Tacrolimus - Dosage, Uses, Limitations, and Side Effects

Overview:

Tacrolimus is an immunosuppressive drug. It works by reducing the activity of the individual's immune system after organ transplantation, thus decreasing the risk of organ rejection. It is also used as a topical ointment in treating atopic dermatitis, refractory uveitis after bone marrow transplants, and vitiligo. It was discovered in 1984. It is a macrolide. It reduces the activity of peptidyl-prolyl isomerase by attaching to the immunophilin FKBP-12 (FK506 binding proteins), creating a new complex. This FKBP12-FK506 complex impairs calcineurin which inhibits the transduction of T-lymphocyte and IL-2 transcription.

How Does Tacrolimus Work?

The mode of action of Tacrolimus in atopic dermatitis is unknown. It has been found that Tacrolimus inhibits the activation of T-lymphocytes by binding to FKBP-12, an intracellular protein. Tacrolimus-FKBP-12 forms a complex with calmodulin, calcium, and calcineurin, inhibiting the phosphatase activity of calcineurin, thus preventing the translocation and dephosphorylation of the nuclear factor of activated T-cells, which is thought to start the transcription of genes for the formation of lymphokines. Tacrolimus impairs the transcription of genes responsible for encoding the factors involved in the activation of T-cells like GM-CSF, IL-3, IL-4, IL-5, and TNF. Tacrolimus has also been found to impair the release of mediators from the mast cells and basophils of the skin and to decrease the expression of FceRI on Langerhans cells.

What Are the Uses of Tacrolimus?

Topical Tacrolimus ointment has the following uses:

• For the treatment of short-term moderate-to-severe atopic dermatitis in non-immunocompromised adults and kids who did not respond well to other topical treatments or for whom other treatments are not advised.

Immediate-release Tacrolimus is indicated for the following:

• To inhibit organ rejection in adult and pediatric patients receiving transplants in combination with other immunosuppressants.

Extended-release Tacrolimus is indicated for:

• To inhibit organ rejection in adult and pediatric patients receiving kidney transplants and other immunosuppressants.

What Are the Limitations of Tacrolimus?

Tacrolimus should not be used in kids younger than two years of age.

Dosage Restrictions:

1. Route of Administration- Topical application.

2. Dosage Strengths:

• 0.03 %.

• 0.1 %.

3. Dosage Forms

• Ointment.

Special Considerations:

• Pregnancy - There are not enough studies on the use of Tacrolimus in pregnant women. The data on Tacrolimus ointment used by pregnant women is too small to identify its safety during pregnancy. The administration of Tacrolimus during pregnancy has been associated with renal dysfunction and neonatal hyperkalemia. Tacrolimus ointment should be used in pregnancy only if the benefit to the mother justifies more than the risk to the fetus.

• Breastfeeding Mothers - Tacrolimus is excreted in human milk. There is a potential for developing adverse reactions in infants from Tacrolimus.

• Pediatric Use - Tacrolimus ointment should not be used in kids younger than two years. Only 0.03 % of the ointment is recommended for treating moderate to severe atopic dermatitis in non-immunocompromised kids between the age group of two to 15 years who did not respond to other treatments for atopic dermatitis, or other treatments are not advisable.

• Geriatric Use - The side effects of the drug were similar to that of adult individuals.

Warnings and Contraindications:

• A small population of individuals who used Tacrolimus ointment or other similar medicine has been found to develop skin cancer or lymphoma (cancer in a part of the immune system). However, insufficient information is available to suggest whether Tacrolimus ointment caused cancer. More studies are needed to understand this risk.

• Tacrolimus ointment is contraindicated in individuals with a hypersensitivity to the drug or any other component of the drug.

What Are the Drug Warnings and Precautions?

• General: Tacrolimus ointment should be avoided on skin with pre-malignant and malignant lesions. Certain malignant skin conditions, such as cutaneous T-cell lymphoma, might resemble atopic dermatitis. The use of Tacrolimus ointment is not advisable in individuals with skin problems in which there are chances of systemic absorption of the drug, such as in Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous graft versus host disease. Oral application is also not advisable. Tacrolimus ointment may cause a burning sensation and itching of the skin. Ointment application should be avoided on malignant skin conditions, such as cutaneous T-cell lymphoma.

• Bacterial and Viral Skin Infections: Individuals with atopic dermatitis have skin infections like eczema, treatment with the ointment can be associated with an increased risk of herpes simplex virus infection, varicella-zoster virus infection, or eczema herpeticum. The bacterial or viral skin infections should be resolved before starting with the ointment. The safety of Tacrolimus ointment in treating infected atopic dermatitis has yet to be evaluated.

• Patients with Lymphadenopathy: Lymphadenopathy patients related to skin infections have been found to resolve with antibiotics. Patients with organ transplants receiving immunosuppressive drugs (systemic Tacrolimus) are at an increased risk of developing lymphoma. Such patients should get investigated for their cause of lymphadenopathy. The ointment should not be used in the absence of a cause for lymphadenopathy or during acute infectious mononucleosis.

• Sun Exposure: During the treatment with the drug, individuals should reduce or avoid sun exposure. It is unknown whether the drug interferes with the response of the skin to ultraviolet damage from the sun.

• Immunocompromised Patients: The safety of the ointment has yet to be extensively studied in immunocompromised individuals.

• Renal Insufficiency: Rare cases of acute renal failure have been found in individuals treated with Tacrolimus ointment. Systemic absorption is likely to occur in individuals with skin defects.

For Patients

What Is Atopic Dermatitis?

Atopic dermatitis is also known as eczema. It is a skin condition that causes itchy, dry, and inflamed skin. It commonly occurs in young kids but can occur in any age group. Atopic dermatitis is a chronic condition that tends to flare up due to certain triggers. It is not a contagious disease.

Why Is Tacrolimus Prescribed for Moderate To Severe Atopic Dermatitis?

Tacrolimus ointment is used to treat atopic dermatitis or eczema. Atopic dermatitis is a skin condition that makes the skin dry and itchy with reddish, scaly rashes. It is also used in individuals who did not respond well to the other medications for dermatitis or who cannot use other medications for their condition. Tacrolimus belongs to a group of medications known as topical calcineurin inhibitors. They inhibit the immune system from producing certain chemicals, causing eczema.

How Should One Take Tacrolimus?

Tacrolimus ointment is used for external application on the skin. It is applied twice daily on the affected area at the same time daily. Tacrolimus should be used exactly as prescribed and not be used less or more.

Application ways of the ointment are as follows:

• Wash the hands thoroughly with soap and water.

• Before application, the skin in the affected area should be dry.

• Apply a very thin layer of the ointment to the affected areas of the skin.

• Gently rub the ointment into the skin.

• To remove any leftover ointment, wash the hands with soap and water.

• Cover the treated areas with normal cotton clothing, no bandages or dressings.

• Do not wash the ointment from the affected areas of the skin. Ensure not to shower, swim, or bathe immediately after applying the ointment.

What Should One Discuss With the Doctor Before Beginning Tacrolimus?

• The physician should be informed in case of any allergy to Tacrolimus or other medicines.

• Inform the physician about the non-prescription and prescription medicines, supplements, vitamins, and herbal products that one is taking. Do not forget to mention if one is taking any of these antifungals like: Fluconazole, Ketoconazole, and Itraconazole; calcium channel blockers like Diltiazem and Verapamil; Cimetidine; Erythromycin; and other creams, ointments, or lotions. The doses of the medicines can be changed accordingly.

• Inform the physician in case of a skin infection, Netherton's syndrome (an inherited condition with red, itchy, and scaly skin), kidney disease, skin redness and peeling, any type of skin infection such as shingles (skin infection in individuals with a history of chickenpox), chicken pox, cold sores, or eczema herpeticum (a viral infection with fluid-filled blisters on the skin of people with eczema). Inform the doctor if the eczematous rash has become crusty, blistered, or infected.

• Inform the physician if one is pregnant, planning to become pregnant, or breastfeeding. If one becomes pregnant while using the ointment, it is better to inform the doctor.

• In case of any surgery, including dental surgery, inform the doctor or dentist about the ointment usage.

• Alcoholic beverages should be consumed only after the doctor's approval as the skin or face may become reddish, and one might feel hot if one drinks alcohol during the treatment.

• If one gets exposed to one of the other viruses while using Tacrolimus ointment, the doctor should be informed soon.

• A good skincare regime and moisturizers help relieve dry skin caused by eczema. Take the doctor's advice about the moisturizers one should use and apply those after applying the ointment.

Is Tacrolimus Safe?

The efficacy and safety of using Tacrolimus ointment for a longer period are unknown.

Is Tacrolimus Effective?

Yes, Tacrolimus is effective in treating atopic dermatitis.

What Side Effects Can You Expect With Tacrolimus?

• Tingling skin.

• Skin burning, stinging, redness, or soreness.

• Increased skin sensitivity to hot or cold temperatures

• Skin itching.

• Swollen or infected hair follicles.

• Acne.

• Headache.

• Stuffed or runny nose.

• Muscle or back pain.

• Flu-like symptoms.

• Nausea.

Serious side effects include the following:

• Cold sores.

• Swollen glands.

• Rashes.

• Crusting, blistering, oozing, or other signs of skin infection.

• Chickenpox or other blisters.

• Swelling of the hands, arms, feet, ankles, or lower legs.

Can You Stop Taking Tacrolimus Without Your Doctor's Approval?

The medicine application should only be stopped with the doctor's approval.

Are There Any Dietary Restrictions to Consider When Taking Tacrolimus?

Take the doctor's advice on eating grapes or grapefruit juice.

How Should One Store Tacrolimus?

The medication should be kept in a tightly closed container and out of children's reach. It should be stored at room temperature and away from moisture and heat.

How Should One Dispose of Tacrolimus?

Unused medications should be disposed of so that pets, kids, and other people cannot use them. The medicine should not be thrown into the toilet. The best way to dispose of the medicine is through a medicine take-back program.

What To Do in Case of Overdose?

In case of an overdose, the poison control team should be informed. Emergency services should be immediately contacted if the individual has a seizure, collapses, has trouble breathing, or cannot be awakened.

For Doctors

Indications-

Tacrolimus ointment is available in both 0.1 % and 0.03 % for adults and only 0.03 % for children aged between two to 15 years. It is indicated as second-line therapy for the non-continuous, short-term treatment of moderate to severe atopic dermatitis in non-immunocompromised individuals who have either failed to respond to other treatments for eczema or atopic dermatitis or other treatments are not advisable.

Pharmacology of Tacrolimus-

Description- Tacrolimus ointment contains Tacrolimus, an immunosuppressant synthesized by Streptomyces tsukubensis. It is for external usage only. Chemically, Tacrolimus is [3S-[3R[E(1S,3S,4S)],4S,5R,8S,9E,12R,14R,15S,16R,18S,19S,26aR]]­ 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy3-[2-(4-hydroxy-3-methoxy cyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10, 12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. The formula of Tacrolimus is C44H69NO12.H2O and has a molecular weight of 822.03.

Components-

1. Active Ingredients-

• Tacrolimus.

2. Inactive Ingredients-

• Mineral oil.

• Paraffin.

• Propylene carbonate.

• White petrolatum.

• White wax.

Clinical Pharmacology-

1. Mechanism of Action- The mode of action of Tacrolimus in atopic dermatitis is unknown. It has been found that Tacrolimus inhibits the activation of T-lymphocytes by first binding to FKBP-12, an intracellular protein. Then a complex of Tacrolimus-FKBP-12, calcineurin, calcium, and calmodulin is formed, and calcineurin's phosphatase activity is prevented. This effect impairs the translocation and dephosphorylation of the nuclear factor of activated T-cells, which is thought to start gene transcription for the formation of lymphokines like interleukin-2 and gamma interferon. Tacrolimus is also found to inhibit the transcription for genes encoding IL-3, IL-4, IL-5, GM-CSF, and TNF alpha. Tacrolimus has also been found to prevent the release of pre-formed mediators from mast cells and basophils of the skin and to reduce the expression of FceRI on Langerhans cells.

2. Pharmacokinetics-

A. Distribution: Tacrolimus's plasma protein binding capacity is around 99 % and does not depend on the 5 to 50 ng/mL concentration range. Tacrolimus is mainly bound to alpha-1-acid glycoprotein and albumin and collaborates with the erythrocytes. The distribution of Tacrolimus depends on several factors, such as temperature at the time of plasma separation, the concentration of the drug, plasma protein concentration, and hematocrit. The ratio of whole blood concentration to plasma concentration is 35 (ranges from 12 to 67).

B. Metabolism: Tacrolimus is metabolized by the cytochrome P-450 (CYP3A), the mixed-function oxidase system (CYP3A). Demethylation and hydroxylation have been identified as the primary mechanisms of the biotransformation of Tacrolimus. The major metabolite identified is 13-dimethyl Tacrolimus.

C. Excretion: The mean clearance after an intravenous administration of Tacrolimus is 0.040, 0.083, and 0.053 L/hr/kg in healthy individuals, people with kidney transplants, and adult liver transplant patients, respectively.

Recovery of Tacrolimus:

• Urine - Less than one percent is excreted in the urine.

• Feces - 92.4 +/- 1.0 %

Special Considerations:

• Pediatric Use - Tacrolimus ointment should not be used in kids younger than two years. Only 0.03 % of the ointment is recommended for treating moderate to severe atopic dermatitis in non-immunocompromised kids between the ages of two to 15 years who did not respond to other treatments for atopic dermatitis, or other treatments are not advisable.

• Pregnancy - There are no sufficient studies on the topical application of Tacrolimus in pregnant women. The data on Tacrolimus ointment used by pregnant women is too small to identify its safety during pregnancy. The systemic administration of Tacrolimus during pregnancy has been associated with renal dysfunction and neonatal hyperkalemia. Tacrolimus ointment should be used in pregnancy only if the benefit to the mother accounts for more than the risk to the fetus.

• Breastfeeding Mothers - The systemic absorption of Tacrolimus after topical applications are minimal compared to systemic administration. Tacrolimus is excreted in human milk. There is a potential for developing adverse reactions in infants from Tacrolimus.

• Geriatric Use - The side effects of the drug have been found to be the same as that of adult individuals.

Drug Interactions-

• Abametapir - The serum concentration of Tacrolimus is increased when combined with Abametapir.

• Acarbose - The therapeutic efficiency of Acarbose is reduced and decreased in combination with Tacrolimus.

• Beclomethasone Dipropionate - Tacrolimus increases the immunosuppressive activities of Beclomethasone dipropionate.

• Bendroflumethiazide - The risk of neutropenia and thrombocytopenia can be increased when Tacrolimus is combined with Bendroflumethiazide.

Clinical Trials-

Three randomized, double-blind, multi-center, vehicle-controlled, phase three studies have been conducted to assess the treatment of patients with moderate to severe atopic dermatitis with Tacrolimus. In these studies, for 12 weeks, the patients applied either 0.03 %, 0.1 %, or vehicle ointment twice daily to 10 % to 100 % of their body surface area. A pediatric study included 351 patients of two to fifteen years of age and the other two with 632 adults aged between 15 and 79. Fifty-five percent of the patients were women, and 27 % were black. Around 58 % of the patients had severe disease, and the mean body surface area affected was 46 %. Over 80 % of the patients had eczema or atopic dermatitis.

Results-

In the pediatric study, a good amount of patients achieved at least 90 % improvement with 0.03 % Tacrolimus ointment group compared to the vehicle group. In both adult studies, a greater percentage of individuals achieved at least 90 % improvement based on the assessment of clinical response in 0.03 % and 0.1 % Tacrolimus ointment treatment groups compared to the vehicle group. Tacrolimus ointment of 0.1% has been proven more effective than 0.03 % ointment. In both the treatment groups involving Tacrolimus ointment 0.03 %, a greater improvement compared to the vehicle was found in the secondary efficacy endpoints of body surface area involvement percentage, patient evaluation of itching, erythema, excoriation, edema, oozing, lichenification, and scaling.

Patient Counseling Information-

Administration Instructions:

• Tacrolimus ointment comes in two strengths, 0.03 % is for kids aged two to 15 years, and either 0.1 % or 0.03 % is used by adults and kids 16 years and above.

• Use Tacrolimus ointment sparingly for a long time.

• Apply a thin layer of the ointment only on the eczematous areas of the skin.

• Do not use Tacrolimus ointment on children under two years.

• Use Tacrolimus ointment as prescribed by the doctor.

• Use Tacrolimus only on the eczematous areas of the skin.

• Use Tacrolimus ointment for shorter periods, and if required, and can be repeated after breaks.

• Follow the doctor's advice if eczema returns even after treatment.

• Avoid using ultraviolet light, sun lamps, or tanning beds during treatment with Tacrolimus.

• During treatment with Tacrolimus ointment, one should limit sun exposure even when the medicine is not applied.

• After applying the Tacrolimus ointment, wear loose-fitting cotton clothing to protect the area from sunlight.

• Avoid getting Tacrolimus ointment in the eyes or mouth.

• Do not swallow the ointment.

Complications or Side Effects:

• Burning sensation.

• Itching.

• Erythema of the skin.

• Flu-like symptoms.

• Headache.

• Seizures

• Infections.

• Neoplasms.

• Renal impairment.

• Acute renal failure in patients with or without Netherton's syndrome.

• Rosacea and application site edema.