Actinac (Chloramphenicol)

ACTINAC®

Hoechst Marion Roussel

Chloramphenicol – Hydrocortisone Acetate – Butoxyethylnicotinate – Allantoin – Precipitated Sulfur

Acne Therapy

Action And Clinical Pharmacology: The roles of the individual ingredients in Actinac and their collective mechanisms of action in the topical treatment of acne have not been elucidated. Hydrocortisone, chloramphenicol and precipitated sulfur are however, widely recognized for their respective anti-inflammatory, antibacterial and desquamating properties.

Chloramphenicol is usually bacteriostatic in action, but may be bactericidal in high concentrations or against highly susceptible organisms. Chloramphenicol acts by inhibiting the protein synthesis in susceptible organisms by binding reversibly to the 50S ribosomal subunits, thus preventing successful attachment of complete transfer RNA to the ribosome and consequently disrupting peptide bound formation and protein synthesis.

Following topical application, corticosteroids produce anti-inflammatory, antipruritic and vasoconstrictor actions. The activity of the drugs is thought to result at least in part from binding with a steroid receptor. Corticosteroids decrease inflammation by stabilizing leukocyte lysosomal membranes, preventing release of destructive acid hydrolases from leukocytes; inhibiting macrophage accumulation in inflamed areas; reducing leukocyte adhesion to capillary endothelium; reducing capillary wall permeability and edema formation; decreasing complement components; antagonizing histamine activity and release of kinine from substrates; reducing fibroblast proliferation, collagen deposition, and subsequent scar tissue formation; and possibly by other mechanisms as yet unknown.

At a concentration greater than 5%, as contained in Actinac, sulfur exerts a keratolytic effect. Although the mechanism of sulfur’s keratolytic action has not been determined, it may depend on formation of hydrogen sulfide when the drug comes in contact with skin. Topically applied sulfur has mild antifungal and antibacterial activity. It has been suggested that when applied topically to the skin, sulfur forms hydrogen sulfide and/or polythionic acid, which may exert germicidal activity. In vitro sulfur has also been shown to have some antibacterial activity. The exact mechanism(s) of action of sulfur in the treatment of acne is not fully understood but is presumed to involve the drug’s keratolytic and antibacterial effects.

Allantoin assists in the healing of damaged epithelium, by fibrinolysis of damaged tissue, stimulation of cell granulation and keratolytic activity.

Butoxyethylnicotinate, an ester of nicotinic acid, produces a rapid vasodilatation of moderate intensity and duration and increases local blood flow allowing the active ingredients to diffuse into the affected tissue.

Indications And Clinical Uses: For the topical treatment of acne vulgaris where treatment with chloramphenicol and a steroid is considered appropriate. The use of Actinac has been associated with a reduction in papules, pustules and the accompanying inflammation and erythema. Its efficacy in treating the comedone and cyst components of acne has not been established. Actinac should be restricted to conditions where safer agents are considered inappropriate.

Cases of significant blood dyscrasias or aplastic anemia have been reported with the oral, parenteral and ophthalmic use of chloramphenicol. Although this has not been reported following the topical use of Actinac, the possibility of such serious adverse reactions should always be considered when prescribing Actinac. Hematological parameters should be monitored when possible. Excessively prolonged or irregular applications should be avoided.

Contra-Indications: Patients who have demonstrated sensitivity to any one of its constituents. It is also contraindicated in the presence of tuberculosis of the skin, viral infections including herpes simplex, vaccinia or varicella and superficial fungal or yeast infections. Actinac should not be used in patients with a history of, or presenting with, hematological abnormalities or disorders.

Manufacturers’ Warnings In Clinical States: Bone marrow hypoplasia, including agranulocytosis and aplastic anemia have been reported following the use of chloramphenicol. Chloramphenicol-related agranulocytosis and aplastic anemia have been associated in the vast majority of cases with oral, and rarely with parenteral and ophthalmic administrations. Topicals applied to intact skin have not been implicated. Irreversible bone marrow depression leading to aplastic anemia is not considered dose-related. Aplastic anemia with associated pancytopenia is reported to develop in the first 1 or 2 weeks of therapy but in some patients, aplasia reportedly becomes evident weeks to months after chloramphenicol therapy. The incidence of this adverse reaction was initially estimated to be 1/25 000 to 1/40 000 courses of oral therapy which was said to be approximately 13 times the background incidence in the general population. These figures are considered by some to significantly overestimate risk. The precise mechanism of aplastic anemia is unknown, but toxic chloramphenicol metabolites have been suspected of local marrow suppression in enzyme deficient individuals. Though very little chloramphenicol is absorbed through skin after topical Actinac applications in acne, compared to the use of oral, parenteral and ophthalmic preparations, the possibility of serious adverse reactions should always be considered in patients receiving any form of chloramphenicol, including topicals. Excessively prolonged or irregular applications should be avoided.

Pharmacokinetic studies conducted in healthy volunteers and in patients with acne lesions have shown minimal absorption of chloramphenicol (total absorbed is less than 1% of total dose on average) following repeated applications of Actinac. However, the possibility that the keratolytic agents and the vasodilating effects of butoxyethylnicotinate in this preparation may promote the systemic absorption of chloramphenicol and hydrocortisone, should be considered.

Precautions: Keep away from the eyes and mouth. Discontinue use temporarily if excessive drying, irritation, or scaling occurs. Sensitization and irritation to chloramphenicol and corticosteroids may result from topical application of the drugs. If these occur, the preparation should be discontinued. Application of corticosteroids to extensive areas, too frequent application, or application under occlusive dressings may result in systemic absorption with symptoms of adrenal suppression, or in localized epidermal and dermal atrophy. If secondary bacterial infection exists, other appropriate means of antibacterial therapy may also be initiated. However, if overgrowth develops, medication with Actinac should be discontinued.

Interim assessments of the patient’s progress should be made at not less than 2-week intervals. It is recommended that treatment should be discontinued after maximum benefit has been obtained and reinstituted only when the patient’s condition starts to reoccur. Should no significant improvement in the patient’s condition be seen within 4 to 6 weeks, treatment should be discontinued.

Children: Prolonged percutaneous absorption of the corticosteroid can produce systemic effects such as adrenal suppression, moon facies and suppression of growth in children. Actinac is, however, not intended for pediatric use.

Pregnancy: Safety for use of Actinac in pregnancy has not been established. Topical corticosteroids and chloramphenicol should be used during pregnancy only if therapeutic benefit outweighs the risk to the fetus. Studies in animals have shown that topical corticosteroids are systemically absorbed and may cause teratogenic effects especially when used in large amounts, for prolonged periods of time or if the more potent agents are used. Chloramphenicol readily crosses the placenta.

Lactation: Safety for use of Actinac in lactation has not been established. The use of Actinac is not recommended in nursing mothers. It is not known whether topical corticosteroids are distributed into milk; however, systemically administered corticosteroids are excreted in breast milk. Chloramphenicol is excreted in breast milk.

Patients with Special Diseases and Conditions: Topical corticosteroids should not be used in patients with markedly impaired circulation since skin ulceration has occurred in these patients following use of the drug.

Corticosteroid-containing preparations should be used with caution in patients with impaired T cell function or in those receiving other immunosuppressive therapy. The immunosuppressive effects of corticosteroids may be associated with impairment of the normal function of T cells and macrophages; such impairment may result in activation of latent infection or exacerbations of intercurrent infections.

As for other products containing chloramphenicol, Actinac should not be utilized in patients with abnormal hematology or history of hematopoietic disorders. Actinac should not be administered concomitantly with drugs or chemicals capable of inducing hematopoietic abnormalities (see Contraindications).

Chloramphenicol is metabolized by the liver and excreted largely by the kidney, and therefore ought only be administered with caution to patients with liver or renal impairment, or to patients taking drugs dependent upon liver for their metabolism. The potential for additive and synergistic effects should be kept in mind.

Information for the Patient: Patients should be instructed to use Actinac only as directed by the physician, only for the disorder for which it was prescribed, and for no longer than the time period prescribed. They should also be instructed how to recognize signs of bone marrow depression (unusual fever, fatigue, sore throat and mouth sores) and to immediately report these to their physician. Patients should be instructed that the treated areas of skin should not be bandaged or otherwise covered or wrapped as to be occlusive.

Adverse Reactions: Reported adverse reactions to Actinac lotion include: excessive drying of the skin, erythema, contact dermatitis, eye irritation, a burning sensation and facial flushing. Drying of the skin and erythema have also been noted following use of a vehicle control from which hydrocortisone and chloramphenicol were omitted.

Following topical administration of chloramphenicol preparations, signs of local irritation with subjective symptoms of itching or burning, angioneurotic edema, urticaria, vesicular and maculopapular dermatitis have been reported in patients sensitive to chloramphenicol and are cause for discontinuing the medication (see Warnings).

Chloramphenicol has been reported to cause two forms of hematopoietic failure following oral, parenteral and ophthalmic administrations. This has however not been reported following topical use of Actinac for acne, where only comparatively minimal absorption of chloramphenicol occurs, or with other topicals containing the antibiotic when administered to non-traumatized skin. Agranulocytosis is considered to be dose-related (>25 µg/mL plasma concentration), generally reversible and rarely lethal. Aplastic anemia is considered idiosyncratic, non dose-related and possibly caused by toxic chloramphenicol metabolites in enzyme deficient subjects. It may occur weeks to months after completion of therapy, and can be progressive and very often lethal.

Potential interactions with chloramphenicol include drugs that rely upon the liver for their metabolism as well as drugs, chemicals, diseases or procedures that inhibit hematopoiesis.

Topical corticosteroids may cause atrophy of the epidermis, s.c. tissue, and dermal collagen, and drying and cracking or tightening of the skin. Epidermal thinning, telangiectasia, increased fragility of cutaneous blood vessels, purpura, and atrophic striae may also occur. Other adverse dermatologic effects of topical corticosteroids include acneiform eruption, vesiculation, irritation, pruritus, hypertrichosis, rosacea-like eruptions of the face, erythema, hyperesthesia, perioral dermatitis, burning or stinging sensation, folliculitis and hypopigmentation. Adverse dermatologic effects of topical corticosteroids usually improve when the drug is discontinued but may persist for long periods. Atrophic striae may be permanent. The anti-inflammatory activity of corticosteroids can also mask the manifestations of infections. Predictable adverse reactions to topical corticosteroids are directly related to prolonged use, application on highly absorptive areas (such as face and neck), skin condition and use of occlusive dressings. The frequency of their occurrence is however less with hydrocortisone than with the fluorinated steroids and has not been reported with Actinac.

Topically applied sulfur may cause local irritation of the skin, eyes or respiratory tract. Allergic reactions to sulfur occur rarely. Repeated applications may cause dermatitis.

Systemic toxicity (e.g., headache, vomiting, muscle cramps, dizziness, collapse) has reportedly occurred following topical application of precipitated sulfur to patients with eczema but symptoms resolved within several hours.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In case of accidental ingestion of Actinac lotion, the amount swallowed would be expected to be small. The chloramphenicol content of a whole bottle is 200 mg. Oral chloramphenicol is usually administered as 50 mg/kg/day in divided doses. Hence, in the case of accidental ingestion of Actinac lotion, the chloramphenicol content ingested is well below the minimum content of the usual oral therapeutic dose. Symptoms would probably consist of mild gastrointestinal disturbances. In the event of a severe reaction, emergency treatment consists of general measures such as induction of emesis, gastric lavage, catharsis and forcing of fluids.

Dosage And Administration: Should be applied twice daily in the morning and at bedtime, for the first 4 days and once daily at bedtime thereafter, to the areas affected by acne. Before application these areas should be washed with mild soap, well rinsed and dried. The reconstituted Actinac lotion should be applied with cotton wool or gauze. Duration of treatment: for 4 to 6 weeks or as instructed by treating physician.

Availability And Storage: Each g of powder contains: chloramphenicol BP 40 mg, hydrocortisone acetate BP 40 mg, 2-butoxyethylnicotinate 24 mg, allantoin 24 mg and precipitated sulfur BPC 320 mg. Nonmedicinal ingredients: myrj 53, powdered tragacanth, purified td talc, syloid 244 and titanium dioxide. The vehicle is composed by lavender water soluble and, as a preservative, benzoic acid BP 0.1%, in purified water BP. Concentrations of the active ingredients in the reconstituted suspension are chloramphenicol 0.97%, hydrocortisone acetate 0.97%, 2-butoxyethylnicotinate 0.58%, allantoin 0.58%, sulfur 7.78%. Single pack of 2 bottles each containing 5 g of powder and 2 bottles each containing 16 mL of aqueous vehicle. Store at room temperature, below 25°C. Excessive heat should be avoided.

The lotion is prepared by emptying the contents of 1 bottle of aqueous vehicle (white cap) into 1 bottle of powder (black cap). The cap should then be replaced securely and the bottle shaken until the 2 ingredients are thoroughly mixed. The lotion remains stable at room temperature for 21 days.

ACTINAC® Hoechst Marion Roussel Chloramphenicol – Hydrocortisone Acetate – Butoxyethylnicotinate – Allantoin – Precipitated Sulfur Acne Therapy

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Acne

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