Tacrolimus (Page 4 of 17)
5.13 Myocardial Hypertrophy
Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2)].
5.14 Immunizations
Whenever possible, administer the complete complement of vaccines before transplantation and treatment with tacrolimus.
The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.
5.15 Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. A mechanism for tacrolimus-induced PRCA has not been elucidated. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. If PRCA is diagnosed, discontinuation of tacrolimus should be considered [see Adverse Reactions (6.2)].
5.16 Thrombotic Microangiopathy (Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura)
Cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients treated with tacrolimus. TMA may have a multifactorial etiology. Risk factors for TMA that can occur in transplant patients include, for example, severe infections, graft-versus-host disease (GVHD), Human Leukocyte Antigen (HLA) mismatch, the use of calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These risk factors may, either alone or combined, contribute to the risk of TMA.
In patients with signs and symptoms of TMA, consider tacrolimus as a risk factor. Concurrent use of tacrolimus and mTOR inhibitors may contribute to the risk of TMA.
5.17 Cannabidiol Drug Interactions
When cannabidiol and tacrolimus are co-administered, closely monitor for an increase in tacrolimus blood levels and for adverse reactions suggestive of tacrolimus toxicity. A dose reduction of tacrolimus should be considered as needed when tacrolimus is co-administered with cannabidiol [see Dosage and Administration (2.2, 2.6) and Drug Interactions (7.3)].
6 ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- •
- Lymphoma and Other Malignancies [see Warnings and Precautions (5.1)]
- •
- Serious Infections [see Warnings and Precautions (5.2)]
- •
- New Onset Diabetes After Transplant [see Warnings and Precautions (5.4)]
- •
- Nephrotoxicity [see Warnings and Precautions (5.5)]
- •
- Neurotoxicity [see Warnings and Precautions (5.6)]
- •
- Hyperkalemia [see Warnings and Precautions (5.7)]
- •
- Hypertension [see Warnings and Precautions (5.8)]
- •
- Anaphylactic Reactions with Tacrolimus Injection [see Warnings and Precautions (5.9)]
- •
- Myocardial Hypertrophy [see Warnings and Precautions (5.13)]
- •
- Pure Red Cell Aplasia [see Warnings and Precautions (5.15)]
- •
- Thrombotic Microangiopathy, Including Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura [see Warnings and Precautions (5.16)]
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In addition, the clinical trials were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below.
Kidney Transplantation
The incidence of adverse reactions was determined in three randomized kidney transplant trials. One of the trials used azathioprine (AZA) and corticosteroids and two of the trials used mycophenolate mofetil (MMF) and corticosteroids concomitantly for maintenance immunosuppression.
Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a trial where 205 patients received tacrolimus-based immunosuppression and 207 patients received cyclosporine-based immunosuppression. The trial population had a mean age of 43 years (mean ± SD was 43 ± 13 years on tacrolimus and 44 ± 12 years on cyclosporine arm), the distribution was 61% male, and the composition was White (58%), African-American (25%), Hispanic (12%), and Other (5%). The 12-month post-transplant information from this trial is presented below.
The most common adverse reactions (≥ 30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia. Based on reported adverse reaction terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients.
Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:
Tacrolimus/AZA (N = 205) | Cyclosporine/AZA (N = 207) | |
Nervous System | ||
Tremor | 54% | 34% |
Headache | 44% | 38% |
Insomnia | 32% | 30% |
Paresthesia | 23% | 16% |
Dizziness | 19% | 16% |
Gastrointestinal | ||
Diarrhea | 44% | 41% |
Nausea | 38% | 36% |
Constipation | 35% | 43% |
Vomiting | 29% | 23% |
Dyspepsia | 28% | 20% |
Cardiovascular | ||
Hypertension | 50% | 52% |
Chest Pain | 19% | 13% |
Urogenital | ||
Creatinine Increased | 45% | 42% |
Urinary Tract Infection | 34% | 35% |
Metabolic and Nutritional | ||
Hypophosphatemia | 49% | 53% |
Hypomagnesemia | 34% | 17% |
Hyperlipemia | 31% | 38% |
Hyperkalemia | 31% | 32% |
Diabetes Mellitus | 24% | 9% |
Hypokalemia | 22% | 25% |
Hyperglycemia | 22% | 16% |
Edema | 18% | 19% |
Hemic and Lymphatic | ||
Anemia | 30% | 24% |
Leukopenia | 15% | 17% |
Miscellaneous | ||
Infection | 45% | 49% |
Peripheral Edema | 36% | 48% |
Asthenia | 34% | 30% |
Abdominal Pain | 33% | 31% |
Pain | 32% | 30% |
Fever | 29% | 29% |
Back Pain | 24% | 20% |
Respiratory System | ||
Dyspnea | 22% | 18% |
Cough Increased | 18% | 15% |
Musculoskeletal | ||
Arthralgia | 25% | 24% |
Skin | ||
Rash | 17% | 12% |
Pruritus | 15% | 7% |
Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-U.S. trial (Study 1), the incidence of adverse reactions was based on 1195 kidney transplant patients that received tacrolimus (Group C, n = 403), or one of two cyclosporine (CsA) regimens (Group A, n = 384 and Group B, n = 408) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The trial population had a mean age of 46 years (range 17 to 76); the distribution was 65% male, and the composition was 93% Caucasian. The 12-month post-transplant information from this trial is presented below.
Adverse reactions that occurred in ≥ 10% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 1 [Note: This trial was conducted entirely outside of the United States. Such trials often report a lower incidence of adverse reactions in comparison to U.S. trials] are presented below:
Tacrolimus (Group C) (N = 403) | Cyclosporine (Group A) (N = 384) | Cyclosporine (Group B) (N = 408) | |
Diarrhea | 25% | 16% | 13% |
Urinary Tract Infection | 24% | 28% | 24% |
Anemia | 17% | 19% | 17% |
Hypertension | 13% | 14% | 12% |
Leukopenia | 13% | 10% | 10% |
Edema Peripheral | 11% | 12% | 13% |
Hyperlipidemia | 10% | 15% | 13% |
Key: Group A = CsA/MMF/CS, B = CsA/MMF/CS/Daclizumab, C = Tac/MMF/CS/Daclizumab CsA = Cyclosporine, CS = Corticosteroids, Tac = Tacrolimus, MMF = mycophenolate mofetil |
In the U.S. trial (Study 2) with tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids, 424 kidney transplant patients received tacrolimus (n = 212) or cyclosporine (n = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The trial population had a mean age of 48 years (range 17 to 77); the distribution was 63% male, and the composition was White (74%), African-American (20%), Asian (3%), and Other (3%). The 12-month post-transplant information from this trial is presented below.
Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with MMF in Study 2 are presented below:
Tacrolimus/MMF (N = 212) | Cyclosporine/MMF (N = 212) | |
Gastrointestinal Disorders | ||
Diarrhea | 44% | 26% |
Nausea | 39% | 47% |
Constipation | 36% | 41% |
Vomiting | 26% | 25% |
Dyspepsia | 18% | 15% |
Injury, Poisoning, and Procedural Complications | ||
Post-Procedural Pain | 29% | 27% |
Incision Site Complication | 28% | 23% |
Graft Dysfunction | 24% | 18% |
Metabolism and Nutrition Disorders | ||
Hypomagnesemia | 28% | 22% |
Hypophosphatemia | 28% | 21% |
Hyperkalemia | 26% | 19% |
Hyperglycemia | 21% | 15% |
Hyperlipidemia | 18% | 25% |
Hypokalemia | 16% | 18% |
Nervous System Disorders | ||
Tremor | 34% | 20% |
Headache | 24% | 25% |
Blood and Lymphatic System Disorders | ||
Anemia | 30% | 28% |
Leukopenia | 16% | 12% |
Miscellaneous | ||
Edema Peripheral | 35% | 46% |
Hypertension | 32% | 35% |
Insomnia | 30% | 21% |
Urinary Tract Infection | 26% | 22% |
Blood Creatinine Increased | 23% | 23% |
Less frequently observed adverse reactions in kidney transplantation patients are described under the subsection “Less Frequently Reported Adverse Reactions (> 3% and < 15%) in Liver, Kidney, and Heart Transplant Studies.”
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.