Tacroz/Tacroz Forte

Tacroz/Tacroz Forte

tacrolimus

Manufacturer:

Glenmark

Distributor:

SB Pharma
Full Prescribing Info
Contents
Tacrolimus.
Description
Tacroz: Tacrolimus USP 0.03% w/w; Ointment base q.s.
Tacroz Forte: Tacrolimus USP 0.1% w/w; Ointment base q.s.
Excipients/Inactive Ingredients: White soft paraffin, Liquid paraffin, White beeswax, Hard paraffin, Propylene carbonate.
Action
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ.
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w does not affect collagen synthesis in humans.
Pharmacokinetics: Tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.
Absorption: There is little or no systemic exposure to tacrolimus following single or repeated topical application of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w.
Most atopic dermatitis patients (adults and children) treated with single or repeated application of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w, and infants from age of 5 months treated with Tacrolimus Ointment 0.03% w/w had blood concentrations <1.0 ng/ml. When observed, blood concentrations exceeding 1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w.
Distribution: As systemic exposure is low with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.
Metabolism: Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.
Elimination: When administered intravenously, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-treated with drugs that are potent inhibitors of CYP3A4.
Following repeated topical application of the ointment, the average half-life of tacrolimus was estimated to be 75 hours for adults and 65 hours for children.
Paediatric population: The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation (see as previously mentioned).
Indications/Uses
Tacroz: Tacrolimus Ointment 0.03% w/w is indicated in adults, adolescents and children from the age of 2 years.
Atopic Dermatitis flare treatment: Adults and adolescents (16 years of age and above): Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.
Children (2 years of age and above): Treatment of moderate to severe atopic dermatitis in children who failed to respond adequately to conventional therapies such as topical corticosteroids.
Maintenance treatment: Treatment of moderate to severe atopic dermatitis for the prevention of atopic dermatitis flares and the prolongation of atopic dermatitis flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).
Tacroz Forte: Tacrolimus Ointment 0.1% w/w is indicated in adults and adolescents (16 years of age and above).
Atopic Dermatitis flare treatment: Adults and adolescents (16 years of age and above): Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.
Maintenance treatment: Treatment of moderate to severe atopic dermatitis for the prevention of atopic dermatitis flares and the prolongation of atopic dermatitis flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).
Dosage/Direction for Use
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.
Posology: Atopic Dermatitis flare treatment: Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w can be used for short-term and intermittent long-term treatment. Treatment should not be continuous on a long-term basis.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w treatment should begin at the first appearance of signs and symptoms. Each affected region of the skin should be treated with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w until lesions are cleared, almost cleared or mildly affected. Thereafter, patients are considered suitable for maintenance treatment (see Maintenance treatment as follows). At the first signs of recurrence (atopic dermatitis flares) of the disease symptoms, treatment should be reinitiated.
Adults and adolescents (16 years of age and above): Treatment should be started with Tacrolimus Ointment 0.1% w/w twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Tacrolimus Ointment 0.1% w/w should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Tacrolimus Ointment 0.03% w/w if the clinical condition allows.
Generally, improvement is seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, further treatment options should be considered.
Elderly patients: Specific studies have not been conducted in elderly patients. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.
Paediatric population: Children (2 years of age and above) should use the lower strength Tacrolimus Ointment 0.03% w/w.
Treatment should be started twice a day for up to three weeks. Afterwards, the frequency of application should be reduced to once a day until clearance of the lesion.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be used in children aged below 2 years until further data are available.
Maintenance treatment: Patients who are responding to up to 6 weeks treatment using Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w twice daily (lesions cleared, almost cleared or mildly affected) are suitable for maintenance treatment.
Adults and adolescents (16 years of age and above): Adult patients should use Tacrolimus Ointment 0.1% w/w.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to atopic dermatitis flares. Between applications, there should be 2-3 days without Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w treatment.
After 12 months treatment, a review of the patient's condition should be conducted by the physician and a decision taken whether to continue maintenance treatment in the absence of safety data for maintenance treatment beyond 12 months.
If signs of an atopic dermatitis flare reoccur, twice daily treatment should be reinitiated (see Atopic Dermatitis flare treatment as previously mentioned).
Elderly patients: Specific studies have not been conducted in elderly patients (see Atopic Dermatitis flare treatment as previously mentioned).
Paediatric population: Children (2 years of age and above) should use the lower strength Tacrolimus Ointment 0.03% w/w.
Tacrolimus Ointment 0.03% w/w should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected by atopic dermatitis to prevent progression to atopic dermatitis flares. Between applications, there should be 2-3 days without Tacrolimus Ointment 0.03% w/w treatment.
The review of the child's condition after 12 months treatment should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be used in children aged below 2 years until further data are available.
Method of administration: Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should be applied as a thin layer to affected or commonly affected areas of the skin. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be applied under occlusion because this method of administration has not been studied in patients.
Overdosage
Overdosage following topical administration is unlikely.
If ingested, general supportive measures may be appropriate. These may include monitoring of vital signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of vomiting or gastric lavage is not recommended.
Contraindications
Hypersensitivity to the active substance, macrolides in general, or to any of the excipients.
Special Precautions
Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided during use of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w. Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be applied to lesions that are considered to be potentially malignant or pre-malignant.
The development of any new change different from previous eczema within a treated area should be reviewed by the physician.
The use of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w is not recommended in patients with a skin barrier defect, such as Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft-Versus-Host Disease. These skin conditions may increase systemic absorption of tacrolimus. Oral use of tacrolimus is also not recommended to treat these skin conditions. Post-marketing cases of increased tacrolimus blood level have been reported in these conditions.
Care should be exercised if applying Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w to patients with extensive skin involvement over an extended period of time, especially in children. Patients, particularly paediatric patients, should be continuously evaluated during treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w with respect to the response to treatment and the continuing need for treatment. After 12 months, this evaluation should include suspension of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w treatment in paediatric patients.
The potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) in the long-term (i.e. over a period of years) is unknown.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies. In patients using tacrolimus ointment, cases of malignancies, including cutaneous (i.e. cutaneous T cell lymphomas) and other types of lymphoma, and skin cancers have been reported. Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.
Patients with atopic dermatitis treated with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w have not been found to have significant systemic tacrolimus levels.
Lymphadenopathy is uncommonly (0.8%) reported. The majority of these cases were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic therapy. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at increased risk for developing lymphoma; therefore, patients who receive Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w and who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should be considered.
The effect of treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w on the developing immune system of children aged below 2 years has not been established.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Before commencing treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w, clinical infections at treatment sites should be cleared. Patients with atopic dermatitis are predisposed to superficial skin infections. Treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w may be associated with an increased risk of folliculitis and herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi's varicelliform eruption). In the presence of these infections, the balance of risks and benefits associated with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w use should be evaluated.
Emollients should not be applied to the same area within 2 hours of applying Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w. Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.
Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.
The use of Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w under occlusion has not been studied in patients. Occlusive dressings are not recommended.
As with any topical medicinal product, patients should wash their hands after application if the hands are not intended for treatment.
Tacrolimus is extensively metabolised in the liver and although blood concentrations are low following topical therapy, the ointment should be used with caution in patients with hepatic failure.
Effects on ability to drive and use machines: Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w is administered topically and is unlikely to have an effect on the ability to drive or use machines.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data from the use of tacrolimus ointment in pregnant women. Animal studies have shown reproductive toxicity following systemic administration. The potential risk for humans is unknown.
Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w should not be used during pregnancy unless clearly necessary.
Breastfeeding: Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk. Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breastfeeding during treatment with Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w is not recommended.
Adverse Reactions
Adverse reactions with suspected relationship to treatment are listed as follows by system organ class. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

Post-marketing: Cases of malignancies, including cutaneous (i.e. cutaneous T cell lymphomas) and other types of lymphoma, and skin cancers have been reported in patients using Tacrolimus Ointment 0.03% w/w / Tacrolimus Ointment 0.1% w/w.
Paediatric population: Frequency, type and severity of adverse reactions in children are similar to those reported in adults.
Drug Interactions
Formal topical drug interaction studies with tacrolimus ointment have not been conducted.
Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.
Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4). Systemic exposure from topical application of tacrolimus ointment is low (<1.0 ng/ml) and is unlikely to be affected by concomitant use of substances known to be inhibitors of CYP3A4.
However, the possibility of interactions cannot be ruled out and the concomitant systemic administration of known CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.
Caution For Usage
Special precautions for disposal and other handling: No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store below 30°C. Do not freeze.
MIMS Class
Other Dermatologicals
ATC Classification
D11AH01 - tacrolimus ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.
Presentation/Packing
Form
Tacroz Forte oint 0.1% w/w
Packing/Price
10 g x 1's
Form
Tacroz oint 0.03% w/w
Packing/Price
10 g x 1's
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