Topgraf

Topgraf Uses, Dosage, Side Effects, Food Interaction and all others data.

Topgraf inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Topgraf prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small boweland pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such asallograft rejection, delayed type hypersensitivity, collageninduced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

Topgraf acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Topgraf has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Topgraf has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Trade Name Topgraf
Availability Prescription only
Generic Tacrolimus
Tacrolimus Other Names Tacrolimus
Related Drugs azathioprine, cyclosporine, mycophenolate mofetil, CellCept, Imuran, Prograf, Hecoria
Type Ointment
Formula C44H69NO12
Weight Average: 804.0182
Monoisotopic: 803.481976677
Protein binding

~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.

Groups Approved, Investigational
Therapeutic Class Drugs affecting the immune response
Manufacturer Glaxosmithkline
Available Country India
Last Updated: September 19, 2023 at 7:00 am
Topgraf
Topgraf

Uses

Topgraf ointment is used for short-term and intermittent long-term therapy in the treatment of patients with moderate to severe atopic dermatitis in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies. Topgraf Ointment is also used for other skin conditions such as chronic cutaneous graft-vs-host disease, hand and foot eczema, allergic contact dermatitis, psoriasis, lichen planus, facial lichen, vulvar lichen sclerosus, pyoderma gangrenosum, leg ulcers in rheumatoid arthritis, steroid-induced rosacea & alopecia areata, annular erythema, chronic actinic dermatitis and recalcitrant facial erythema.

Topgraf is a calcineurin-inhibitor immunosuppressant used for the prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants

Topgraf is also used to associated treatment for these conditions: Graft Versus Host Disease (GVHD), Heart Transplant Rejection, Kidney Transplant Rejection, Liver Transplant Rejection, Oral Lichen Planus, Psoriasis, Pyoderma Gangrenosum, Rheumatoid Arthritis, Severe Atopic Dermatitis, Vitiligo, Moderate Atopic dermatitis, Refractory Atopic dermatitis, Refractory Rheumatoid arthritis, Severe Rheumatoid arthritis

How Topgraf works

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Topgraf also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.

Dosage

Topgraf dosage

Apply a thin layer of Topgraf ointment onto the affected skin areas twice daily and rub in gently and completely. Treatment should be continued for one week after clearing of signs and symptoms of atopic dermatitis. The safety of Topgraf ointment under occlusion which may promote systemic exposure has not been evaluated. Topgraf ointment should not be used with occlusive dressings.

Usual Adult Dose for Organ Transplant- Rejection Prophylaxis

KIDNEY TRANSPLANT:

  • In combination with azathioprine: Initial dose: 0.1 mg/kg orally every 12 hours. Initiate within 24 hours of surgery, but delay until renal function has recovered.
  • In combination with mycophenolate mofetil (MMF)/interleukin-2 (IL-2) receptor antagonist: Initial dose: 0.05 mg/kg orally every 12 hours. Initiate within 24 hours of surgery, but delay until renal function has recovered.

LIVER TRANSPLANT:

  • Initial dose: 0.05 to 0.075 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery.

HEART TRANSPLANT:

  • Initial dose: 0.0375 mg/kg orally every 12 hours. Initiate no sooner than 6 hours after surgery

Usual Pediatric Dose for Organ Transplant- Rejection Reversal

LIVER TRANSPLANT:

  • Initial dose: 0.075 to 0.1 mg/kg orally every 12 hours

Topgraf ointment should be applied as a thin layer to affected or commonly affected areas of the skin. Topgraf ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Topgraf ointment should not be applied under occlusion because this method of administration has not been studied in patients.

Side Effects

Transient burning or heat sensation at the site of application is frequently observed. It tends to decrease after repeated applications. Other side-effects include skin erythema, flu-like symptoms, headache and skin infection. It does not cause skin atrophy despite prolonged application.

Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD50=134-194 mg/kg (rat).

Precaution

Cautions should be exercised while treatment with Topgraf ointment in patients with atopic dermatitis predisposed to superficial skin infections. The safety of Topgraf ointment has not been established in patients with generalized erythroderma.

Interaction

Formal topical drug interaction studies with Topgraf ointment have not been conducted. The concomitant administration of known CYP3A4 inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.

Since Topgraf is metabolized mainly by CYP3A enzymes, drugs or substances known to inhibit these enzymes may increase Topgraf whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease Topgraf whole blood concentrations. Dose adjustments may be needed along with frequent monitoring of Topgraf whole blood trough concentrations when Topgraf is administered with CYP3A inhibitors or inducers. In addition, patients should be monitored for adverse reactions including changes in renal function and QT prolongation

Food Interaction

  • Avoid alcohol. Consuming alcohol may increase the rate of tacrolimus release from extended-release formulations.
  • Avoid grapefruit products.
  • Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of tacrolimus; therefore, monitoring tacrolimus whole blood trough concentrations may be warranted.
  • Take at the same time every day.
  • Take on an empty stomach. Take at least 1 hour before or 2 hours after a meal as coadministration with food decreases the rate and extent of absorption.
  • Take separate from antacids. Coadministration of tacrolimus with aluminum or magnesium hydroxide antacids may increase the serum levels of tacrolimus, which poses a risk for toxicity.

[Moderate] ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.



MANAGEMENT: Topgraf should be administered at least one hour before or two hours after meals.



GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations.

Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.br>
MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

Topgraf Hypertension interaction

[Moderate] The use of tacrolimus has been associated with hypertension.

Therapy with tacrolimus should be administered cautiously in patients with elevated blood pressure.

Close monitoring of blood pressure is recommended.

Volume of Distribution

  • 2.6 ± 2.1 L/kg [pediatric liver transplant patients]
  • 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
  • 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
  • 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
  • 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
  • 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

Elimination Route

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Topgraf maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

Half Life

The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.

Clearance

  • 0.040 L/hr/kg [healthy subjects, IV]
  • 0.172 ± 0.088 L/hr/kg [healthy subjects, oral]
  • 0.083 L/hr/kg [adult kidney transplant patients, IV]
  • 0.053 L/hr/kg [adult liver transplant patients, IV]
  • 0.051 L/hr/kg [adult heart transplant patients, IV]
  • 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients]
  • 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]
  • 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
  • 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
  • 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
  • 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
  • 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

Elimination Route

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies of topically administered Topgraf in pregnant women. The experience with Topgraf ointment when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

Nursing Mothers: Although systemic absorption of Topgraf following topical applications of Topgraf ointment is minimal relative to systemic administration, it is known that Topgraf is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Topgraf, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Topgraf ointment is contraindicated in patients with a history of hypersensitivity to Topgraf or any other component of the preparation.

Topgraf capsules are contraindicated in patients with a hypersensitivity to Topgraf. Topgraf injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil). Hypersensitivity symptoms reported include dyspnea, rash, pruritus, and acute respiratory distress syndrome

Special Warning

Pediatric Use: The safety and efficacy of Topgraf in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Topgraf. Two randomized active-controlled trials of Topgraf in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Topgraf-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of Topgraf in living related donor liver transplantation. Pediatric patients generally required higher doses of Topgraf to maintain blood trough concentrations of Topgraf similar to adult patients.

Geriatric Use: Clinical trials of Topgraf did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in Renal Impairment: The pharmacokinetics of Topgraf in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Topgraf at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required

Use in Hepatic Impairment: The mean clearance of Topgraf was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of Topgraf trough concentrations is warranted in patients with hepatic impairment.

The use of Topgraf in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of Topgraf. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients

Acute Overdose

Topgraf ointment is not for oral use. Accidental oral ingestion of Topgraf ointment may lead to adverse effects associated with systemic administration of Topgraf. If oral ingestion occurs, medical advice should be sought.

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that Topgraf is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections).

Storage Condition

Store in a cool & dry place, protected from light.

Innovators Monograph

You find simplified version here Topgraf

Topgraf contains Tacrolimus see full prescribing information from innovator Topgraf Monograph, Topgraf MSDS, Topgraf FDA label

FAQ

What is Topgraf used for?

Topgraf ointment is used to treat the symptoms of eczema in patients who cannot use other medications for their condition or whose eczema has not responded to another medication.

What does Topgraf do to your body?

Topgraf works by suppressing the immune system to prevent the white blood cells from trying to get rid of the transplanted organ.It may also decrease the body's ability to fight infections.

What type of medication is Topgraf?

Topgraf is in a class of medications called immunosupressants. It works by decreasing the activity of the immune system to prevent it from attacking the transplanted organ.

What are the side effects of Topgraf?

Topgraf ointment may cause side effects:

  • skin burning, stinging, redness or soreness
  • tingling skin
  • increased sensitivity of the skin to hot or cold temperatures
  • itching
  • acne
  • swollen or infected hair follicles
  • headache
  • muscle or back pain
  • flu-like symptoms
  • stuffy or runny nose
  • nausea

Who should not take Topgraf?

You should not use this medicine if you are allergic to Topgraf or hydrogenated castor oil, or if you have used cyclosporine (Neoral, Sandimmune, Gengraf) within the past 24 hours.

Is Topgraf safe during pregnancy?

Use is not recommended. This drug can cause fetal harm when administered to a pregnant woman. Infants exposed in utero are at a risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress.

Is Topgraf safe during breasfeeding?

Ingestion of Topgraf by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant Topgraf levels from higher levels present at birth. Women taking Topgraf should not be discouraged from breastfeeding if monitoring of infant levels is available.

Can I drink alcohol with Topgraf?

Do not drink alcoholic beverages while taking Topgraf extended-release capsules. Alcohol may increase blood levels of Topgraf and increase the risk of serious side effects.

What foods interact with Topgraf?

Avoid excessive intake of high potassium foods (bananas, oranges, orange juice, potatoes, spinach, etc)

How long does Topgraf stay in my system?

Topgraf is approximately 12 hours (with a range of 3.5 to 40.5 hours). Only limited information is available on the pharmacokinetics of Topgraf in paediatric patients.

Does Topgraf make your hair fall out?

Topgraf tremors, hair loss, headaches and increased chance of developing diabetes.

Does Topgraf cause weight gain?

The weights of patients in both groups significantly increased after the sixth month.

When is the best time to take Topgraf?

Take it on an empty stomach in the morning, at least 1 hour before or 2 hours after a meal, at the same time every day.

Is Topgraf bad for kidneys?

It can cause side effects that can be very serious, such as kidney problems. It may also decrease the body's ability to fight infections. You and your doctor should talk about the benefits of this medicine as well as the risks of using it.

Can Topgraf cause liver damage?

The liver injury due to Topgraf is usually mild and self-limiting and responses rapidly to dose adjustment or drug discontinuation.

Can I take Topgraf for a long time?

Do not use Topgraf ointment continuously for a long time. Call your doctor if you have used Topgraf ointment for 6 weeks and your eczema symptoms have not improved, or if your symptoms get worse at any time during your treatment.

Is Topgraf safe for long-term use?

Topgraf ointment is safe and effective for long-term treatment of atopic dermatitis in children.

How safe is Topgraf?

Topgraf ointment seems to be safe and effective for moderate to severe atopic dermatitis in children and adults. It should be used with caution, though, in those having diseases with a severely damaged skin barrier. We found no risk of skin thinning with its use, even for longer periods.

Can I use Topgraf every day?

You may use Topgraf everyday but do not use Topgraf ointment continuously for a long time.

Can Topgraf be used on body?

Topgraf ointment as a thin layer to affected areas of your skin.Topgraf ointment may be used on most parts of the body, including the face and neck and in the creases of your elbows and knees. Avoid using the ointment inside your nose or mouth or in your eyes.

Is tacrolimus used for rosacea?

Topgraf ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in steroid-aggravated rosacea and perioral dermatitis.

What happens if Topgraf level is low?

Low Topgraf trough Levels (≤3.5 Ng /ml) Are A Risk Factor For Acute Rejection And Creatinine Doubling.

How fast does oral Topgraf work?

Topgraf does not work immediately. It may be up to 4 months before you notice any benefit

How fast does oral Topgraf work?

Topgraf does not work immediately. It may be up to 4 months before you notice any benefit

Does Topgraf cause insomnia?

Topgraf may causes insomnia.Other of these  commonly reported side effects include hypertension, diarrhea, hyperglycemia, anemia, headache, tremor, , pain, and asthenia.

*** Taking medicines without doctor's advice can cause long-term problems.
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