tacrolimus and Drug-Hypersensitivity

Autoimmune hepatitis (AIH) is a chronic, progressive hepatitis of uncertain cause which has fluctuating activity characterized by periods of flares and remissions. Initial placebo-controlled trials carried out in the 1970s demonstrated that immunosuppression with steroids was extremely effective in reducing flares and progression of disease. The late 1980s-1990s could be described as the 'Dark Ages' of AIH treatment research. Very few clinical studies were performed during this time, although it became increasingly apparent that not all patients tolerated or responded to traditional immunosuppression, and that not all patients were easy to diagnose because of overlapping features with other autoimmune conditions. Fortunately, clinical research in the treatment of AIH has experienced a renaissance in the 21st century.. This review highlights some of the more important recent discoveries, including the creation of the clinically useful short form of the autoimmune hepatitis diagnostic scoring system; accumulation of data supporting the use of mycophenolate and tacrolimus as second-line treatment; and the recent completion of the largest, double-blind, placebo-controlled trial of AIH treatment to date, comparing budesonide to prednisone.. These new findings are pertinent to the everyday clinical management of patients with AIH.

Topics: Azathioprine; Budesonide; Drug Hypersensitivity; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Mycophenolic Acid; Purine-Pyrimidine Metabolism, Inborn Errors; Tacrolimus

Atopic dermatitis (AD) is a common, chronic skin disorder characterized by itch and dry skin, which can develop into pruritic red plaques that ooze when scratched. AD flares often occur in anatomic areas where the skin is naturally thin (the face, neck, and intertriginous zones). Such regions, especially the face, are also areas of sensitive skin and need special consideration when being treated.. This article will briefly review the concepts of thin and sensitive skin and discuss the treatment of AD in such areas.. The MEDLINE database was searched for English-language articles published that contained the text terms atopic dermatitis, sensitive skin, treatment, topical corticosteroids, or topical calcineurin inhibitors. Articles that pertained to the safety and efficacy of various treatments were selected for further review.. Topical corticosteroids (TCSs) are effective for the treatment of AD in thin and sensitive skin areas, but their use is limited due to adverse events, such as skin thinning, and the potential for impairing the skin barrier. Topical calcineurin inhibitors (TCIs) also provide effective AD treatment without impairing the skin barrier or inducing skin thinning. Although TCIs may be associated with a higher incidence of application-site reactions such as pruritus and skin burning, these symptoms are typically transient and mild to moderate in nature.. This analysis focused primarily on relatively recent key trials evaluating the treatment of AD in sensitive skin; due to the limited number of controlled trials evaluating TCS agents, consensus statements and comprehensive review articles were used for most of the information pertaining to this therapeutic option.. Although both TCSs and TCIs have a place in a long-term, comprehensive treatment strategy for AD, TCIs may have a particular use in thin and sensitive skin areas.

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Male; Skin; Tacrolimus

In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions.. A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization.. Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences.. Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences.. Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Desensitization, Immunologic; Double-Blind Method; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus

Drug-induced hypersensitivity reactions attributed to the immunosuppressive agent tacrolimus after an organ transplant are rare in the literature. We present 3 cases of male adult patients grafted with a cadaveric liver who developed delayed hypersensitivity reactions to tacrolimus in the form of the prolonged-release capsules (Advagraf). Furthermore, the appropriate drug concentration solutions used for allergy testing are proposed.. All patients received a liver transplant (LT) because of cirrhosis of various etiologies. They were immunosuppressed with tacrolimus once daily. Several months after they had been placed on an immunosuppressive regimen with tacrolimus in the form of prolonged-release capsules (Advagraf), the patients presented with delayed hypersensitivity reactions and torturous pruritic rash that affected the whole body and was unresponsive to treatment with oral ursodeoxycholic acid, cholestyramine, or levocetirizine. Allergy testing that was performed by skin prick testing was negative. Nevertheless, intradermal testing yielded positive results in all 3 patients. Management was by interruption of the culprit agent, which was followed by symptom resolution. The immunosuppressive treatment was continued with alternative drugs.. Appropriate nonirritating drug concentration solutions of the drug used for intradermal testing were highly sensitive and confirmed the clinical diagnosis of tacrolimus allergy in all the affected patients.. Immunosuppressive treatment with tacrolimus in the form of prolonged-release capsules may cause a drug hypersensitivity reaction. A suspicion of allergy warrants a referral for allergy testing. Pruritic rash refractory to treatment in liver transplanted patients should be evaluated by an allergist for possible drug allergy when bile stasis and graft disease have been excluded. Intradermal testing has proven a highly sensitive method for confirming a drug allergy diagnosis, whereas skin prick testing did not.

Topics: Aged; Delayed-Action Preparations; Drug Hypersensitivity; Exanthema; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Tacrolimus

Calcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases.. A 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension.. Hypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication.. It appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs.

Topics: Administration, Intravenous; Administration, Oral; Cyclosporine; Drug Hypersensitivity; Drug Substitution; Humans; Immunosuppressive Agents; Male; Tacrolimus; Vitamin K; Young Adult

The patient was diagnosed with ulcerative colitis and received remission induction therapy with prednisolone. While they developed muscle pain in the lower extremities after starting prednisolone, they ultimately achieved clinical remission. After discharge, hematemesis and gastric discomfort developed. Esophagogastroduodenoscopy showed mucosal edema, redness, and oozing bleeding in the gastric body. In addition, the patient had bloody stool and was considered to have a relapse of ulcerative colitis. They therefore received remission induction therapy with tacrolimus. The patient achieved clinical remission again; however, gastric discomfort and muscle pain remained. A drug lymphocyte stimulation test revealed positivity for prednisolone; therefore, the patient was diagnosed with an allergy to prednisolone.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Hypersensitivity; Hematemesis; Humans; Male; Mesalamine; Prednisolone; Remission Induction; Tacrolimus; Treatment Outcome

We conducted a study to clarify the incidence, clinical course, and risk factors of de novo allergies after liver transplantation. Ninety-three patients who had been followed longer than one yr and who had no previous allergy history were included. Forty-two patients (45.2%) developed de novo allergy. Of them, food allergy developed in 35 (37.6%). Respiratory allergy was observed in three (3.2%), and a patient (1.1%) had drug allergy. Fifty-two (55.9%) of the 93 patients developed eosinophilia. The median age of patients with de novo allergy was 15 months (IR 11.3-20 months). De novo allergy developed five months after liver transplantation (IR 2.3-9.5 months) and lasted for 16 months (IR 8-34.5 months). Younger age at liver transplantation displayed statistically significant differences in development of allergy between allergy and non-allergy groups. Twenty-nine (69.0%) patients improved from allergy during the follow-up period. No patient with de novo gastrointestinal allergy progressed to any respiratory allergy such as asthma. Older age at transplantation, EBV non-risk, and CMV non-risk had statistical significance in allergy improvement. Younger age at transplant predisposes to the development of allergy, while improvement of allergy is achieved more in older age.

Topics: Age Factors; Child, Preschool; Drug Hypersensitivity; Eosinophilia; Follow-Up Studies; Food Hypersensitivity; Humans; Hypersensitivity; Immunosuppressive Agents; Incidence; Infant; Liver Failure; Liver Transplantation; Proportional Hazards Models; Respiratory Hypersensitivity; Tacrolimus; Time Factors

Topics: Administration, Intravenous; Administration, Oral; Adult; Castor Oil; Drug Delivery Systems; Drug Hypersensitivity; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Tacrolimus

A 15-year-old male with previously documented allergic contact dermatitis from tacrolimus was allergic to pimecrolimus. This was demonstrated by double-blinded, right-versus-left provocative use testing with pimecrolimus cream 1% versus inactive vehicle applied twice daily to normal skin. The active cream but not its vehicle caused preauricular dermatitis starting after 1 week and caused isolated papules on the extensor wrist starting after 2 weeks. Patch testing on the patient's back was weakly positive (1+) with pimecrolimus cream 1% and negative with the vehicle. Higher concentrations of pimecrolimus were not available for testing. Patch tests on 30 control patients with pimecrolimus cream 1% were negative.

Topics: Adolescent; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dermatologic Agents; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Male; Patch Tests; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Allergic Contact; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Propolis; Tacrolimus; Waxes

Topics: Child; Cyclosporine; Drug Hypersensitivity; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous

From 1992 to 2003, 407 kidney transplantations were performed on 403 patients using cyclosporine (CyA) or tacrolimus (Tac), mycophenolate (MMF), and steroid immunosuppression. Patient records examined for adverse events (AE) and MMF dose reductions or discontinuations during 100 days posttransplant were correlated with data on rejections, graft function, and survival. AEs occurred in 79.1% of transplantations. Gastrointestinal (GI) symptoms, infections, and cytopenias were common. Surprisingly, in 50% of all transplantations serum alanine transferase (ALAT) was elevated, among 21% the change was over three times the upper limit of normal. Patients with delayed graft function showed increased incidences of GI symptoms and thrombocytopenias. There were more ALAT increases and thrombocytopenias in patients on CyA and more GI symptoms in patients on Tac. In 34% of transplantations, the MMF dose was reduced or discontinued. In CyA patients with MMF reduction by day 21, rejection incidence during the subsequent 21 days was 10% versus 0.6% in patients with full-dose MMF until day 21 (P < .002). Among Tac patients no increased rejection frequency was seen after reducing MMF.

Topics: Adult; Alanine Transaminase; Drug Hypersensitivity; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

Immunosuppression with FK506 for pediatric heart transplantation has been used in this institution since 1989. This study reports the unique toxicity of this macrolide agent in these heart transplant recipients.. Between October 1989 and August 1994, 49 patients were managed with FK506, which was the initial primary agent in 38 patients. The remaining 11 were switched from cyclosporine A because of persistent rejection or side effects from the cyclosporine A or prednisone. Data were obtained retrospectively from medical records.. Mean duration of follow-up was 29 months (median 37 months, range 3 to 96 months). Twenty-nine patients (59%) were receiving FK506 alone; 20 patients (41%) were receiving additional treatment with azathioprine, prednisone, or methotrexate. There were seven deaths. Twenty patients (41%) had elevated creatinine levels between 1 to 2 mg/dl. Five patients (11%) had levels greater than 2 mg/dl. Two patients with preexisting renal dysfunction while receiving cyclosporine A had chronic renal failure 32 and 36 months after switching to FK506 and required kidney transplantation. Hyperkalemia was a persistent finding in 26 patients. Of eight patients with hypertension, four had preexisting disease while receiving cyclosporine A; two had impaired renal function, and two were receiving prednisone. Severe anemia developed in eight patients (16%), two of whom had parvovirus. Moderate anemia developed in 21 patients (43%). Eosinophilia occurred in 19 patients; 11 of 19 patients (58%) had allergic symptoms. There was one case of diabetes mellitus. There were 12 significant infections with four infection-related deaths. Lymphoproliferative disease was noted in three patients, two of whom survived. Gastrointestinal symptoms, including chronic diarrhea, recurrent abdominal pain, and reflux esophagitis were present in 10 patients.. In our experience, anemia, renal toxicity, hyperkalemia, chronic diarrhea, and allergies were the most common adverse effects of FK506. Unlike cyclosporine A, hypertension, gingival hyperplasia, coarsening of facial features, and hirsutism were not seen.

Topics: Anemia; Case-Control Studies; Child; Cyclosporine; Drug Hypersensitivity; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Heart Transplantation; Humans; Hyperkalemia; Immunosuppressive Agents; Kidney Diseases; Male; Retrospective Studies; Tacrolimus; Time Factors