Tacrolimus (Page 4 of 9)

5.14 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)].

5.15 Immunizations

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.

5.16 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)].

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 Box Warning, Warnings and Precautions (5.2)]
  • Serious Infections [see Box Warning, Warnings and Precautions (5.3)]
  • Polyoma Virus Infections [see Box Warning, Warnings and Precautions (5.4)]
  • CMV Infections [see Box Warning, Warnings and Precautions (5.5)]
  • New Onset Diabetes After Transplant [see Warnings and Precautions (5.6)]
  • Nephrotoxicity [see Warnings and Precautions (5.7)]
  • Neurotoxicity [see Warnings and Precautions (5.8)]
  • Hyperkalemia [see Warnings and Precautions (5.9)]
  • Hypertension [see Warnings and Precautions (5.10)]
  • Anaphylaxis with Tacrolimus Injection [see Warnings and Precautions (5.11)]
  • Myocardial Hypertrophy [see Warnings and Precautions (5.14)]
  • Pure Red Cell Aplasia [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 Transplant

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 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%), Black (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.

Adverse reactions that occurred in ≥ 15% of kidney transplant patients treated with tacrolimus in conjunction with azathioprine are presented below:

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)
Tacrolimus/AZA (N=205) Cyclosporine/AZA (N=207)
Nervous SystemTremorHeadacheInsomniaParesthesiaDizziness GastrointestinalDiarrheaNauseaConstipationVomitingDyspepsia CardiovascularHypertensionChest Pain UrogenitalCreatinine IncreasedUrinary Tract Infection Metabolic and NutritionalHypophosphatemiaHypomagnesemiaHyperlipemiaHyperkalemiaDiabetes MellitusHypokalemiaHyperglycemiaEdema Hemic and LymphaticAnemiaLeukopenia MiscellaneousInfectionPeripheral EdemaAstheniaAbdominal PainPainFeverBack Pain Respiratory SystemDyspneaCough Increased MusculoskeletalArthralgia SkinRashPruritus 54%44%32%23%19%44%38%35%29%28%50%19%45%34%49%34%31%31%24%22%22%18%30%15%45%36%34%33%32%29%24%22%18%25%17%15% 34%38%30%16%16%41%36%43%23%20%52%13%42%35%53%17%38%32%9%25%16%19%24%17%49%48%30%31%30%29%20%18%15%24%12%7%

Two trials were conducted for tacrolimus-based immunosuppression in conjunction with MMF and corticosteroids. In the non-US 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:

Table 5. Kidney Transplantation: Adverse Reactions Occurring in ≥ 10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)

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

Tacrolimus (Group C) (N=403) Cyclosporine (Group A) (N=384) Cyclosporine (Group B) (N=408)
DiarrheaUrinary Tract InfectionAnemiaHypertensionLeucopeniaEdema PeripheralHyperlipidemia 25%24%17%13%13%11%10% 16%28%19%14%10%12%15% 13%24%17%12%10%13%13%

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%), Black (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:

Table 6. Kidney Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 2)
Tacrolimus /MMF (N=212) Cyclosporine/MMF (N=212)
Gastrointestinal DisordersDiarrheaNauseaConstipationVomitingDyspepsia Injury, Poisoning, and Procedural ComplicationsPost Procedural PainIncision Site ComplicationGraft Dysfunction Metabolism and Nutrition DisordersHypomagnesemiaHypophosphatemiaHyperkalemiaHyperglycemiaHyperlipidemiaHypokalemia Nervous System DisordersTremorHeadache Blood and Lymphatic System DisordersAnemiaLeukopenia MiscellaneousEdema PeripheralHypertensionInsomniaUrinary Tract InfectionBlood creatinine increased 44%39%36%26%18%29%28%24%28%28%26%21%18%16%34%24%30%16%35%32%30%26%23% 26%47%41%25%15%27%23%18%22%21%19%15%25%18%20%25%28%12%46%35%21%22%23%

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

Liver Transplantation

There were two randomized comparative liver transplant trials. In the U.S. trial, 263 adult and pediatric patients received tacrolimus and steroids and 266 patients received cyclosporine-based immunosuppressive regimen (CsA/AZA). The trial population had a mean age of 44 years (range 0.4 to 70), the distribution was 52% male, and the composition was White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 270 patients received tacrolimus and steroids and 275 patients received CsA/AZA. The trial population had a mean age of 46 years (range 15 to 68), the distribution was 59% male, and the composition was White (95.4%), Black (1%), Asian (2%) and Other (2%).

The proportion of patients reporting more than one adverse event was > 99% in both the tacrolimus group and the CsA/AZA group. Precautions must be taken when comparing the incidence of adverse reactions in the U.S. trial to that in the European trial. The 12-month post-transplant information from the U.S. trial and from the European trial is presented below. The two trials also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse reactions reported in ≥15% in tacrolimus patients (combined trial results) are presented below for the two controlled trials in liver transplantation.

The most common adverse reactions (≥ 40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia. These all occur with oral and IV administration of tacrolimus and some may respond to a reduction in dosing (e.g., tremor, headache, paresthesia, hypertension). Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Table 7. Liver Transplantation: Adverse Reactions Occurring in ≥ 15% of Patients Treated with Tacrolimus
U.S. TRIAL EUROPEAN TRIAL
Tacrolimus (N=250) Cyclosporine/AZA (N=250) Tacrolimus (N=264) Cyclosporine/AZA (N=265)
Nervous SystemHeadache InsomniaTremor Paresthesia GastrointestinalDiarrheaNauseaLFT AbnormalAnorexiaVomitingConstipation CardiovascularHypertension UrogenitalKidney Function Abnormal Creatinine Increased BUN Increased OliguriaUrinary Tract Infection Metabolic and NutritionalHypomagnesemiaHyperglycemiaHyperkalemia Hypokalemia Hemic and LymphaticAnemiaLeukocytosisThrombocytopenia MiscellaneousPainAbdominal PainAstheniaFeverBack PainAscitesPeripheral Edema Respiratory SystemPleural EffusionDyspneaAtelectasis Skin and AppendagesPruritusRash 64%64%56%40%72%46%36%34%27%24%47%40%39%30%18%16%48%47%45%29%47%32%24%63%59%52%48%30%27%26%30%29%28%36%24% 60%68%46%30%47%37%30%24%15%27%56%27%25%22%15%18%45%38%26%34%38%26%20%57%54%48%56%29%22%26%32%23%30%20%19% 37%32%48%17%37%32%6%7%14%23%38%36%24%12%19%21%16%33%13%13%5%8%14%24%29%11%19%17%7%12%36%5%5%15%10% 26%23%32%17%27%27%5%5%11%21%43%23%19%9%12%19%9%22%9%16%1%8%19%22%22%7%22%17%8%14%35%4%4%7%4%

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described under the subsection Less Frequently Reported Adverse Reactions.

New Onset Diabetes After Transplant

Kidney Transplant

New Onset Diabetes After Transplant (NODAT) is defined as a composite of fasting plasma glucose ≥126 mg/dL, HbA1C ≥ 6%, insulin use ≥30 days or oral hypoglycemic use. In a trial in kidney transplant patients (Study 2), NODAT was observed in 75% in the tacrolimus-treated and 61% in the Neoral-treated patients without pre-transplant history of diabetes mellitus (Table 9) [see Clinical Studies (14.1)].

Table 9. Incidence of New Onset Diabetes After Transplant at 1 year in Kidney Transplant Recipients in a Phase 3 Trial (Study 2)
Parameter Treatment Group
Tacrolimus /MMF (n = 212) Neoral/MMF (n = 212)
NODAT 112/150 (75%) 93/152 (61%)
Fasting Plasma Glucose≥ 126 mg/dL 96/150 (64%) 80/152 (53%)
HbA1C ≥ 6% 59/150 (39%) 28/152 (18%)
Insulin Use ≥ 30 days 9/150 (6%) 4/152 (3%)
Oral Hypoglycemic Use 15/150 (10%) 5/152 (3%)

In early trials of tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was evaluated with a more limited criteria of “use of insulin for 30 or more consecutive days with < 5 day gap” in patients without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus. Data are presented in Tables 10 to 12. PTDM was reported in 20% of tacrolimus/Azathioprine (AZA)-treated kidney transplant patients without pre-transplant history of diabetes mellitus in a Phase 3 trial (Table 10). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post-transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM (Table 11).

Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)

a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

Status of PTDM a Tacrolimus/AZA CsA/AZA
Patients without pre-transplant history of diabetesmellitus 151 151
New onset PTDMa , 1st Year 30/151(20%) 6/151(4%)
Still insulin-dependent at one year in those withoutprior history of diabetes 25/151(17%) 5/151(3%)
New onset PTDM a post 1 year 1 0
Patients with PTDMa at 2 years 16/151(11%) 5/151(3%)
Table 11. Development of Post-Transplant Diabetes Mellitus by Race or Ethnicity and by Treatment Group During First Year Post Kidney Transplantation in a Phase 3 Trial

a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

Patient Race Patients Who Developed PTDM a
Tacrolimus Cyclosporine
Black 15/41 (37%) 3 (8%)
Hispanic 5/17 (29%) 1 (6%)
Caucasian 10/82 (12%) 1 (1%)
Other 0/11 (0%) 1 (10%)
Total 30/151 (20%) 6 (4%)

Liver Transplant

Insulin-dependent PTDM was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post-transplant, in the U.S. and European randomized trials, respectively, (Table 12). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized trials, respectively, and may require treatment [see Adverse Reactions (6.1)].

Table 12. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

a) Use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin-dependent diabetes mellitus or non-insulin dependent diabetes mellitus.

b) Patients without pre-transplant history of diabetes mellitus.

Status of PTDM a US Trial European Trial
Tacrolimus Cyclosporine Tacrolimus Cyclosporine
Patients at riskb 239 236 239 249
New Onset PTDMa 42 (18%) 30 (13%) 26 (11%) 12 (5%)
Patients still oninsulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%)

Less Frequently Reported Adverse Reactions (>3% and <15%)

The following adverse reactions were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.

Nervous System [see Warnings and Precautions (5.8)]

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired

Special Senses

Abnormal vision, amblyopia, ear pain, otitis media, tinnitus

Gastrointestinal

Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis

Cardiovascular

Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation

Urogenital

Acute kidney failure [see Warnings and Precautions (5.7)], albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis

Metabolic/Nutritional

Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, dehydration, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenase increase, weight gain

Endocrine

Cushing’s syndrome

Hemic/Lymphatic

Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, polycythemia, prothrombin decreased, serum iron decreased

Miscellaneous

Abdomen enlarged, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling abnormal, flu syndrome, generalized edema, hernia, mobility decreased, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer

Musculoskeletal

Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis

Respiratory

Asthma, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

Skin

Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

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