-allergic (vasomotor) rhinitis. Prevention of recurrence of nasal polyps following surgical removal.

Chloramphenicol is used for Ocular infections, Bacterial meningitis, Anaerobic bacterial infections, Anthrax, Brain abscess, Ehrlichiosis, Gas gangrene, Granuloma inguinale, Infections caused by H. influenzae, Listeriosis, Plague, Psittacosis, Q fever, Severe gastroenteritis, Severe melioidosis, Severe systemic infections with Camphylobacter fetus, Tularaemia, Whipple's disease, Otitis externa

The confirmed indication for Clotrimazole include:

• All dermatomycoses due to dermatophytes (e.g. Trichophyton species).
• All dermatomycoses due to yeasts (Candida species).
• Dermatomycoses due to moulds and other fungi.
• Skin diseases showing superinfections with these fungi.

To the dermatomycoses listed under 1-4 belong for example, interdigital myocoses (e.g. athlete’s foot), paronychias (associated with nail mycoses), myocoses in skin folds, Candida vulvitis, Candida balanitis, Pityriasis versicolor, erythrasma.

Clotrimazole rectal preparation is used for vaginal itching, burning and discharge associated with recurrent vaginal yeast infections (Vaginal candidiasis) and also in viginitis due to Candida species as well as Mycotic infections complicated by other microorganisms sensitive to the drug.

Clotrimazole Sterile Eye Ointment is used for the treatment of fungal keratitis due to filamentous fungi and Candida species.

Clotrimazole Ear Drop is used for the treatment of fungal infections of the ear.

Candibiotic is also used to associated treatment for these conditions: Asthma, Bacterial Sinusitis, Chronic Obstructive Pulmonary Disease (COPD), Chronic Sinusitis, Dermatosis, Fungal skin infection, Perennial Allergic Rhinitis (PAR), Seasonal Allergic Rhinitis, Vasomotor Rhinitis, Corticosteroid-responsive dermatoses, Recurrent nasal polypsAcne, Bacterial Conjunctivitis, Bacterial Conjunctivitis caused by susceptible bacteria, Bacterial Infections, Bacterial dacryocystitis, Bacterial diarrhoea, Conjunctivitis allergic, Corneal Inflammation, Eye swelling, Keratitis bacterial, Ocular Inflammation, Trachoma, Anterior eye segment inflammation, Bacterial blepharitis, Bacterial corneal ulcers, Non-purulent ophthalmic infections caused by susceptible bacteria, Superficial ocular infections, Skin disinfectionBalanitis candida, Candidiasis, Dermatitis, Dermatomycoses, Ear infection fungal, Erythrasma, Fungal Vaginal Infections, Fungal skin infection, Genital candidiasis, Inflammation, Mixed Vaginal Infections, Oropharyngeal Candidiasis, Pityriasis versicolor, Pyoderma, Ringworm, Skin Infections, Skin candida, Tinea Corporis, Tinea Cruris, Tinea Pedis, Tinea inguinalis, Trichophytosis, Vaginal Candidiasis, Vaginal Mycosis, Vulvitis, Cutaneous candidiasis, Infection mycotic, Susceptible Bacterial Infections, Symptomatic Tinea Corporis caused by Trichophyton mentagrophytes, Trichophyton rubrum, Epidermophyton floccosum, Symptomatic Tinea Cruris caused by Trichophyton mentagrophytes, Trichophyton rubrum, Epidermophyton floccosum, Symptomatic Tinea Pedis caused by Trichophyton mentagrophytes, Trichophyton rubrum, Epidermophyton floccosum, Tinea versicolor caused by Malassezia infection

How Candibiotic works

Beclomethasone dipropionate is a corticosteroid and prodrug that is rapidly activated by hydrolysis to the active monoester, 17 monopropionate (17-BMP), which mediates anti-inflammatory actions. 17-BMP has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone and 25 times that of beclomethasone dipropionate. Upon binding of the ligand, the glucocorticoid receptors dimerize and translocate into the nucleus, where they subsequently bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, leading to changes in transcription. There are several proposed mechanisms for the anti-inflammatory action of corticosteroids. Corticosteroids may work by increasing the transcription of genes coding for anti-inflammatory proteins, including lipocortin-1 and interleukin-10. Corticosteroids were also shown to inhibit the expression of multiple genes that encode pro-inflammatory factors, such as cytokines, chemokines, and adhesion molecules, that are activated during the chronic inflammatory process. This is thought to be due to the direct inhibitory interaction between activated glucocorticoid receptors and activated pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein-1. Chronic inflammation is often characterized by enhanced expression of these transcription factors that bind to and activate coactivator molecules, which then acetylate core histones to switch on gene transcription to further amplify the inflammatory process. Corticosteroids suppress the multiple inflammatory gene expression by promoting histone deacetylation, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites.

Chloramphenicol is lipid-soluble, allowing it to diffuse through the bacterial cell membrane. It then reversibly binds to the L16 protein of the 50S subunit of bacterial ribosomes, where transfer of amino acids to growing peptide chains is prevented (perhaps by suppression of peptidyl transferase activity), thus inhibiting peptide bond formation and subsequent protein synthesis.

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. Clotrimazole causes inhibition of ergosterol biosynthesis, an essential constituent of fungal cell membranes. If ergosterol synthesis is either completely or partially inhibited, the cell is no longer able to construct an intact and functional cell membrane ,. Because ergosterol directly promotes the growth of fungal cells in a hormone‐like fashion, rapid onset of the above events leads to dose-dependent inhibition of fungal growth .

Though decreased ergosterol, due to the inhibition of lanosterol 14-demethylase (also known as CYP51) is accepted to be primarily responsible for the antimycotic properties of clotrimazole, this drug also shows other pharmacological effects. These include the inhibition of sarcoplasmic reticulum Ca2+‐ATPase, depletion of intracellular calcium, and blocking of calcium‐dependent potassium channels and voltage‐dependent calcium channels . The action of clotrimazole on these targets accounts for other effects of this drug that are separate from its antimycotic activities .

Dosage

Candibiotic dosage

Dosage of intranasal Beclomethasone Dipropionate must be carefully adjusted according to individual requirements and response.

Adults: Recommended usual dosage: 02 (two) sprays (50 µgm/spray) in each nostril twice daily. For some patients, 01 (one) spray in each nostril 3 to 4 times daily may be preferred. Total daily doses of 400 µgm (08 sprays) should not generally be exceeded.

Children (6 to 12 years of age): Usual dose: 01 (one) spray in each nostril twice daily. Patients not adequately responding, or those with more severe symptoms may use 02 (two) sprays in each nostril twice daily.

Children under 6 years of age: Not recommended since safety profile studies have not been conducted. After the first few days, patients may be able to reduce their dosage to 100 µg (one spray in each nostril) once daily for maintenance therapy.

For Eye: Adults, children and infants (all age groups): One or two drops 4 to 6 times a day should be placed in the infected eyes. If necessary the frequency of dose can be increased. Treatment should be continued for approximately 7 days but should not be continued for more than three weeks without re-evaluation by the prescribing physician.

For Ear: 2 to 3 drops into ear canal thrice or four times daily.

Otic/Aural: Otitis externa:Instill 2-3 drops of a 5% solution into the ear bid-tid.

Oral:Bacterial meningitis, Anaerobic bacterial infections, Anthrax, Brain abscess, Ehrlichiosis, Gas gangrene, Granuloma inguinale, Infections caused by H. influenzae, Listeriosis, Plague, Psittacosis, Q fever, Severe gastroenteritis, Severe melioidosis, Severe systemic infections with Camphylobacter fetus, Tularaemia, Whipple's disease:

• Adult:50 mg/kg/day in 4 divided doses increased to 100 mg/kg/day for meningitis or severe infections due to moderately resistant organisms. Continue treatment after the patient's temperature has normalised for a further 4 days in rickettsial disease and 8-10 days in typhoid fever.
• Child:Premature and full-term neonates: 25 mg/kg/day in 4 divided doses. Full-term infants >2 wk: 50 mg/kg/day in 4 divided doses. Children: 50 mg/kg/day in 4 divided doses increased to 100 mg/kg/day for meningitis or severe infections.

Topical

Wash skin with soap and water and dry thoroughly. Apply a thin layer of the cream or solution 2-3 times daily and gently massage over affected area as directed by the doctor. For Athlete’s foot, pay special attention to the spaces between the toes. Best results in Athlete's foot and ringworm are usually obtained with 4 weeks use of this product. The cream should be applied two or three times daily for one month or for at least two weeks after the disappearance of all signs of infection. If satisfactory results have not occurred within these times consultation with doctor is essential. For best results, follow directions and continue treatment for length of time indicated. The duration of treatment varies; it depends among other factors on the extent and localization of the disease.

Recommended duration of treatment :

• Dermatomycoses: 3-4 weeks
• Candida vulvitis and candida balanitis: 1-2 weeks
• Erythrasma and pityriasis versicolor (approx.): 3 weeks
• In fungal infection of the feet, to prevent relapses:Treatment should be continued for about 2 weeks beyond the disappearance of all signs of disease.

Clotrimazole cream is odourless, can be washed off and does not stain.

Rectal

First infections: In general, a 3-day treatment is sufficient for Candida vaginitis. On 3 consecutive nights, Clotrimazole 200 mg vaginal preparation is inserted as deeply as possible into the vagina. This is best achieved when lying on one's back with the knees slightly bent.

Re-infections: In general, a 6-day treatment is sufficient. This applies also to mixed infections with the above-mentioned causative organisms. On six consecutive nights, 1 Clotrimazole 100 mgvaginal preparation is inserted as deeply as possible into the vagina. If necessary, 2 Clotrimazole 100 mg(1 in the morning and 1 in the evening) or 1 Clotrimazole 200 mg daily can be used for 6-12 days. Treatment should be timed so as to avoid the menstrual period and be finished before the onset of menstruation. To avoid re-infection, the partner should undergo local treatment with Clotrimazole cream at the same time.

Clotrimazole 500 mg vaginal preparation: Single dose, complete treatment with one vaginal tablet. The tablet should be inserted as deeply as possible into the vagina. This is best achieved when lying on one's back with the knees slightly bent. It is recommended that the treatment should be timed so as to avoid the menstrual period. For prevention of re-infection the partner should be treated locally with Clotrimazole cream at the same time.

Clotrimazolevaginal preparation are colorless and do not stain the underwear.

Eye

Adult: It should be applied thinly and evenly to the conjunctival sac every 4 hours daily or as advised by a physician.

Children: Safety and effectiveness in children have been established for Clotrimazole when used as indicated and in the recommended dosage.

Ear

Instill 2-3 drops of Clarizol Ear Drops in the affected ear two or three times daily.The treatment should be continued for at least two weeks after the disappearance of all signs of infection to prevent re-infection.

For the treatment to become a complete success, reliable and sufficiently long application of Clotrimazole cream is important. The duration of treatment varies; it depends among other factors on the extent and localisation of the disease.

Side Effects

Rare instances of nasal septum perforation have been reported following intranasal administration. As with other nasal sprays, dryness and irritation of the nose and throat, unpleasant taste & smell and epistaxis have been reported rarely. Rare instances of wheezing, cataracts, glaucoma and increased intra-ocular pressure have been reported following the intranasal use of Beclomethasone.

Oral: GI symptoms; bleeding; peripheral and optic neuritis, visual impairment, blindness; encephalopathy, confusion, delirium, mental depression, headache. Haemolysis in patients with G6PD deficiency.

ophthalmic application: Hypersensitivity reactions including rashes, fever and angioedema.

Ear drops: Ototoxicity.

Clotrimazole is generally well tolerated after local application but the few side effects have been reported infrequently like erythema, stinging, blistering, peeling, oedema, pruritus, urticaria and general irritation.

Since there is practically no Clotrimazole absorption through the vaginal skin, no systemic effect is expected. The local tolerance of Clotrimazole vaginal tablet is generally good. Local irritation or burning sensation may occur in a very few cases but these symptoms are not considered harmful.

Rarely patients may experience burning or irritation immediately after applying the ointment.

Toxicity

The oral LD₅₀ in rats is >3750 mg/kg.

The acute toxicity of beclometasone dipropionate is low. The only harmful effect that follows inhalation of large amounts of the drug over a short period of time is suppression of hypothalamic-pituitary-adrenal (HPA) function. Chronic: The excessive use of beclometasone dipropionate over a long period could lead to adrenal suppression.

Oral, mouse: LD₅₀ = 1500 mg/kg; Oral, rat: LD₅₀ = 2500 mg/kg. Toxic reactions including fatalities have occurred in the premature and newborn; the signs and symptoms associated with these reactions have been referred to as the gray syndrome. Symptoms include (in order of appearance) abdominal distension with or without emesis, progressive pallid cyanosis, vasomotor collapse frequently accompanied by irregular respiration, and death within a few hours of onset of these symptoms.

Symptoms of overdose include erythema, stinging, blistering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin, and cramps. As with all topical agents, skin sensitization may result .

Oral LD50 (rat): 708 mg/kg; Intraperitoneal LD50 (rat): 445 mg/kg; Subcutaneous LDLO (rat): 10 g/kg; Oral LD50 (mouse): 761 mg/kg; Subcutaneous LDLO (mouse): 10 g/kg; Intraperitoneal LD50 (mouse): 108 mg/kg;

Overdose

This drug poses no risk of acute intoxication, as it is unlikely to occur following a single vaginal or dermal application of an overdose (application over a large area under conditions favorable to absorption) or accidental oral ingestion. There is no specific antidote .

Effects on Fertility

No human studies of the effects of clotrimazole on fertility have been conducted; however, animal studies have not shown any effects on the drug on fertility .

Use in Pregnancy

There are limited data regarding the use of clotrimazole in pregnant women. Animal studies do not show direct or indirect harmful effects on reproduction. Although the topical application of clotrimazole may result in very low serum and tissue levels, the use of clotrimazole topical cream by pregnant women is not recommended unless it is advised by the prescribing physician. Clotrimazole topical cream should not be used in the first trimester of pregnancy unless it is considered by the physician to be essential to patient well-being .

Use in Breastfeeding

Available pharmacodynamic/toxicological studies in animals have shown excretion of clotrimazole/metabolites in breastmilk. Clotrimazole should not be administered during breastfeeding. Although the topical application of clotrimazole has resulted in very low serum and tissue levels, the use of clotrimazole topical cream by lactating women is not recommended unless it recommended by the prescribing physician .

Precaution

Care must be taken while transferring patients from systemic steroid to Beclomethasone nasal spray if there is any reason to suppose that their adrenal function is impaired.

Impaired renal or hepatic function; premature and full-term neonates. Monitor plasma concentrations to avoid toxicity.

If local intolerance develops, consider withdrawal of the medicine and institution of appropriate therapy. Clotrimazole solution is not intended for ophthalmic use. Avoid contact with eyes upon topical application. Children 3 yrs. Pregnancy, lactation. If irritation or sensitivity develops with the use of Clotrimazole ointment, treatment should be discontinued.

Interaction

Decreased effects of iron and vitamin B12 in anaemic patients. Phenobarbitone and rifampin reduce efficacy of chloramphenicol. Impairs the action of oral contraceptives.

There have been reports of a heat reaction when this medication used concomitantly with Sofradex drops in the ear.

Antagonism with polyene antibiotics.

Volume of Distribution

Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate.

The topical form is minimally absorbed in the serum and tissues . Clotrimazole is a lipophilic drug , and has been shown to be secreted in breastmilk in animal studies . There are limited data available regarding the volume of distribution following oral troche administration.

Elimination Route

Following oral inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing.

In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, respectively.

Rapidly and completely absorbed from gastrointestinal tract following oral administration (bioavailability 80%). Well absorbed following intramuscular administration (bioavailability 70%). Intraocular and some systemic absorption also occurs after topical application to the eye.

Because clotrimazole is generally not significantly absorbed, drug interactions are not a major issue with its use .

Half Life

Following intravenous administration, the half life of beclomethasone dipropionate was 0.5 hours while the half life of the active metabolite 17-BMP was 2.7 hours. Following oral and intranasal administration, the half life of 17-BMP was 8.8 and 5.7 hours, respectively.

Half-life in adults with normal hepatic and renal function is 1.5 - 3.5 hours. In patients with impaired renal function half-life is 3 - 4 hours. In patients with severely impaired hepatic function half-life is 4.6 - 11.6 hours. Half-life in children 1 month to 16 years old is 3 - 6.5 hours, while half-life in infants 1 to 2 days old is 24 hours or longer and is highly variable, especially in low birth-weight infants.

Clearance

Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively.

Elimination Route

Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being excreted in the urine.

Mainly hepatic .

Pregnancy & Breastfeeding use

Beclomethasone should be used during pregnancy, if the potential benefit justifies the potential risks to fetus. In addition, as there is natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

As other corticosteroids are excreted in human milk, caution should be exercised when Beclomethasone nasal spray is administered to a nursing woman.

Pregnancy Category C. Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Pregnancy:Clotrimazole is recommended during pregnancy only after first consulting a doctor.

Lactation:Because systemic absorption of clotrimazole following topical application is marginal, there should be no risk for the infant during lactation.

Contraindication

Contraindicated in patients with a history of hypersensitivity to any of its components. Infections of the nasal passages and paranasal sinuses should be appropriately treated but do not constitute a specific contraindication to treatment with Beclomethasone nasal spray.

History of hypersensitivity or toxic reaction to the drug; pregnancy, lactation; porphyria; parenteral admin for minor infections or as prophylaxis; preexisting bone marrow depression or blood dyscrasias.

Hypersensitivity to clotrimazole.

Acute Overdose

Inhalation of excessive doses over a short time period may suppress hypothalamic pituitary adrenal (HPA) function, and no special emergency action need to be taken, rather treatment should be continued at recommended dose. HPA function recovers within one or two day

Supportive measures should be taken incase of accidental oral ingestion.

In case of accidental oral ingestion, supportive measures should be taken.

Storage Condition

Store at a temperature not exceeding 30˚ C. Protect from light & moisture. Keep out of the reach of children.

Cap/susp: Store at temp not exceeding 30°C.

Ophth/otic preparation: Store between 2-8°C. Do not freeze. Protect from light.

Store at a cool and dry place. Protect from light. Do not freeze.

Innovators Monograph

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