Tacrolimus Prescribing Details

Insert in the package or product label
Dosage form: capsule
Type of Drug: Calcineurin inhibitors are a type of drug.

^a) In a second, smaller study, Tacrolimus was given at a starting dose of 0.15 to 0.0.2 mg/kg/day, with observed Tacrolimus concentrations of 6 to 16 ng/mL for months 1-3 and 5 to 12 ng/mL for months 4 to 12 [see Clinical Trials (14.1)].

Titration of the dose should be based on clinical evaluations of tolerance and rejection. As a maintenance medication, Tacrolimus dosages that are less than the recommended initial dosage may be adequate. Early on after transplant, adjunct therapy with adrenal corticosteroids is advised.

According to the results in kidney transplant patients, Black patients needed a larger dose than White patients to reach equivalent trough concentrations Table 2.

Table 1. Comparative Dose and Trough Concentrations Based on Race
Time After Transplant	Caucasian		Black
	n=114		n=56
	Dose (mg/kg)	Trough Concentrations	Dose	Trough Concentrations (ng/mL)
		(ng/mL)	(mg/kg)
Day 7	0.18	12	0.23	10.9
Month 1	0.17	12.8	0.26	12.9
Month 6	0.14000000000000001	11.8	0.24	11.5
Month 12	0.13	10.1	0.19	11

First dose—Injection

Tacrolimus injection should only be used as a continuous IV infusion or when a person can’t take Tacrolimus capsules by mouth. Tacrolimus injections should stop as soon as the patient can take Tacrolimus by mouth, which is usually within two to three days. If a person is getting an IV infusion, the first dose of oral medicine should be given 8 to 12 hours after the IV infusion stops.

The trough concentrations mentioned above only apply to patients who took Tacrolimus by mouth. It may be helpful to keep an eye on Tacrolimus concentrations in patients who get Tacrolimus injections as a continuous IV infusion, but the concentrations seen will not be comparable to the exposures estimated by the trough concentrations seen in patients who took Tacrolimus by mouth.

In a kidney or liver transplant, the starting dose of Tacrolimus injection is 0.03–0.05 mg/kg/day. In a heart transplant, the starting dose is 0.01 mg/kg/day, given as a continuous IV infusion. Patients who are adults should get doses at the lower end of the range. Early on after a transplant, corticosteroid therapy for the adrenal glands is recommended.

There have been anaphylactic reactions to injectables like Tacrolimus that contain castor oil derivatives [see warnings and precautions (5.11)].

Dosage for Children Who Have Had a Liver Transplant
Table 3 shows the initial recommendations for oral doses for children with liver transplants, as well as recommendations for whole blood trough concentrations. [See Dosage and Administration (2.6)] for information on how to check the blood concentration. If needed, a dose of 0.03–0.05 mg/kg/day can be given through an IV to a child.

Table 2. Summary of Initial Oral Dosage Recommendations and Observed Whole Blood Trough Concentrations in Children
Patient Population	Recommended Tacrolimus Initial Oral DosageNote: daily doses should be administered as two divided doses, every 12 hours	Observed Tacrolimus Whole Blood Trough Concentrations
Pediatric liver transplant patients	0.15-0.20 mg/kg/day	Month 1-12: 5-20 ng/mL

Children who had liver transplants and didn’t already have kidney or liver problems needed and could handle higher doses than adults to reach the same blood levels. We don’t have a lot of experience with transplanting a kidney or heart into a child.

Changing the dose for people with kidney problems
Due to its potential to harm the kidneys, Tacrolimus should be given at the lower end of the therapeutic dosing range to people who have had a liver or heart transplant or who already have kidney damage. There may be a need to lower the dose even more than the targeted range.

The first dose of Tacrolimus should be given to kidney transplant patients with post-operative oliguria no sooner than 6 hours and no later than 24 hours after the transplant, but it can be put off until the kidney function shows signs of getting better.

Changing the dose for people with liver problems
Patients with severe hepatic impairment (Child Pugh 10) may need lower doses of Tacrolimus because the drug doesn’t get out of the body as quickly and has a longer half-life. It is important to keep a close eye on blood levels.

High concentrations of Tacrolimus in the whole blood may make it more likely for people who have had a liver transplant and are now having problems with their liver to develop renal insufficiency. These patients should be closely watched and their doses might need to be changed. Some evidence suggests that lower doses should be given to these patients [see Dosage and Administration (2.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

How to run the business
If possible, patients should start Tacrolimus treatment by taking capsules by mouth.

Table 1 shows the initial dose and observed Tacrolimus whole blood trough concentrations for adults, while Table 3 shows the same information for children [see Dosage and Administration (2.1, 2.2)]. See Dosage and Administration (2.1) for information on how to monitor blood concentrations in kidney transplant patients.

It is important to take Tacrolimus capsules every day at the same time, with or without food, because food changes the way Tacrolimus capsules work [see Clinical Pharmacology (12.3)].

When taking Tacrolimus capsules, people shouldn’t eat grapefruit or drink grapefruit juice [see Drug Interactions (7.2)].

You shouldn’t take cyclosporine and tacrolimus capsules at the same time. At least 24 hours should pass after stopping tacrolimus or cyclosporine before starting the other. When either Tacrolimus or cyclosporine levels are high, the other drug’s dose should usually be put off even longer.

If a patient can’t take Tacrolimus capsules by mouth, they may start treatment with an IV infusion of Tacrolimus. If you need IV therapy, you should switch from IV to oral Tacrolimus as soon as you can handle oral therapy. This usually happens in two to three days. When a patient is getting an IV infusion, the first dose of oral medicine should be given 8 to 12 hours after the IV infusion stops.

Keeping track of how drugs are used
Monitoring the amount of Tacrolimus in a patient’s blood, along with other laboratory and clinical parameters, is thought to be an important part of patient management for figuring out rejection, toxicity, dose changes, and compliance. Table 1 shows the whole blood trough concentrations that have been seen. Factors that affect how often a patient is monitored include, but are not limited to, hepatic or renal dysfunction, the addition or removal of drugs that might interact, and the amount of time since the transplant. Blood concentration monitoring is not a substitute for checking on the kidneys and liver and taking tissue samples. From clinical trials, we know that the concentrations of Tacrolimus in the whole blood were most different in the first week after a transplant.

Whole blood trough concentrations of Tacrolimus are linked to the relative risks of toxicity and failure to work. So, it is recommended to keep an eye on whole blood trough concentrations to help with the clinical evaluation of toxicity and failure of efficacy.

Immunoassays and high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS) are two common ways to test for Tacrolimus. Immunoassays can work with both the parent compound and its metabolites. Because of this, the results of immunoassays may be more positive than the results of HPLC/MS. The bias could be different depending on the assay and the lab. Using the current assays, it is important to know a lot about the assay methods and biological matrices used in order to compare the concentrations in published literature to the concentrations in patients. Whole blood is the best matrix, and samples should be put into tubes with ethylene diamine tetraacetic acid (EDTA) to stop the blood from clotting. Anti-clotting with heparin is not recommended because it tends to form clots when stored. Samples that can’t be tested right away should be kept at room temperature or in a refrigerator and tested within 7 days; see the assay instructions for more information. If samples need to be kept for a long time, they should be frozen to a temperature of -20° C. In one study, samples kept at -20° C for 6 months were able to recover more than 90% of the drug. After 6 months, the recovery rate dropped.

Dosage Forms and Strengths
•An oblong, hard capsule that is taken by mouth contains anhydrous Tacrolimus USP.

o Tacrolimus Capsules USP, 0.5 mg are white to off-white powder in a hard gelatin capsule of size ‘4’ with a yellow opaque cap and yellow opaque body. “BP 665” is printed twice on the body, and “0.5 mg” is printed twice on the cap, both in red ink.

o Tacrolimus Capsules USP, 1 mg are a white to off-white powder filled in a hard gelatin capsule of size ‘4’ with a white opaque cap and a white opaque body that says “BP 666” twice on the body and “1 mg” twice on the cap in red ink.

o Tacrolimus Capsules USP, 5 mg are a white to off-white powder that comes in a hard gelatin capsule of size ‘4’ with a salmon opaque cap and body. “BP 667” is written in white ink on the body, and “5 mg” is written twice on the cap.

Contraindications
If a person is allergic to Tacrolimus, they shouldn’t take Tacrolimus capsules. If a person is allergic to HCO-60, they shouldn’t get a tacrolimus injection (polyoxyl 60 hydrogenated castor oil). There have been reports of dyspnea, rash, itching, and acute respiratory distress syndrome as signs of hypersensitivity [see Adverse Reactions (6)].

Warnings and Safety Measures
How Immunosuppression Is Handled
Tacrolimus should only be used by doctors who know how to treat immunosuppression and take care of organ transplant patients. Patients who take the drug should be cared for in facilities with enough labs and other medical resources to help them. [See Boxed Warning] The doctors in charge of maintenance therapy should have all the information they need to keep track of the patient.

Lymphoma, along with other cancers
People who take immunosuppressants, like Tacrolimus, are more likely to get lymphomas and other cancers, especially ones that affect the skin [see Boxed Warning]. The risk seems to have more to do with the amount and length of immunosuppression than with any particular agent.

As usual, people who are more likely to get skin cancer should wear protective clothing and use a sunscreen with a high protection factor to limit their exposure to sunlight and UV light.

Post-transplant lymphoproliferative disorder (PTLD) has been seen in people who have had their immune systems weakened by an organ transplant. Most cases of PTLD seem to be caused by the Epstein Barr Virus (EBV). The risk of PTLD seems to be highest for people who don’t have antibodies against EBV. This group includes many young children.

Infections That Are Bad
Patients who take immunosuppressants, like Tacrolimus, are more likely to get bacterial, viral, fungal, protozoal, and opportunistic infections [see Boxed Warning and Warnings and Precautions (5.4, 5.5)].

These infections can cause serious problems, even death. Because too much immune system suppression can make a person more likely to get sick, combination immunosuppressant therapy should be used with care.

Infections by the Polyoma virus

People who take immunosuppressants like Tacrolimus are more likely to get opportunistic infections like polyoma virus infections. Infections with the polyoma virus in transplant patients can be dangerous and sometimes even kill them. These include polyoma virus-associated nephropathy (PVAN), which is usually caused by a BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML), which has been seen in patients taking Tacrolimus [see Adverse Reactions (6.2)].

PVAN is linked to bad outcomes, such as worsening kidney function and loss of a kidney graft [see Adverse Reactions (6.2)]. Patients who are at risk for PVAN may be easier to spot if they are being watched.

Patients who were given Tacrolimus have been found to have PML. PML, which can sometimes be fatal, is often marked by hemiparesis, apathy, confusion, problems with thinking, and shakiness. Immunosuppressants and other treatments that weaken the immune system are risk factors for PML. When immunosuppressed patients report neurological symptoms, doctors should think about PML as a possible cause, and a consultation with a neurologist should be considered if it’s clinically necessary.

Patients who show signs of PVAN or PML should think about lowering their immunosuppression. Doctors should also think about the risk that less immunosuppression poses to an allograft that is still working.

Infections with the Cytomegalovirus (CMV)
CMV viremia and CMV disease are more likely to happen in people who take immunosuppressants like Tacrolimus. People who don’t have CMV antibodies at the time of transplant but get a graft from a person who does have CMV antibodies are most likely to get CMV disease. There are therapeutic ways to limit CMV disease, and they should be used regularly. Patients who are at risk for CMV disease might be found through monitoring. Patients with CMV viremia and/or CMV disease should think about lowering the amount of immunosuppression they are on.

New Onset Diabetes After Transplant
In clinical trials of kidney, liver, and heart transplants, it was found that Tacrolimus capsules can cause diabetes to start up for the first time. Some people who get diabetes after a transplant may be able to get rid of it. Black and Hispanic people who need a kidney transplant are at a higher risk. Patients who take Tacrolimus should have their blood glucose levels closely watched [see Side Effects (6.1)].

Nephrotoxicity
Like other calcineurin-inhibitors, tacrolimus can cause kidney damage if it is used in high doses or for a long time. Most of the time, acute nephrotoxicity is caused by vasoconstriction of the afferent renal arteriole. It is marked by an increase in serum creatinine, high potassium levels, and/or a drop in urine output, and it is usually reversible. Chronic calcineurin-inhibitor nephrotoxicity is linked to an increase in serum creatinine, a shorter life span for kidney grafts, and specific histologic changes that can be seen on a kidney biopsy. The changes linked to chronic calcineurin-inhibitor nephrotoxicity usually get worse over time. When a patient’s kidneys don’t work as well as they should, the dose of Tacrolimus may need to be lowered. If a patient’s serum creatinine level stays high even after changing the dose, and the patient doesn’t respond to other dose changes, the patient may need to switch to a different immunosuppressive therapy.

Nephrotoxicity was reported in about 52% of kidney transplant patients, 40% and 36% of liver transplant patients receiving Tacrolimus in U.S. and European randomized trials, and 59% of heart transplant patients in a European randomized trial [see Adverse Reactions (6.1)].

When giving Tacrolimus with other drugs that may affect kidney function, care should be taken because the effects of both drugs could add up or make each other worse. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (like tenofovir), and protease inhibitors (e.g., ritonavir, indinavir). Also, CYP3A4 inhibitors like antifungal drugs (like ketoconazole), calcium channel blockers (like diltiazem and verapamil), and macrolide antibiotics (like clarithromycin, erythromycin, and troleandomycin) should be given with care because they slow down the body’s ability to break down Tacrolimus [see Drug Interactions (7.3, 7.4, 7.5, and 7.6)].

Neurotoxicity
When used in high doses, tacrolimus can cause a wide range of neurotoxicities. Neurotoxicities like posterior reversible encephalopathy syndrome (PRES), delirium, and coma are among the worst. People who were given Tacrolimus have been said to get PRES. Headaches, changes in mental state, seizures, problems with vision, and high blood pressure are all signs of PRES. Radiological tests can be used to confirm a diagnosis. If PRES is suspected or confirmed, the blood pressure should be kept under control and immunosuppression should be stopped right away. This syndrome is marked by symptoms that go away when immunosuppression is lessened or stopped.

High levels of Tacrolimus in the blood have also been linked to coma and delirium in people who don’t have PRES. Tacrolimus has been linked to seizures in both adults and children [see Adverse Reactions (6.1)].

Less serious neurotoxicities include tremors, paresthesias, headaches, and other changes in motor function, mental status, and sensory function [see Adverse Reactions (6.1)]. High levels of Tacrolimus in the whole blood have been linked to tremors and headaches, which may go away if the dose is changed.

Hyperkalemia
Taking Tacrolimus has been linked to hyperkalemia. Potassium levels in the blood should be watched. Care should be taken before using other drugs that can also cause hyperkalemia, such as potassium-sparing diuretics, ACE inhibitors, and angiotensin receptor blockers, while taking Tacrolimus [see Adverse Effects (6.1)].

Hypertension
Hypertension is a common side effect of taking Tacrolimus, and it may need treatment [see Adverse Reactions (6.1)]. Controlling blood pressure can be done with any of the common antihypertensive drugs, but those linked to high potassium levels (like potassium-sparing diuretics, ACE inhibitors, and angiotensin receptor blockers) should be used with caution [see Warnings and Precautions(5.9)]. Calcium-channel blocking drugs may raise the amount of Tacrolimus in the blood, so the dose of Tacrolimus may need to be lowered [see Drug Interactions (7.5)].

Injections of Tacrolimus Can Cause Anaphylactic Reactions
A small number of patients (0.6%) have had anaphylactic reactions to injectables like Tacrolimus that contain castor oil derivatives. No one knows for sure what causes these reactions. Patients who can’t take Tacrolimus capsules should get an injection instead [see When to Use and How to Use (1.4)].
Patients who get an injection of Tacrolimus should be constantly watched for at least the first 30 minutes after the infusion starts, and then often after that. If there are signs or symptoms of anaphylaxis, you should stop the infusion. At the bedside, there should be both an epinephrine solution in water and a source of oxygen.

Use along with Sirolimus
In kidney transplant patients, it has not been proven that Tacrolimus with sirolimus is safe or works well.

In studies of people who had never had a liver transplant before, combining sirolimus and Tacrolimus led to more deaths, graft loss, and hepatic artery thrombosis (HAT). This combination is not recommended [see Indications and Uses (1.4)].

In a U.S. trial, heart transplant patients who took sirolimus (2 mg per day) with Tacrolimus had a higher risk of kidney function problems, wound healing problems, and insulin-dependent diabetes mellitus after the transplant. This combination is not recommended [see Clinical Studies (14.3)].

Use with drugs that slow down or speed up CYP3A4
When coadministering Tacrolimus with strong CYP3A4 – inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin) adjustments in the dosing regimen of Tacrolimus and subsequent frequent monitoring of Tacrolimus whole blood trough concentrations and Tacrolimus associated adverse reactions are recommended [see Drug Interactions (7)].

QT Prolongation
Torsade de Pointes may be caused by Tacrolimus Capsules if they make the QT/QTc interval longer. Patients who were born with long QT syndrome should not take Tacrolimus. Patients with congestive heart failure, bradyarrhythmias, or who are taking certain antiarrhythmic medications or other medicines that cause QT prolongation, as well as those with electrolyte disturbances like hypokalemia, hypocalcemia, or hypomagnesemia, should have electrocardiograms and have their magnesium, potassium, and calcium levels checked every so often while they are being treated.

When Tacrolimus Capsules are given with other substrates and/or inhibitors of CYP3A4 that can also lengthen the QT interval, the Tacrolimus dose should be lowered, the Tacrolimus concentration in the whole blood should be checked often, and the QT interval should be checked for lengthening. When Tacrolimus Capsules are taken with amiodarone, the levels of Tacrolimus in the whole blood have been shown to rise, with or without QT prolongation [see Drug Interactions (7)].

Myocardial Hypertrophy is the thickening of the heart muscle.

Myocardial hypertrophy has been seen in babies, kids, and adults, especially those with high Tacrolimus trough concentrations. It is usually shown by concentric increases in the thickness of the left ventricular posterior wall and the interventricular septum, which can be seen on an echocardiogram. Most of the time, this condition seems to go away when the treatment is stopped or the dose is lowered. When a patient is being treated with Tacrolimus and develops renal failure or shows signs of ventricular dysfunction, an echocardiogram should be considered. If myocardial hypertrophy is found, the dose of Tacrolimus may need to be lowered or the drug may need to be stopped [see Side Effects (6.2)].

Immunizations

Live vaccines should not be used while taking Tacrolimus. Some examples are the intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines, but this list is not complete.

A lack of red blood cells.

Pure red cell aplasia, or PRCA, has been seen in people who have been given Tacrolimus. No clear explanation has been found for how Tacrolimus causes PRCA. All of the patients said they had risk factors for PRCA, such as a parvovirus B19 infection, a disease that was already there, or medications they were taking at the same time. If PRCA is found, you might want to stop taking Tacrolimus [see Adverse Reactions (6.2)].

Perforation of the intestines

People who took Tacrolimus Capsules, USP have reported gastrointestinal perforation. All of the reported cases were thought to be a side effect of transplant surgery or to be caused by an infection, diverticulum, or malignant neoplasm. As gastrointestinal perforation can be serious or even life-threatening, it should be treated quickly with the right medical or surgical care [see Adverse Effects (6.1)].

Bad Side Effects

Other parts of the labeling go into more detail about the following serious and otherwise important side effects:

• Lymphoma and other cancers [see Boxed Warning, Warnings and Precautions (5.2)]
• Severe infections [see Boxed Warning, Warnings and Precautions (5.3)]
• Infections with the Polyoma virus [see Boxed Warning, Warnings and Precautions (5.4)]
• Infections with CMV [see Boxed Warning, Warnings and Precautions (5.5)]
• New Diabetes After Transplant [See Warnings and Precautions (5.6)]
• Nephrotoxicity [See Precautions and Warnings (5.7)]
• [See Warnings and Precautions (5.8)] Neurotoxicity
• Hyperkalemia [see Precautions and Warnings (5.9)]
• Hypertension [see Caution and Precautions (5.10)]
• Anaphylaxis from Tacrolimus Injection [see Warnings and Precautions (5.11)]
• Myocardial Hypertrophy [See Caution and Warnings (5.15)]
• Pure Red Cell Aplasia [See Cautions and Precautions (5.17)]
• Gastrointestinal Perforation [See Caution and Warnings (5.18)]

Clinical Studies Experience

Because clinical trials are done under a wide range of different conditions, the rates of side effects seen in one drug’s trials can’t be directly compared to the rates seen in trials of another drug, and the rates seen in practice may not match the rates seen in trials. Also, the clinical trials were not made to find out if there were differences between the study arms when it came to the side effects listed below.

Transplanting a kidney

In three randomized kidney transplant trials, the number of bad reactions was counted. For maintenance immunosuppression, one of the trials used azathioprine (AZA) and corticosteroids at the same time, and two of the trials used mycophenolate mofetil (MMF) and corticosteroids at the same time.

In a trial, immunosuppression with Tacrolimus, azathioprine, and corticosteroids was compared to immunosuppression with cyclosporine and azathioprine and corticosteroids after a kidney transplant. 205 patients got immunosuppression with Tacrolimus and 207 patients got immunosuppression with cyclosporine. The average age of the people in the trial group was 43 (meansd was 4313 years on the Tacrolimus arm and 4412 years on the cyclosporine arm), 61% were men, and the group was made up of White (58%), Black (25%), Hispanic (12%), and Other (5%). The results of this trial at 12 months after the transplant are shown below.

Infection, tremor, high blood pressure, abnormal kidney function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia are the side effects that happen most often (more than 30%).

Here are some side effects that happened in at least 15% of kidney transplant patients who took Tacrolimus and Azathioprine together:

Table 3. Kidney Transplantation: Adverse Reactions Occurring in ≥15% of Patients Treated with Tacrolimus in Conjunction with Azathioprine (AZA)
	Tacrolimus /AZA	Cyclosporine/AZA
	(N=205)	(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%

Immunosuppression with Tacrolimus, MMF, and corticosteroids was tested in two clinical trials. In the non-US trial (Study 1), 1195 kidney transplant patients were given Tacrolimus (Group C, n=403) or one of two cyclosporine (CsA) regimens (Group A, n=384 and Group B, n=408) along with MMF and corticosteroids. All patients, except those in one of the two cyclosporine groups, were also given daclizumab to start the transplant process. The average age of the people in the trial group was 46, but their ages ranged from 17 to 76. There were 65% men in the group, and 93% of them were Caucasians. The results of this trial at 12 months after the transplant are shown below.

Side effects that happened in less than 10% of kidney transplant patients who were given Tacrolimus and MMF in Study 1. [Note: This trial was done entirely outside of the US. When compared to U.S. trials, such trials often report a lower number of negative side effects.

Table 4. Kidney Transplantation: Adverse Reactions Occurring in ≥10% of Patients Treated with Tacrolimus in Conjunction with MMF (Study 1)
	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 along with MMF and corticosteroids, 424 kidney transplant patients were given either Tacrolimus (n=212) or cyclosporine (n=212) along with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. The average age of the people in the trial group was 48 (range: 17–77), 63% were men, and they were White (74%), Black (20%), Asian (3%) and other (3%). The results of this trial at 12 months after the transplant are shown below.

In Study 2, 15% of patients who had a kidney transplant and were treated with Tacrolimus and MMF had the following side effects:

Table 5. 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 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%

Under “Less Often Reported Adverse Reactions,” you can read about the less common side effects that people with liver transplants and kidney transplants have had.

Transplantation of the liver

There were two randomized, controlled studies that compared liver transplants. In the U.S. trial, 263 adults and children got Tacrolimus and steroids, and 266 people got an immunosuppressive regimen based on cyclosporine (CsA/AZA). The average age of the people in the trial was 44 (range: 0.4 to 70), 52% were men, and they were White (78%), Black (5%), Asian (2%), Hispanic (13%) and Other (2%). In the European trial, 275 people got CsA/AZA and 270 people got Tacrolimus and steroids. The average age of the people in the trial was 46 (the range was 15–68), 59% were men, and they were White (95.4%), Black (1%), Asian (2%) and Other (2%).

Both the Tacrolimus group and the CsA/AZA group had more than 99% of their patients report more than one side effect. When comparing the number of bad side effects in the U.S. trial to those in the European trial, care must be taken. Below are the results of the U.S. trial and the European trial 12 months after the transplant. The patients in the two trials were also different, and they were treated with different levels of immunosuppressive drugs. For the two controlled trials on liver transplantation, the side effects that were reported by 15% of Tacrolimus patients are listed below.

When Tacrolimus is used to treat liver transplant patients, the most common side effects are tremor, headache, diarrhea, high blood pressure, nausea, abnormal kidney function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia (high blood sugar). All of these can happen when Tacrolimus is taken by mouth or through an IV, and some of them may get better if the dose is lowered (e.g., tremor, headache, paresthesia, hypertension). Sometimes diarrhea was linked to other stomach problems, like feeling sick or throwing up.

Table 6. 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 System
Headache	64%	60%	37%	26%
Insomnia	64%	68%	32%	23%
Tremor	56%	46%	48%	32%
Paresthesia	40%	30%	17%	17%
Gastrointestinal
Diarrhea	72%	47%	37%	27%
Nausea	46%	37%	32%	27%
LFT Abnormal	36%	30%	6%	5%
Anorexia	34%	24%	7%	5%
Vomiting	27%	15%	14%	11%
Constipation	24%	27%	23%	21%
Cardiovascular
Hypertension	47%	56%	38%	43%
Urogenital
Kidney Function Abnormal	40%	27%	36%	23%
Creatinine Increased	39%	25%	24%	19%
BUN Increased	30%	22%	12%	9%
Oliguria	18%	15%	19%	12%
Urinary Tract Infection	16%	18%	21%	19%
Metabolic and Nutritional
Hypomagnesemia	48%	45%	16%	9%
Hyperglycemia	47%	38%	33%	22%
Hyperkalemia	45%	26%	13%	9%
Hypokalemia	29%	34%	13%	16%
Hemic and Lymphatic
Anemia	47%	38%	5%	1%
Leukocytosis	32%	26%	8%	8%
Thrombocytopenia	24%	20%	14%	19%
Miscellaneous
Pain	63%	57%	24%	22%
Abdominal Pain	59%	54%	29%	22%
Asthenia	52%	48%	11%	7%
Fever	48%	56%	19%	22%
Back Pain	30%	29%	17%	17%
Ascites	27%	22%	7%	8%
Peripheral Edema	26%	26%	12%	14%
Respiratory System
Pleural Effusion	30%	32%	36%	35%
Dyspnea	29%	23%	5%	4%
Atelectasis	28%	30%	5%	4%
Skin and Appendages
Pruritus	36%	20%	15%	7%
Rash	24%	19%	10%	4%

Less Commonly Reported Adverse Events describes less often observed adverse reactions in both liver transplant and kidney transplant patients.

transplantation of a heart

Based on data from two primary orthotopic heart transplantation trials, the prevalence of adverse responses was calculated. In a study carried out in Europe, 314 patients had an 18-month regimen of Tacrolimus (n=157) or cyclosporine (n=157), azathioprine (AZA), corticosteroids, and antibody induction. The trial population’s demographics included a mean age of 51 years (with a range of 18 to 65), an 82% male distribution, and a makeup of 96% White, 3% Black, and 1% Other.

Atypical renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, and infection are the most frequent adverse events (15%) seen in Tacrolimus-treated heart transplant patients.

	Tacrolimus/AZA	Cyclosporine/AZA
	(n=157)	(n=157)
Cardiovascular System
Hypertension	62%	69%
Pericardial Effusion	15%	14%
Body as a Whole
CMV Infection	32%	30%
Infection	24%	21%
Metabolic and Nutritional Disorders
Diabetes Mellitus	26%	16%
Hyperglycemia	23%	17%
Hyperlipemia	18%	27%
Hemic and Lymphatic System
Anemia	50%	36%
Leukopenia	48%	39%
Urogenital System
Kidney Function Abnormal	56%	57%
Urinary Tract Infection	16%	12%
Respiratory System
Bronchitis	17%	18%
Nervous System
Tremor	15%	6%

In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (100 to 200 ng/mL) at Day 122 and later in 32 to 68% of the cyclosporine treatment group, while in 74 to 86% of the Tacrolimus treatment group, the trough concentrations were within the pre-defined target range (5 to 15 ng/mL).

In the U.S. trial, 331 heart transplant patients who got corticosteroids and Tacrolimus in combination with sirolimus (n=109), Tacrolimus in combination with MMF (n=107), or cyclosporine modified in combination with MMF (n=115) for a year were used to figure out how often bad side effects happened. The average age of the people in the trial was 53 (ages ranged from 18 to 75), 78% were men, and they were White (83%), Black (13%), and other (4%).

In the U.S. heart transplantation trial, only certain treatment-related side effects were recorded. Patients who took Tacrolimus and MMF reported the following side effects at a rate of 15% or higher: any target adverse reactions (99%), hypertension (89%), hyperglycemia requiring antihyperglycemic therapy (70%), hypertriglyceridemia (65%), anemia (hemoglobin 10 g/dL) (65%), fasting blood glucose > 140 mg/dL (on two separate occasions) (61%), hypercholesterolemia (57%), hyperlipidemia

Other targeted treatment-emergent side effects in patients who took Tacrolimus were Cushingoid features, slow wound healing, hyperkalemia, Candida infection, and CMV infection/syndrome. These side effects happened in less than 15% of patients.

Diabetes Starts Up Again After Transplant

Transplanting a kidney

New Onset Diabetes After Transplant (NODAT) is a combination of fasting plasma glucose 126 mg/dL, HbA1C 6%, insulin use 30 days, or oral hypoglycemic use. In a trial of kidney transplant patients (Study 2), 75% of the Tacrolimus-treated patients and 61% of the Neoral-treated patients with no history of diabetes mellitus before the transplant had NODAT (see Clinical Studies (14.1)).

Table 7. 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	Neoral/MMF
	(n = 212)	(n = 212)
NODAT	112/150 (75%)	93/152 (61%)
Fasting Plasma Glucose ≥126 mg/dL	96/150 (64%)	80/152 (53%)
HbA 1C ≥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 the first tests of Tacrolimus, Post-Transplant Diabetes Mellitus (PTDM) was measured by “use of insulin for 30 or more consecutive days with 5 day gap” in patients who had never had insulin-dependent or non-insulin-dependent diabetes mellitus before. The information is shown in Tables 10 through 13. In a Phase 3 trial, 20% of kidney transplant patients on Tacrolimus/Azathioprine (AZA) who had never had diabetes mellitus before the transplant were found to have PTDM (Table 10) The average time it took for PTDM to start was 68 days. Insulin dependence could be reversed in 15% of these PTDM patients one year after the transplant and in 50% of them two years after the transplant. PTDM was more likely to happen in kidney transplant patients who were black or Hispanic (Table 11)

Table 8. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in a Phase 3 Trial using Azathioprine (AZA)
Status of PTDM a	Tacrolimus/AZA	CsA/AZA
Patients without pre-transplant history of diabetes mellitus	151	151
New onset PTDMa, 1st Year	30/151 (20%)	6/151 (4%)
Still insulin-dependent at one year in those without prior history of diabetes	25/151 (17%)	5/151 (3%)
New onset PTDMa post 1 year	1	0
Patients with PTDMa at 2 years	16/151 (11%)	5/151 (3%

^a) Using insulin for 30 or more days in a row, with no more than a 5-day break, and not having a history of either insulin-dependent diabetes or non-insulin dependent diabetes.

Table 9. 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
	Patients Who Developed PTDM a
Patient Race	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%)

^a) Using insulin for at least 30 days in a row, with no breaks longer than 5 days, and no history of insulin-dependent or non-insulin-dependent diabetes mellitus.

Liver Transplant

Insulin-dependent PTDM was found in 18% and 11% of Tacrolimus-treated liver transplant patients in the U.S. and Europe, respectively. It went away in 45% and 31% of these patients one year after the transplant (Table 12). In randomised trials in the U.S. and Europe, the use of Tacrolimus was linked to hyperglycemia in 47% and 33% of liver transplant recipients, respectively. This condition may need treatment [see Adverse Reactions(6.1)].

Table 10. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients
	US Trial		EuropeanTrial
Status of PTDM a	Tacrolimus	Cyclosporine	Tacrolimus	Cyclosporine
Patients at riskb	239	236	239	249
New Onset PTDMa	42 (18%)	30 (13%)	26 (11%)	12 (5%)
Patients still on insulin at 1 year	23 (10%)	19 (8%)	18 (8%)	6 (2%)

a) Using insulin for at least 30 days in a row, with no breaks longer than 5 days, and no history of insulin-dependent or non-insulin-dependent diabetes mellitus.

b) Patients who did not have diabetes mellitus before the transplant.

Getting a new heart

Insulin-dependent PTDM was found in 13% and 22% of Tacrolimus-treated heart transplant patients taking mycophenolate mofetil (MMF) or azathioprine (AZA), and it went away in 30% and 17% of these patients one year after the transplant in U.S. and European randomised trials, respectively (Table 13). In randomised trials in the U.S. and Europe, 32% and 35% of heart transplant recipients who took Tacrolimus plus MMF or AZA were found to have hyperglycemia, which is defined as two fasting plasma glucose levels of 126 mg/dL. This condition may need treatment [see Clinical Studies (6.1)].

Table 11. Incidence of Post-Transplant Diabetes Mellitus and Insulin Use at 1 Year in Heart Transplant Recipients
Status of PTDM a	US Trial		European Trial
	Tacrolimus/MMF	Cyclosporine/MMF	Tacrolimus/AZA	Cyclosporine/AZA
Patients at riskb	75	83	132	138
New Onset PTDMa	10 (13%)	6 (7%)	29 (22%)	5 (4%)
Patients still on insulin at 1 yearc	7 (9%)	1 (1%)	24 (18%)	4 (3%)

a) Using insulin for 30 days or more in a row without a history of insulin-dependent or non-insulin-dependent diabetes mellitus.

bPatients who did not have diabetes mellitus before the transplant.

7–12 months for the trial in the U.S.

Less Often Reported Side Effects (between 3% and 15%)

In clinical trials, people who had transplants of the liver, kidney, or heart and were given Tacrolimus reported the following side effects.

Nervous System [See Precautions and Warnings (5.8)]

Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, high mood, emotional instability, encephalopathy, haemorrhagic stroke, hallucinations, hypertonia, incoordination, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, flaccid paralysis, psychosis, quadriparesis, somnolence, thinking abnormally, vertigo,

Special Senses

Eye problems, amblyopia, ear pain, otitis media, and tinnitus are some examples.

Gastrointestinal

Cholangitis, cholestatic jaundice, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal haemorrhage, gastrointestinal haemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, oesoph

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, decreased heart rate, haemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypo

Urogenital

Acute kidney failure (see Warnings and Precautions section 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, abnormal healing, hypercalcemia, hypercholesterolemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, lactic dehydrogenas

Endocrine

Cushing’s syndrome is a medical condition.

Hemic/Lymphatic

Coagulation disorder, ecchymosis, increased haematocrit, abnormal haemoglobin, hypochromic anaemia, leukocytosis, polycythemia, decreased prothrombin, and decreased serum iron.

Miscellaneous

Abdominal swelling, abscess, accidental injury, allergic reaction, cellulitis, chills, fall, feeling off, flu syndrome, generalised edoema, hernia, decreased mobility, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer.

Musculoskeletal

Arthralgia, cramps, generalised spasm, joint disorder, leg cramps, myalgia, myasthenia, and osteoporosis.

Respiratory

Asthma, emphysema, hiccups, lung disorder, decreased lung function, pharyngitis, pneumonia, pneumothorax, pulmonary edoema, respiratory disorder, rhinitis, sinusitis, voice change.

Skin

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

Adverse Reactions After Marketing
Tacrolimus has been sold all over the world, and the following side effects have been reported. Because these reactions are reported voluntarily by a population whose size is unknown, it is not always possible to get a good estimate of how often they happen or prove that they are caused by the drug. Most of the time, the decision to put these reactions on the label depends on one or more of the following: (1) how bad the reaction was, (2) how often it was reported, or (3) how strong the link was to the drug.

Some other responses are:

Cardiovascular

Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, deep vein thrombosis, ventricular extrasystoles, ventricular fibrillation, myocardial hypertrophy (see Warnings and Precautions (5.15)).

Gastrointestinal

Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastroesophageal reflux disease, hepatic cytolysis, hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis hemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease.

Hemic/Lymphatic

Agranulocytosis, disseminated intravascular coagulation, hemolytic anaemia, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and pure red cell aplasia [see Warnings and Precautions (5.17)]

Infections

Cases of progressive multifocal leukoencephalopathy (PML), which can sometimes be fatal; polyoma virus-associated nephropathy (PVAN), including graft loss [see Warnings and Precautions (5.4)]

Metabolic/Nutritional

Glycosuria, an increase in amylase, which can lead to pancreatitis, and a loss of weight.

Miscellaneous

Feeling hot and cold, being jumpy, having hot flushes, failing organs, and primary graft dysfunction are all symptoms of cancer.

Nervous System

Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope.

Respiratory

Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, and respiratory failure

Skin

Stevens-Johnson syndrome and toxic epidermal necrolysis

Special Senses

Blindness, cortical blindness, hearing loss, including deafness, and light sensitivity (photophobia)

Urogenital

Acute renal failure, hemorrhagic cystitis, hemolytic-uremic syndrome, and micturition disorder

How Drugs Interact
Since CYP3A enzymes are mostly responsible for breaking down Tacrolimus, drugs or substances that are known to stop these enzymes from working may raise the amount of Tacrolimus in the blood. Drugs that are known to increase CYP3A enzymes can lower the amount of Tacrolimus in the blood [see Warnings and Precautions (5.13) and Clinical Pharmacology (12.3)]. When Tacrolimus is given with CYP3A inhibitors or inducers, the dose may need to be changed and the concentration of Tacrolimus in the blood may need to be checked often. Patients should also be kept an eye on for side effects, such as changes in renal function and QT prolongation [see Warnings and Precautions (5.7) and (5.14)].

Products with Mycophenolic Acid
With a given dose of mycophenolic acid (MPA) products, MPA exposure is higher when Tacrolimus is given along with them than when cyclosporine is given along with them. This is because cyclosporine stops the enterohepatic recirculation of MPA, but Tacrolimus doesn’t. Clinicians should be aware that a patient who switches from cyclosporine to Tacrolimus and is also taking MPA-containing products could have more MPA in their bodies.

Grapefruit Juice
Grapefruit juice stops CYP3A enzymes from working, which raises the amount of Tacrolimus in the blood. Patients taking Tacrolimus should not eat grapefruit or drink grapefruit juice [see Dosage and Administration (2.5)].

Inhibitors of Protease
Most protease inhibitors stop CYP3A enzymes from working, which may raise the amount of Tacrolimus in the blood. It is best not to use Tacrolimus with nelfinavir at the same time unless the benefits are greater than the risks [see Clinical Pharmacology (12.3)]. When Tacrolimus is given with telaprevir or boceprevir, its concentration in the whole blood goes up by a lot [see Clinical Pharmacology (12.3)]. When Tacrolimus and protease inhibitors (like ritonavir, telaprevir, or boceprevir) are used together, it is important to keep an eye on how much Tacrolimus is in the blood and if there are any side effects. The dosing schedule for Tacrolimus may also need to be changed.

Antifungal Agents
When starting or stopping the use of the following antifungal drugs with Tacrolimus [see Clinical Pharmacology (12.3)], it is important to keep an eye on whole blood concentrations and adjust the dose of Tacrolimus as needed.

Azoles: Voriconazole, posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of Tacrolimus and increase Tacrolimus whole blood concentrations. When starting therapy with voriconazole or posaconazole in patients who are already taking Tacrolimus, it is recommended that the Tacrolimus dose be lowered to one-third of the original dose and that future Tacrolimus doses be adjusted based on the Tacrolimus whole blood concentrations.

Caspofungin is an inducer of CYP3A, and it lowers the amount of Tacrolimus in the blood as a whole.

Blockers of calcium channels
Verapamil, diltiazem, nifedipine, and nicardipine can stop CYP3A from breaking down Tacrolimus, which may raise the amount of Tacrolimus in the blood. When these calcium channel blocking drugs and Tacrolimus are used together, whole blood concentrations should be checked and the dose of Tacrolimus should be changed as needed.

Antibacterials
Erythromycin, clarithromycin, troleandomycin, and chloramphenicol can stop Tacrolimus from being broken down by CYP3A, which may raise the amount of Tacrolimus in the blood. When these drugs and Tacrolimus are used together, blood levels should be checked and the dose of Tacrolimus should be changed as needed.

Antimycobacterials
Rifampin [see Clinical Pharmacology (12.3)] and rifabutin are CYP3A enzyme inducers, so they may lower the amount of Tacrolimus in the whole blood. When these antimycobacterial drugs and Tacrolimus are used together, whole blood concentrations should be checked and the dose of Tacrolimus should be changed as needed.

Anticonvulsants
Phenytoin, carbamazepine, and phenobarbital make CYP3A enzymes work harder, which may lower the amount of Tacrolimus in the blood. When these drugs are taken with Tacrolimus, whole blood concentrations should be checked and the dose of Tacrolimus should be changed as needed.

Giving phenytoin and Tacrolimus at the same time may also raise the amount of phenytoin in the blood. When Tacrolimus and phenytoin are given together, it is important to keep an eye on the levels of phenytoin in the blood and change the dose of phenytoin as needed.

John’s Wort (Hypericum perforatum)
St. John’s Wort makes CYP3A enzymes work harder, which may lower the amount of Tacrolimus in the whole blood. When St. John’s Wort and Tacrolimus are given together, whole blood concentrations should be checked and the dose of Tacrolimus should be changed as needed.

Gastric Acid Neutralizers or Suppressors
As substrates for CYP2C19 and CYP3A4, lansoprazole and omeprazole could stop CYP3A4 from breaking down Tacrolimus. This could cause Tacrolimus levels in the blood to rise significantly, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers compared to those who are good CYP2C19 metabolizers.

Cimetidine may also stop CYP3A4 from breaking down Tacrolimus, which would significantly raise the amount of Tacrolimus in the blood.

When taken at the same time as magnesium and aluminium hydroxide antacids, the amount of Tacrolimus in the whole blood goes up [see Clinical Pharmacology (12.3)]. When these drugs are taken with Tacrolimus, whole blood concentrations should be checked and the dose of Tacrolimus should be changed as needed.

Others
Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone, methylprednisolone, and herbal products with schisandra sphenanthera extracts may stop Tacrolimus from being broken down by CYP3A, which could lead to higher levels of Tacrolimus in the blood. When these drugs are given with Tacrolimus, blood levels should be checked and the dose of Tacrolimus should be changed as needed.

USE IN PARTICULAR GROUPS
Pregnancy
Category C: No good, well-controlled studies have been done on pregnant women. The drug tacrolimus is passed through the placenta. People who used Tacrolimus while they were pregnant were more likely to have babies with high potassium levels and kidney problems. When pregnant rabbits were given 0.5 to 4.3 times the clinical dose of tacrolimus orally, and pregnant rats were given 0.8 to 6.9 times the clinical dose, there was a higher rate of foetal death in utero, foetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis), and toxic effects on the mother. Tacrolimus shouldn’t be used when a woman is pregnant unless the possible benefits to the mother outweigh the possible risks to the baby.

Tacrolimus given orally to pregnant rabbits at doses of 0.32 mg/kg to 1.0 mg/kg, which is 0.5 to 4.3 times the clinical dose range (0.075 mg/kg to 0.2 mg/kg) based on body surface area, caused harm to the mother and more abortions. At a dose of 1 mg/kg, foetal rabbits had a higher rate of malformations and developmental changes, such as ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosus, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and absence of gallbladder. Tacrolimus given orally to pregnant rats at doses of 3.2 mg/kg, which is 2.6 to 6.9 times the clinical dose range, caused maternal toxicity, an increase in late resorptions, fewer live births, and smaller, less healthy pups. Tacrolimus given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, which is 0.8 to 6.9 times the recommended clinical dose range, caused the pups to be smaller and less likely to live (only at 3.2 mg/kg). Kidney hydronephrosis was more common in the pups that died early from the high dose.

Women who breastfeed
Tacrolimus is passed out of the body in the milk. Since it is not known what happens when healthy babies are exposed to Tacrolimus over a long period of time, women who are taking Tacrolimus should stop nursing, especially if the drug is important to the mother.

Pediatric Use
The safety and effectiveness of Tacrolimus in children who have had kidney or heart transplants have not been proven. Using Tacrolimus, liver transplants have been done successfully on children as young as 16 years old. 56 children took part in two randomised, active-controlled trials of Tacrolimus in primary liver transplantation. Thirty-one patients were given treatments based on Tacrolimus, and 25 were given treatments based on cyclosporine. Also, at least 122 children were studied in an uncontrolled trial of Tacrolimus in liver transplants from living related donors. In general, children needed higher doses of Tacrolimus than adults did to keep the same level of Tacrolimus in their blood [see Dosage and Administration (2.2)].

Geriatric Use
In clinical trials of Tacrolimus, there were not enough people 65 and older to find out if they responded differently than younger people. Other clinical reports have not found any differences in how older and younger patients respond. In general, when choosing a dose for an elderly patient, you should be careful and start at the low end of the dosing range. This is because they are more likely to have decreased liver, kidney, or heart function, or to be taking other drugs or have a disease at the same time.

Use in Kidney Disease
The way Tacrolimus worked in people with kidney problems was the same as in healthy volunteers with normal kidney function. Tacrolimus should, however, be given at the lower end of the therapeutic dosing range to people who have had a liver or heart transplant and had kidney damage before the transplant. It may be necessary to lower the dose below the target range (see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) for more information).

Use for Hepatic Impairment
Patients with severe liver damage (mean Child-Pugh score >10) had a much lower average clearance of Tacrolimus than healthy volunteers with normal liver function. Patients with hepatic impairment should keep a close eye on their Tacrolimus trough concentrations [see Clinical Pharmacology (12.3)].

High whole-blood trough concentrations of Tacrolimus may increase the risk of developing renal insufficiency in people who have had a liver transplant and are experiencing hepatic impairment after the transplant. These patients should be closely watched and their doses might need to be changed. There is some evidence that these patients should be given lower doses [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Overdosage
Limited overdosage experience is available. Up to 30 times the intended dose has been reported as a sudden overdose. Almost all of the cases had no symptoms, and all of the people who got sick got better with no lasting effects. Some cases of acute overdose were followed by side effects like those listed in Adverse Reactions (6), like tremors, abnormal kidney function, high blood pressure, and peripheral edoema. In one case of acute overdose, transient urticaria and tiredness were seen. Based on the fact that Tacrolimus doesn’t dissolve well in water and that it binds strongly to erythrocytes and plasma proteins, it is likely that it can’t be dialyzed very well. Charcoal hemoperfusion hasn’t been tried yet. There have been reports of people taking activated charcoal by mouth to treat acute overdoses, but not enough people have done this for it to be recommended. In every case of overdose, general supportive measures and treatment for specific symptoms should be taken.

In studies of acute oral and IV toxicity, rats died at or above the following doses: 52 times the recommended oral dose for humans in adult rats, 16 times the recommended oral dose for immature rats, and 16 times the recommended IV dose for adults (all based on body surface area corrections).

Tacrolimus Description
Anhydrous lactose NF DT, hypromellose USP, croscarmellose sodium NF, and magnesium stearate NF are some of the inactive ingredients in Tacrolimus Capsules, USP. The capsules can be taken by mouth and contain the equivalent of 0.5 mg, 1 mg, or 5 mg of anhydrous Tacrolimus USP. The shell of the 0.5 mg capsule is made of gelatin, titanium dioxide, and yellow iron oxide. The shell of the 1 mg capsule is made of gelatin and titanium dioxide, and the shell of the 5 mg capsule is made of gelatin, titanium dioxide, and red iron oxide.
Shellac Glaze, Iron Oxide Red, and Simethicone USP are non-volatile parts of the ink.
The active ingredient in Tacrolimus capsules, USP is Tacrolimus USP, which used to be known as FK506. Streptomyces tsukubaensis makes tacrolimus, which is an immunosuppressant called a macrolide. The chemical name for 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-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-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.
Tacrolimus is made up of the following chemicals:

The empirical formula for tacrolimus is C 44H 69NO 12•H2O, and the formula weight is 822.03. Tacrolimus looks like white crystals or a powder made of crystals. It doesn’t dissolve much at all in water, but it does dissolve easily in ethanol, methanol, and chloroform.

People use USP Dissolution Test 6. Procedure 2 of the USP for Organic Impurities is used.

Clinical Pharmacology of Tacrolimus
How something works
The exact way that tacrolimus stops T-lymphocytes from becoming active is not known. Experiments show that Tacrolimus binds to a protein inside cells called FKBP-12. Then, a complex is made of Tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin, which stops calcineurin from making phosphatase. This effect may stop nuclear factor of activated T-cells (NF-AT) from becoming dephosphorylated and moving. NF-AT is a nuclear component thought to start gene transcription for the production of lymphokines (such as interleukin-2, gamma interferon). The end result is that T-lymphocyte activation is slowed down (i.e., immunosuppression).

In animal transplant models of the liver, kidney, heart, bone marrow, small intestine and pancreas, lung and trachea, skin, cornea, and limb, tacrolimus makes both the host and the transplanted graft live longer.

On animals, Tacrolimus has been shown to suppress some humoral immunity and, to a greater extent, cell-mediated reactions like allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

Pharmacokinetics
The main thing that makes tacrolimus work is the parent drug. After giving Tacrolimus intravenously (IV) and/or orally (PO) to healthy volunteers and people who had a kidney transplant, liver transplant, or heart transplant, the pharmacokinetic parameters (meanS.D.) were found (Table 14).

Table 12. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients
Population	N	Route	Parameters
		(Dose)	C max	T max	AUC	t 1/2	CI	V
			(ng/mL)	(hr)	(ng hr/mL)	(hr)	(L/hr/kg)	(L/kg)
Healthy	8	IV (0.025 mg/kg/4hr)	a	a	598 b± 125	34.2 ± 7.7	0.040 ± 0.009	1.91 ± 0.31
Volunteers	16	PO (5 mg)	29.7 ± 7.2	1.6 ± 0.7	243 c ± 73	34.8 ± 11.4	0.041 d ± 0.008	1.94d ± 0.53
Kidney	26	IV (0.02 mg/kg/12 hr)	a	a	294 e ± 262	18.8 ± 16.7	0.083 ± 0.050	1.41 ± 0.66
Transplant		PO (0.2 mg/kg/day)	19.2 ± 10.3	3	203 e ± 42	f	f	f
Patients		PO (0.3 mg/kg/day)	24.2 ± 15.8	1.5	288 e ± 93	f	f	f
Liver	17	IV (0.05 mg/kg/12 hr)	a	a	3300 e ± 2130	11.7 ± 3.9	0.053 ± 0.017	0.85 ± 0.30
Transplant
Patients		PO (0.3 mg/kg/day)	68.5 ± 30	2.3 ± 1.5	519 e ± 179	f	f	f
Heart	11	IV (0.01 mg/kg/day as a continuous infusion)	a	a	954 g ± 334	23.6 ± 9.22	0.051 ± 0.015	f
Transplant	11	PO (0.075 mg/kg/day)h	14.7 ± 7.79	2.1 [0.5-6] i	82.7 j ± 63.2	a	f	f
Patients	14	PO (0.15 mg/kg/day) h	24.5 ± 13.7	1.5 [0.4-4] i	142j ± 116	a	f	f

1. not applicable
2. AUC _0-120
3. AUC _0-72
4. Corrected for individual bioavailability
5. AUC _0-inf
6. not applicable
7. AUC _0-t
8. Determined after the first dose
9. Median [range]
10. AUC _0-12

Due to the fact that Tacrolimus pharmacokinetics vary from person to person, each person’s treatment needs to be tailored to them [see Dosage and Administration (2.6)]. Pharmacokinetic data show that whole blood concentrations, not plasma concentrations, are a better way to describe Tacrolimus pharmacokinetics.

Absorption

When Tacrolimus is taken by mouth, it is only partially and not always absorbed by the GI tract. Absolute bioavailability of Tacrolimus was 1710% in adult kidney transplant patients (N=26), 226% in adult liver transplant patients (N=17), 239% in adult heart transplant patients (N=11), and 185% in healthy volunteers (N=16).

The bioequivalence of the 1 mg and 5 mg capsules was tested with a single dose on 32 healthy people. Another single-dose test with 32 healthy people showed that the 0.5 mg and 1 mg capsules have the same effect on the body. Maximum blood levels of tacrolimus (C max) and the area under the curve (AUC) seemed to go up in a way that was proportional to the dose in 18 healthy volunteers who had just eaten and were given a single oral dose of 3, 7, or 10 mg.

In 18 people who had kidney transplants, Tacrolimus trough concentrations of 3 to 30 ng/mL measured 10 to 12 hours after the last dose (C min) matched the AUC well (correlation coefficient 0.93). Between 10 and 60 ng/mL, the correlation coefficient was 0.94 for 24 people who had a liver transplant. After a steady-state oral dose of 0.075 or 0.15 mg/kg/day, the correlation coefficient was 0.89 in 25 heart transplant patients with a concentration range of 2 to 24 ng/mL.

What Food Does

When the person was hungry, the rate and amount of Tacrolimus absorption was the best. When Tacrolimus was given to 15 healthy volunteers, the rate and amount of absorption were both slowed down by the fact that they were eating.

The effect was most noticeable with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased by 37% and 77%, respectively, and T max was lengthened by 5 times. A meal with a lot of carbs (668 kcal and 85% carbs) lowered the average C max and AUC by 28% and 65%, respectively.

The time of the meal also changed how well Tacrolimus worked in 16 healthy volunteers. When given right after a meal, the mean C max was 71% lower and the mean AUC was 39% lower than when the people had not eaten. When given 1.5 hours after a meal, the mean C max was 63% lower and the mean AUC was 39% lower than in the fasted state.

In 11 liver transplant patients, giving Tacrolimus 15 minutes after a high-fat (400 kcal, 34% fat) breakfast decreased AUC (2718%) and C max (5019%) compared to when the patients hadn’t eaten anything.

Tacrolimus capsules should be taken every day, either with food or on an empty stomach, because food changes the way Tacrolimus works [see Dosage and Administration (2.5)].

Distribution

Tacrolimus binds to proteins in the blood by about 99%, and this is true for concentrations between 5 and 50 ng/mL. Most of the time, tacrolimus is linked to albumin and alpha-1-acid glycoprotein, and it has a strong connection to erythrocytes. The amount of Tacrolimus in whole blood and plasma depends on a number of things, such as the hematocrit, the temperature when the plasma is taken out, the drug concentration, and the amount of plasma proteins. In a U.S. trial, the ratio of whole blood concentration to plasma concentration was on average 35 (range 12 to 67).

Metabolism

Tacrolimus is mostly broken down by the cytochrome P-450 system and the mixed-function oxidase system (CYP3A). It has been suggested that there is a metabolic pathway that could lead to the formation of 8 different metabolites. In vitro, the main ways that biotransformation happens were found to be demethylation and hydroxylation. 13-demethyl Tacrolimus is the main metabolite found when human liver microsomes are mixed with the drug. In studies done in the lab, it was found that a 31-demethyl metabolite had the same effect as Tacrolimus.

Excretion
When Tacrolimus is given by IV, the average clearance is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adults with kidney transplants, adults with liver transplants, and adults with heart transplants, respectively. Less than 1% of the dose given to a man is passed through his urine unaltered.

In a mass balance study where radiolabeled Tacrolimus was given by IV to six healthy volunteers, the average amount of radiolabel that was recovered was 77.812.7%. 92.41% of the Tacrolimus was eliminated through the feces, and the half-life for this was 48.115.9 hours based on radioactivity and 43.511.6 hours based on the amount of Tacrolimus in the body. The average radiolabel clearance was 0.0290.015 L/hr/kg, and the average Tacrolimus clearance was 0.0290.009 L/hr/kg. When given by mouth (PO), the average radiolabel recovery was 94.930.7%. 92.630.7% of Tacrolimus was eliminated through feces, 2.31.1% through urine, and the half-life of Tacrolimus was 31.910.5 hours based on radioactivity and 48.412.3 hours based on concentrations. The average radiolabel clearance was 0.2260.116 L/hr/kg, and the average Tacrolimus clearance was 0.1720.088 L/hr/kg.

Specific Populations

Pediatric

The effects of Tacrolimus on the body have been looked at in people with liver transplants who were between 0.7 and 13.2 years old. After giving a dose of 0.037 mg/kg/day by IV to 12 children, the mean terminal half-life, volume of distribution, and clearance were, respectively, 11.53.8 hours, 2.62.1 L/kg, and 0.1380.071 L/hr/kg. After 9 patients took the drug by mouth, the average AUC and C max were 337167 nghr/mL and 48.427.9 ng/mL, respectively. The total bioavailability was 3 and a quarter percent.

Whole blood trough concentrations from 31 patients younger than 12 years old showed that pediatric patients needed higher doses than adults to get the same Tacrolimus trough concentrations [see Dosage and Administration (2.2)].

Tacrolimus’s pharmacokinetics have also been looked at in people with kidney transplants who were 8.22.4 years old. After giving 0.06 to 0.09 mg/kg/day by IV to 12 children (8 boys and 4 girls), the mean terminal half-life and clearance were 10.2 to 5.0 hours (range: 3.4 to 25 hours) and 0.12 to 0.04 L/hr/kg, respectively. When the same patients took the drug by mouth, the mean AUC and C max were 18165 nghr/mL (range: 81–300) and 3011 (range: 14–49) ng/mL, respectively. The absolute bioavailability was 1914 (range: 5.2% to 56%).

Damage to the kidneys and liver
Table 15 shows the mean pharmacokinetic parameters for Tacrolimus after a single dose given to people with kidney and liver problems.

Table 13. Pharmacokinetic In Renal and Hepatic Impaired Patients
Population	Dose	AUC 0-t	t 1/2	V	CI
(No. of Patients)		(ng·hr/mL)	(hr)	(L/kg)	L/hr/kg)
Renal	0.02	393±123	26.3±9.2	1.07	3.7999999999999999E-2
Impairment	mg/kg/4hr	(t=60 hr)		±0.20	±0.014
(n=12)	IV
Mild Hepatic	0.02	367±107	60.6±43.8	3.1±1.6	4.2000000000000003E-2
Impairment	mg/kg/4hr	(t=72 hr)	Range: 27.8 to 141		±0.02
(n=6)	IV
	7.7 mg	488±320	66.1±44.8	3.7±4.7 a	3.4000000000000002E-2
	PO	(t=72 hr)	Range: 29.5 to 138		±0.019 a
Severe	0.02 mg/kg/4hr	762±204	198±158	3.9±1.0	1.7000000000000001E-2
Hepatic	IV (n=2)	(t=120 hr)	Range: 81 to 436		±0.013
Impairment	0.01 mg/kg/8hr	289±117
(n=6, IV)	IV (n=4)	(t=144 hr)
(n=5, PO) b	8 mg PO	658	119±35	3.1±3
	(n=1)	(t=120 hr)	Range: 85-178
	5 mg PO	533±156
	(n=4)	(t=144 hr)
	4 mg PO
	(n=1)

a) Adjusted for how well the drug works
b)One person didn’t get the PO dose

Renal Impairment: Before a kidney transplant, the pharmacokinetics of tacrolimus after a single IV dose were studied in 12 patients, 7 of whom were not on dialysis and 5 of whom were on dialysis. Their serum creatinine levels were 3.91.6 mg/dL and 12.02.4 mg/dL, respectively. The pharmacokinetic parameters found for both groups were the same. Table 15 shows that the average clearance of Tacrolimus in people with kidney problems was the same as in healthy volunteers (see Dosage and Administration (2.3) and Use in Special Populations (8.6)).

Hepatic Impairment: The pharmacokinetics of tacrolimus have been studied in six people with mild hepatic dysfunction (mean Pugh score: 6.2) after a single IV and oral dose. The average amount of Tacrolimus that was cleared from the body by patients with mild hepatic dysfunction was not much different from that of healthy volunteers (see previous table). The pharmacokinetics of tacrolimus were studied in 6 people with severe liver problems (mean Pugh score: >10). No matter how the drug was given, the average clearance was much lower in people with severe liver damage [see Dosage and Administration (2.4) and Use in Special Populations (8.7)].

R ace
After giving a single dose of Tacrolimus by IV and by mouth to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers, the drug’s pharmacokinetics were looked at. After a 4-hour IV infusion of 0.015 mg/kg, there were no big differences in how the drug moved through the three groups of people. But after a single oral dose of 5 mg, the mean (SD) Cmax of Tacrolimus in African-Americans was significantly lower (23.612.1 ng/mL) than in Caucasians (40.212.6 ng/mL) and Latino-Americans (36.215.8 ng/mL) (p0.01). African-Americans had a mean AUC 0-inf of 203115 ng/hr/mL, which was lower than that of Caucasians (344186 ng/hr/mL) and Latino-Americans (274150 ng/hr/mL). African-Americans (124.5%) and Latino-Americans (147.4%) had significantly lower absolute oral bioavailability (F) than Caucasians (195.8%, p=0.011). There wasn’t a big difference between the three groups in terms of mean terminal T1/2 (range from approximately 25 to 30 hours). A look back at kidney transplant patients of African-American and Caucasian descent showed that African-American patients needed higher doses of Tacrolimus to reach the same trough concentrations [see Dosage and Administration (2.1)].

Gender

No formal test has been done to see how gender affects the way Tacrolimus works in the body. However, in the kidney transplant trial, there was no difference in dosing based on gender. A comparison of pharmacokinetics between healthy volunteers and people who had had kidney, liver, or heart transplants showed that there were no differences between men and women.

How Drugs Interact

When starting or stopping the use of the following drugs with Tacrolimus [see Drug Interactions (7)], it is important to keep an eye on whole blood concentrations and adjust the dose of Tacrolimus as needed.

Telaprevir: In a single-dose study with 9 healthy volunteers, giving Tacrolimus (0.5 mg) and telaprevir (750 mg three times a day for 13 days) together increased the Tacrolimus dose normalized C max by 9.3-fold and AUC by 70-fold compared to giving Tacrolimus alone [see Drug Interactions (7.3)].

Boceprevir: In a single-dose study with 12 people, giving Tacrolimus (0.5 mg) and boceprevir (800 mg three times a day for 11 days) together increased the Cmax and AUC of Tacrolimus by 9.9 and 17 times, respectively, compared to giving Tacrolimus alone [see Drug Interactions (7.3)].

Nelfinavir: A clinical study of 5 people who had liver transplants showed that giving Tacrolimus and nelfinavir together increased blood levels of Tacrolimus by a lot. As a result, the Tacrolimus dose had to be cut by an average of 16-fold to keep blood levels of Tacrolimus at 9.7 ng/mL. It is best not to take Tacrolimus and nelfinavir at the same time unless the benefits are greater than the risks [see Drug Interactions (7.3)].

Rifampin: When given at the same time as Tacrolimus, the oral bioavailability of Tacrolimus dropped significantly from 14% to 7% in a study of 6 healthy volunteers (600 mg). Also, when rifampin was given at the same time as Tacrolimus, there was a significant increase in Tacrolimus clearance (0.0360.008 L/hr/kg vs. 0.0530.010 L/hr/kg) [see Drug Interactions (7.7)].

Magnesium-aluminum-hydroxide: In a single-dose crossover study with healthy volunteers, giving Tacrolimus and magnesium-aluminum-hydroxide together led to a 21% increase in the mean Tacrolimus AUC and a 10% decrease in the mean Tacrolimus Cmax compared to giving Tacrolimus alone [see Drug Interactions (7.10)].

Ketoconazole: When ketoconazole was given at the same time as Tacrolimus to six healthy volunteers, the oral bioavailability of Tacrolimus went from 15% to 30%. (200 mg). The oral clearance of Tacrolimus was much lower when ketoconazole was given than when Tacrolimus was given alone (0.4300.129 L/hr/kg vs. 0.1480.043 L/hr/kg). Overall, co-administering ketoconazole with Tacrolimus did not change IV clearance of Tacrolimus very much, but clearance varied a lot between patients [see Drug Interactions (7.4)].

Voriconazole (see full prescribing information for VFEND®): Repeated oral doses of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased the Cmax and AUC of Tacrolimus (0.1 mg/kg single dose) by an average of 2 times (90% CI: 1.9–2.5) and 3 times (90% CI: 2.7–3.8), respectively, in healthy people.

Posaconazole (see full prescribing information for Noxafil®): Repeated oral administration of 400 mg twice a day for 7 days of posaconazole increased the Cmax and AUC of Tacrolimus (0.05 mg/kg single dose) in healthy subjects by an average of 2 times (90% CI: 2.01, 2.42) and 4.5 times (90% CI: 4.03, 5.19), respectively.

Caspofungin (see the full CANCIDAS® prescribing information): Caspofungin decreased the blood levels of Tacrolimus by about 20%, the peak blood concentration (Cmax) by 16%, and the 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when Tacrolimus was given in two doses of 0.1 mg/kg 12 hours apart on the 10th day of CANCIDAS® 70 mg daily. This was compared to the results from a control

Nonclinical Toxicology
Cancer, birth defects, and infertility can all be caused by chemicals.
Rats and mice, both male and female, were used to test for carcinogenicity. In the 80-week study with mice and the 104-week study with rats, there was no link between the amount of Tacrolimus and the number of tumors. The highest doses used in mice were 3.0 mg/kg/day (0.9 to 2.2 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) and 5.0 mg/kg/day (0.265 to 0.65 times the AUC at clinical doses of 0.075 to 0.2 mg/kg/day) [see Boxed Warning and Warnings and Precautions (5.2)].

Mice were given Tacrolimus ointment (0.03% to 3%) for 104 weeks. This is the same as giving Tacrolimus doses of 1.1–118 mg/kg/day or 3.3–354 mg/m2/day. In the study, the number of skin tumors was low, and applying Tacrolimus topically was not linked to the growth of skin tumors under normal room lighting. In the mouse dermal carcinogenicity study, however, there was a statistically significant rise in the number of pleomorphic lymphomas in high-dose male (25/50) and female (27/50) animals and in the number of undifferentiated lymphomas in high-dose female (13/50) animals. In the mouse skin cancer study, a daily dose of 3.5 mg/kg (0.1% Tacrolimus ointment) led to lymphomas. In the mouse skin carcinogenicity study, a daily dose of 1.1 mg/kg (0.03% Tacrolimus ointment) did not cause any tumors. It is not known if putting Tacrolimus on the skin has any effect when the drug is taken by mouth.

There aren’t many ways that these carcinogenicity studies can be used to help people. For example, the animals were given doses of Tacrolimus that probably made their immune systems weaker, making it harder for their immune systems to stop cancers that weren’t caused by Tacrolimus.

There was no evidence of genotoxicity in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays in mice. Tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range of 0.075 to 0.2 mg/kg/day based on body surface area) to male and female rats before and during mating, as well as to dams during pregnancy and lactation, was linked to embryolethality and bad effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were shown by a higher rate of pre-implantation loss and a higher number of unborn and dead pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), Tacrolimus was linked to toxicity in both mothers and fathers, as well as toxicity in reproduction, including major problems with estrus cycles, birth, pup viability, and birth defects.

Clinical Studies
Transplanting a kidney
Tacrolimus/azathioprine (AZA): A randomized, multicenter, non-blinded, prospective trial looked at how well immunosuppression with tacrolimus, azathioprine, and corticosteroids worked after a kidney transplant. There were 412 people who needed a kidney transplant and signed up at 19 clinical sites in the US. When a serum creatinine level of 4 mg/dL showed that the kidney function was stable (on average, about 4 days after the transplant, but it could be anywhere from 1 to 14 days), the therapy for the study began. Patients younger than 6 years old were not included. 205 patients were given immunosuppression with Tacrolimus, and 207 patients were given immunosuppression with cyclosporine. All of the patients were given an antilymphocyte antibody preparation, corticosteroids, and azathioprine as preventive induction therapy. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively.Data from this trial of Tacrolimus in conjunction with azathioprine indicate that during the first three months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.Tacrolimus/mycophenolate mofetil (MMF)Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In Study 1, 1589 kidney transplant patients were given Tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) along with MMF and corticosteroids. All patients, except those in one of the two cyclosporine groups, were also given daclizumab to start the transplant process. The trial took place outside of the United States, and 93% of the people who took part were Caucasian. In this trial, the death rate at 12 months was the same for patients who got Tacrolimus/MMF (3%), cyclosporine/MMF (3% and 2%), or sirolimus/MMF (3%). Patients in the Tacrolimus group had higher estimated creatinine clearance rates (eCLcr) when the Cockcroft-Gault formula was used (Table 16). They also had fewer efficacy failures, which were defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or being lost to follow-up (Table 17). Patients who were given tacrolimus/MMF were more likely to get diarrhea and diabetes after the transplant, but they got infections at the same rate as patients who were given either cyclosporine/MMF regimen [see Adverse Reactions (6.1)].

Table 14. Estimated Creatinine Clearance at 12 Months (Study 1)
	eCLcr [mL/min] at Month 12 a
Group	N	MEAN	SD	MEDIAN	Treatment Difference with Group C (99.2% CIb)
(A) CsA/MMF/CS	390	56.5	25.8	56.9	-8.6 (-13.7, -3.7)
(B) CsA/MMF/CS/Daclizumab	399	58.9	25.6	60.9	-6.2 (-11.2, -1.2)
(C) Tac/MMF/CS/Daclizumab	401	65.099999999999994	27.4	66.2	–
(D) Siro/MMF/CS/Daclizumab	399	56.2	27.4	57.3	-8.9 (-14.1, -3.9)
Total	1589	59.2	26.8	60.5
Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

a)All death/graft loss (n=41, 27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D, respectively) were inputed with Glomerular Filtration Rate (GFR) of 10 mL/min; a subject’s last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D, respectively). If weight wasn’t known, it was made up when figuring out the estimated GFR.
b) Bonferroni corrections were used to account for the fact that there were six pairwise comparisons.

Table 15. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 1)
	Group AN=390	Group BN=399	Group CN=401	Group DN=399
Overall Failure	141 (36.2%)	126 (31.6%)	82 (20.4%)	185 (46.4%)
Components of efficacy failure
BPAR	113 (29.0%)	106 (26.6%)	60 (15.0%)	152 (38.1%)
Graft loss excluding death	28 (7.2%)	20 (5.0%)	12 (3.0%)	30 (7.5%)
Mortality	13 (3.3%)	7 (1.8%)	11 (2.7%)	12 (3.0%)
Lost to follow-up	5 (1.3%)	7 (1.8%)	5 (1.3%)	6 (1.5%)
Treatment Difference of efficacy failure compared to Group C (99.2% CIa )	15.8% (7.1%, 24.3%)	11.2% (2.7%, 19.5%)	–	26.0% (17.2%, 34.7%)
Key: Group A=CsA/MMF/CS, B=CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab

a) Bonferroni corrections were used to account for the six pairwise comparisons. Protocol-specified target Tacrolimus trough concentrations (C trough,Tac) were 3–7 ng/mL, but the observed median Ctroughs,Tac were about 7 ng/mL over the course of the 12-month trial (Table 18). About 80% of patients kept their whole blood concentrations of Tacrolimus between 4 and 11 ng/mL for a year after the transplant.

Table 16. Tacrolimus Whole Blood Trough Concentrations (Study 1)
Time	Median (P10-P90a) Tacrolimus whole blood trough concentrations(ng/mL)
Day 30 (N=366)	6.9 (4.4 to 11.3)
Day 90 (N=351)	6.8 (4.1 to 10.7)
Day 180 (N=355)	6.5 (4.0 to 9.6)
Day 365 (N=346)	6.5 (3.8 to 10.0)

a) 10th to 90th percentile: range of Ctrough, Tac that doesn’t include the lowest 10% and highest 10% of Ctrough, Tac. Target cyclosporine trough concentrations (C trough,CsA) for Group B were between 50 and 100 ng/mL, but the median C troughs,CsA were around 100 ng/mL over the course of the 12-month trial. Protocol-specified target C troughs, CsA for Group A were 150–300 ng/mL for the first 3 months and 100–200 ng/mL from month 4 to month 12; the observed median C troughs, CsA were about 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12. Patients in all groups started out taking 1 gram of MMF twice a day, but by month 12, 63% of patients in the Tacrolimus group had their dose cut to less than 2 g per day (Table 19). About 50% of these MMF dose cuts were due to side effects. By month 12, the MMF dose was cut down to less than 2 g per day in 49% and 45% of patients in Group A and Group B, respectively, who were taking cyclosporine. About 40% of MMF dose cuts were caused by side effects.

Table 17. MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)
Time period (Days)	Time-averaged MMF dose (grams per day) a
	Less than 2.0	2	Greater than 2.0
0-30 (N=364)	37%	60%	2%
0-90 (N=373)	47%	51%	2%
0-180 (N=377)	56%	42%	2%
0-365 (N=380)	63%	36%	1%
Key: Time-averaged MMF dose = (total MMF dose)/(duration of treatment)

a) The number of patients who were in each time-averaged MMF dose range during different treatment times. A time-averaged MMF dose of 2 g per day means that the amount of MMF given to these patients did not change during their treatment. In a second randomized, open-label, multi-center trial (Study 2), Tacrolimus (N=212) or cyclosporine (N=212) was given to 424 kidney transplant patients along with MMF 1 gram twice a day, basiliximab induction, and corticosteroids. In this trial, the rate of BPAR, graft failure, death, and/or being lost to follow-up at 12 months was the same in both the Tacrolimus/MMF group and the cyclosporine/MMF group. There was, however, a difference in the death rate at 12 months between those who got Tacrolimus/MMF (4%) and those who got cyclosporine/MMF (2%), with some deaths being caused by too much immune suppression (Table 20).

Table 18. Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months (Study 2)
	Tacrolimus/MMF (N=212)	Cyclosporine/MMF (N=212)
Overall Failure	32 (15.1%)	36 (17.0%)
Components of efficacy failure
BPAR	16 (7.5%)	29 (13.7%)
Graft loss excluding death	6 (2.8%)	4 (1.9%)
Mortality	9 (4.2%)	5 (2.4%)
Lost to follow-up	4 (1.9%)	5 (2.4%)
Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CIa)		1.9% (-5.2%, 9

a) Fisher’s Exact Test was used to figure out the 95% confidence interval.

In Study 2, the target concentrations of Tacrolimus in the blood (C trough,Tac) were 7–16 ng/mL for the first three months and 5–15 ng/mL after that. During the first three months, the median C troughs,Tac were about 10 ng/mL, and from month 4 to month 12, they were about 8 ng/mL. (Table 21). About 80% of patients kept their blood levels of Tacrolimus between 6 and 16 ng/mL during the first three months, and then between 5 and 12 ng/mL from the fourth month to the end of the year.

Table 19. Tacrolimus Whole Blood Trough Concentrations (Study 2)
Time	Median (P10-P90a) Tacrolimus whole blood trough concentrations(ng/mL)
Day 30 (N=174)	10.5 (6.3-16.8)
Day 60 (N=179)	9.2 (5.9-15.3)
Day 120 (N=176)	8.3 (4.6-13.3)
Day 180 (N=171)	7.8 (5.5-13.2)
Day 365 (N=178)	7.1 (4.2-12.4)

a) 10th to 90th Percentile: range of Ctrough, CsA that doesn’t include the lowest 10% and highest 10% of Ctrough, Tac. Whole blood concentrations of cyclosporine (C trough,CsA) were supposed to be between 125 and 400 ng/mL for the first three months and between 100 and 300 ng/mL after that. During the first three months, the median C troughs, CsA, were about 280 ng/mL, and from month 4 to month 12, they were about 190 ng/mL. Both groups of patients began taking MMF at a dose of 1 gram twice a day. By month 12, the amount of MMF given to 62% of patients in the Tacrolimus/MMF group and 47% of patients in the cyclosporine/MMF group was cut to less than 2 grams per day. About 63% and 55% of these MMF dose reductions were due to side effects in the Tacrolimus/MMF and cyclosporine/MMF groups, respectively [see Adverse Reactions (6.1)].

Table 20. MMF Dose Over Time in the Tacrolimus /MMF Group (Study 2)
Time period (Days)	Time-averaged MMF dose (grams per day) a
	Less than 2.0	2	Greater than 2.0
0-30 (N=212)	25%	69%	6%
0-90 (N=212)	41%	53%	6%
0-180 (N=212)	52%	41%	7%
0-365 (N=212)	62%	41%	7%
Key: Time-averaged MMF dose=(total MMF dose)/(duration of treatment)

a) The number of patients who were in each time-averaged MMF dose range during different treatment times. Two grams of MMF per day, averaged over time, means that the amount of MMF given to these patients did not go down while they were being treated.

Transplantation of the liver

Two prospective, randomized, non-blinded, multicenter trials were done to test the safety and effectiveness of Tacrolimus-based immunosuppression after orthotopic liver transplantation. The immunosuppressive regimen (CsA/AZA), which was based on cyclosporine, was used to treat the active control groups. Immunosuppressants were used in both trials, and corticosteroids were given to the adrenal glands at the same time. In these tests, the survival rates of patients and grafts were compared 12 months after a transplant.

In one trial, 529 people were signed up at 12 clinics in the US. Before surgery, 263 people were given the Tacrolimus-based immunosuppressive regimen and 266 people were given the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, but in 2 sites, different control protocols were used. Patients with kidney problems, cancer, or fulminant hepatic failure with Stage IV encephalopathy were not allowed to take part in this trial. Patients younger than 12 years old were, however.

In the second trial, 545 people were signed up at 8 clinical sites in Europe. Before surgery, 270 people were given the Tacrolimus-based immunosuppressive regimen and 275 people were given the CsA/AZA regimen. In the active-control arm of this study, each center used its local standard CsA/AZA protocol. This study didn’t include children, but people with kidney problems, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases were allowed to join.

In both trials, patient survival and graft survival at one year were the same in the Tacrolimus-based treatment groups as in the CsA/AZA treatment groups. In the U.S. trial, 88% of people who were treated with CsA/AZA and 78% of people who were treated with Tacrolimus lived for at least one year. In the U.S. trial, 81% of grafts lived for a year after treatment with CsA/AZA or Tacrolimus. In the European trial, 73% of grafts lived for a year after treatment with CsA/AZA or Tacrolimus. In both trials, the average time it took to switch from giving Tacrolimus by IV to giving it by mouth was 2 days.

Even though there isn’t a direct link between the amount of Tacrolimus in the blood and how well the drug works, data from clinical trials of liver transplant patients has shown that the number of side effects goes up as trough blood concentrations go up. When trough whole blood concentrations stay between 5 and 20 ng/mL, most patients are stable. People who have had a transplant for a long time are often kept at the low end of this target range.

From the U.S. clinical trial, we know that the median trough blood concentrations ranged from 9.8 ng/mL to 19.4 ng/mL. This was measured at different times between the second week and one year after the transplant.

Getting a new heart

The safety and effectiveness of Tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation were studied in two randomized, open-label trials. In a trial done in Europe, 314 people took a combination of Tacrolimus or cyclosporine modified with antibody induction, corticosteroids, and azathioprine for 18 months. In the US, 331 patients took corticosteroids and either Tacrolimus plus sirolimus, Tacrolimus plus mycophenolate mofetil (MMF), or cyclosporine modified plus MMF for a year.

In the European trial, patient and graft survival was the same 18 months after the transplant, with 92% in the Tacrolimus group and 90% in the cyclosporine group still alive. In the U.S. trial, 93% of patients and 86% of grafts were still alive after 12 months in the Tacrolimus plus MMF group and in the cyclosporine modified plus MMF group, respectively. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (100 to 200 ng/mL) at Day 122 and later in 32 to 68% of the cyclosporine-treated patients, but in 74 to 86% of the Tacrolimus-treated patients, the trough concentrations were within the pre-defined target range (5 to 15 ng/mL). From one week to three months after the transplant, about 80% of the patients kept their trough concentrations between 8 and 20 ng/mL, and from three months to 18 months after the transplant, about 80% of the patients kept their trough concentrations between 6 and 18 ng/mL.

The third arm of the U.S. trial was a combination regimen of sirolimus, 2 mg per day, and full-dose Tacrolimus. However, this regimen was linked to a higher risk of wound healing problems, impaired kidney function, and insulin-dependent diabetes mellitus after transplant, so it is not recommended [see Warnings and Precautions (5.12)].

How Delivered, Stored, and Handled

Tacrolimus Capsules USP

Tacrolimus Capsules USP, 0.5 mg are a white to off-white powder that comes in a hard gelatin capsule of size “4” with a yellow opaque cap and a yellow opaque body that has “BP 665” and “0.5 mg” written in red ink twice on the body and twice on the cap.

Lots of 100 bottles. NDC 82983-400-10

Tacrolimus Capsules USP, 1 mg are a white to off-white powder that comes in a hard gelatin capsule of size ‘4’ with a white opaque cap and a white opaque body that says “BP 666” twice on the body and “1 mg” twice on the cap in red ink.

100 bottles. NDC: 82983-401-10.

Tacrolimus Capsules USP, 5 mg are a white to off-white powder that comes in a hard gelatin capsule of size 4, with a salmon opaque cap and a salmon opaque body that has “BP 667” printed on the body and “5 mg” written twice in white ink on the cap.

100 bottles. NDC: 82983-402-10.

Note: Tacrolimus capsules are not filled all the way to the top. Each capsule has the amount written on it.

Store and Dispense

Store at 25°C (77°F); deviations are allowed between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].

Information for Patient Counseling

Administration

Tell your patients to:

• Take Tacrolimus at the same time every day, every 12 hours, to keep the blood concentrations the same.
• Take Tacrolimus regularly, either with or without food. The presence and make-up of food decreases how well Tacrolimus works in the body.
• Don’t eat grapefruit or drink grapefruit juice while taking Tacrolimus. For more information, see Drug Interactions (7.2).

How Lymphoma and other cancers come to be

Immunosuppression makes patients more likely to get lymphomas and other cancers, especially of the skin. Tell patients that they should wear protective clothing and use a sunscreen with a high protection factor to limit their exposure to sunlight and ultraviolet (UV) light [see Warnings and Precautions (5.2)].

More likely to get sick

Tell patients that immunosuppression makes them more likely to get infections, including opportunistic infections, and that they should call their doctor if they start to feel sick [see Warnings and Precautions (5.3, 5.4, 5.5)].

New Onset Diabetes After Transplant

Tell patients that Tacrolimus can cause diabetes mellitus and that they should call their doctor if they start to urinate more often, have more thirst, or feel hungry all the time [see Warnings and Precautions (5.6)].

Nephrotoxicity

Tell patients that Tacrolimus can have harmful effects on the kidneys that need to be watched. Tell patients to go to all of their doctor’s appointments and do all of the blood tests that their doctors ask them to do [see Warnings and Precautions (5.7)].

Neurotoxicity

Tell patients that they may have bad neurologic effects, such as a seizure, a change in their mental state, or tremors, and that they should call their doctor if they have vision changes, a change in their mental state, or tremors [see Warnings and Precautions (5.8)].

Hyperkalemia

Tell patients that Tacrolimus can cause high potassium levels. It may be necessary to check potassium levels, especially if they are also taking other drugs that can cause high potassium levels [see Warnings and Precautions (5.9)].

Hypertension

Tell patients that Tacrolimus can cause high blood pressure, which may need to be treated with anti-hypertensive therapy [see Warnings and Precautions (5.10)].

How Drugs Interact

Tell patients to let their doctors know when they start or stop taking any medicine, including prescription and over-the-counter medicines, natural or herbal remedies, nutritional supplements, and vitamins [see Drug Interactions (7)].

Women who are pregnant or who are nursing

[See Use in Specific Populations (8.1, 8.3)] Tell patients to let their doctor know if they want to get pregnant or breastfeed their child.

Immunizations

Tell patients that Tacrolimus can make them less likely to respond normally to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.16)].

Only Rx

Made in the USA

Who Sent It Out:

Ajenat Pharmaceuticals LLC

203 North Marion Street,

Tampa, FL 33602 USA

L54I-AJT

R-2302

Rev: 12/19

PATIENT INFORMATION

Tacrolimus capsules, USP

Read this Patient Information before you start taking Tacrolimus and every time you get a refill. There may be new information. This information does not replace talking to your doctor about your medical condition or treatment.

What should I know about Tacrolimus that is the most important?

Serious side effects can happen from taking Tacrolimus, such as:

1. Higher chance of getting cancer. People who take Tacrolimus have a higher chance of getting some kinds of cancer, like skin cancer and cancer of the lymph glands (lymphoma).

2. Increased risk of infection. Tacrolimus is a medicine that affects your immune system. It can make your immune system less able to fight infections. People who take Tacrolimus can get serious infections that can kill them.

• Fever
• Gets hot or cold
• A cough or signs of the flu
• Muscle aches
• Spots on your skin that are hot, red, or hurt.

Describe Tacrolimus.

Tacrolimus is a prescription medicine that is used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant. Tacrolimus should not be used with medicines called cyclosporines (Gengraf®, Neoral®, and Sandimune®).

People who have had a liver or heart transplant should not take tacrolimus with sirolimus (Rapamune®).

People who have had kidney transplants do not know if Tacrolimus is safe and effective when used with sirolimus.

It is not known if Tacrolimus is safe and effective for children who have had a kidney or heart transplant.

Who shouldn’t take Tacrolimus?

Do not take Tacrolimus if you are allergic to it or any of the ingredients in it. The full list of ingredients in Tacrolimus is at the end of this leaflet.

What do I need to tell my doctor before I can take Tacrolimus?

Before taking Tacrolimus, you should tell your doctor if:

• Plan to get any vaccines with live viruses.
• Have or have had liver, kidney or heart problems
• If you are pregnant or want to become pregnant, talk to your doctor about Tacrolimus. It could hurt your unborn child.
• Are breastfeeding or plan to breastfeed. Tacrolimus can get into your breast milk. You and your doctor should decide if you will take Tacrolimus or breastfeed. You shouldn’t do both.

Tell your doctor about all the medicines you take, whether they are prescribed or not, vitamins, herbal supplements, or over-the-counter drugs.

Especially tell your doctor if you take:

• Cyclosporine is sold under the brand names Gengraf®, Neoral®, and Sandimune®.
• Sirolimus (Rapamune ®)
• Nelfinavir (Viracept ®)
• Telaprevir (Incivek™)
• (victrelistm) boceprevir
• Amiodarone (Cordarone™, Nexterone™, Pacerone™)
• If you aren’t sure if you take any of the medicines above, talk to your doctor or pharmacist.
• Tacrolimus might change how other drugs work, and other drugs might change how Tacrolimus works.
• Keep a list of the medicines you take and show it to your doctor and pharmacist when you need a new one.

How do I take the drug Tacrolimus?

• Follow your doctor’s instructions for how to take Tacrolimus.
• Your doctor will tell you how much and when to take Tacrolimus.
• If necessary, your doctor may change the amount of Tacrolimus you take. Do not stop taking Tacrolimus or change the amount you take without first talking to your doctor.
• Tacrolimus can be taken with or without food.
• Take Tacrolimus the same way every time. For example, if you choose to take it with food, you should always take it with food.
• Take Tacrolimus at the same time every day, 12 hours apart. For example, if you take your first dose at 7:00 a.m., you should take your second dose at 7:00 p.m.
• Taking Tacrolimus at the same time every day helps your body keep enough medicine in it to give your transplanted organ the medicine it needs all the time.
• If you are taking Tacrolimus, don’t eat grapefruit or drink grapefruit juice.
• If you take too much Tacrolimus, call your doctor right away or go to the emergency room of the nearest hospital.

What should I stay away from while I’m on Tacrolimus?

You shouldn’t get any live vaccines while taking Tacrolimus, such as:

• You get the flu shot up your nose.
• Measles
• Mumps
• Rubella
• Mouth to mouth
• BCG (TB vaccine) (TB vaccine)
• Yellow fever means:
• The hives (varicella)
• Typhoid

Don’t go out in the sun or use a tanning bed. Instead, wear protective clothing and use sunscreen.

What are some possible Tacrolimus side effects?

Serious side effects of Tacrolimus include:

See “What’s the most important thing I should know about Tacrolimus?”

While you are taking Tacrolimus, your doctor may do certain tests to check for diabetes. Call your doctor right away if you have:

Frequent urination

Thirst or hunger that got worse

Vision isn’t clear

Confusion

Drowsiness

Loss of hunger

Your breath smells like fruit.

Nausea, vomiting, or pain in the stomach

• Problems with your kidneys. While you take Tacrolimus, your doctor may do certain tests to check how well your kidneys work.
• Problems with your nervous system. If you have any of these symptoms while taking Tacrolimus, call your doctor right away. These could be signs of a serious problem with your nervous system:

Confusion

Coma

Muscle tremors

Feeling numb and tingling

Headache

Seizures

Changes in vision

• High levels of potassium in your blood. While you are taking tacrolimus, your doctor may do certain tests to check your potassium level.
• High blood pressure. While you take tacrolimus, your doctor will keep an eye on your blood pressure.
• Heart problems (myocardial hypertrophy). Tell your doctor right away if you have any of these signs of heart problems while taking tacrolimus:

• I can’t get enough air
• Chest pain
• Feel like passing out
• Feel faint

Most people who get a kidney transplant and take Tacrolimus will experience:

• Infection
• Tremors (shaking of the body) (shaking of the body)
• Blood pressure too high
• Kidney problems
• Constipation
• Diarrhea
• Headache
• Stomach pain
• Trouble sleeping
• Nausea
• Your blood has too little phosphate
• Hands, feet, or legs that are swollen
• Weakness
• Pain
• Fat in your blood in high amounts
• Your blood has a lot of potassium
• Low number of red blood cells (anemia)

When it comes to people getting liver transplants, the most common side effects of Tacrolimus are:

• The body shakes tremors
• Headache
• Diarrhea
• Blood pressure too high
• Nausea
• Kidney problems
• Stomach pain
• Trouble sleeping
• Hands or feet that feel numb or tingly
• Anemia
• Pain
• Fever
• Weakness
• High potassium levels in the blood

blood magnesium levels that are too low

For people who have had a heart transplant, the most common side effects of Tacrolimus are:

• kidney problems
• blood pressure too high

Tell your doctor about any side effects that bother you or don’t go away.

Not all of the side effects of Tacrolimus are listed here. If you want to know more, talk to your doctor or pharmacist.

You can talk to your doctor about side effects or call 1-800-FDA-1088 to tell the FDA about them.

What’s the best way to store Tacrolimus?

• Keep Tacrolimus between 15°C and 30°C (59°F to 86°F).
• Medicine that is out of date or no longer needed should be thrown away in a safe way.

Keep Tacrolimus and all other medicines away from kids.

General information about how to use Tacrolimus safely and effectively

Medicines are sometimes given for reasons that aren’t on the Patient Information leaflet. Don’t use Tacrolimus for something it wasn’t meant for, and don’t give it to anyone else, even if they have the same symptoms as you. It could hurt them.

How does my new organ get protected by Tacrolimus?

When a person has a liver, kidney, or heart transplant, the immune system does not recognize the new organ as part of the body and tries to get rid of it. This is called “rejection.” Tacrolimus protects your new organ by slowing down the body’s immune system.

This Patient Information leaflet is a summary of the most important information about Tacrolimus. If you want more information, talk to your doctor.

Visit www.ajenatpharma.com or call 1-727-234-8872 to find out more.

What kinds of things are in Tacrolimus?

Tacrolimus is the active ingredient.

Anhydrous Lactose, Hypromellose, Croscarmellose Sodium, Magnesium Stearate, Gelatin, Titanium Dioxide, and Ferric Oxide are the ingredients that don’t do anything.

Shellac Glaze, Iron Oxide Red, and Simethicone USP are non-volatile parts of the ink.

Trademarks belong to the people who created them.

The U.S. Food and Drug Administration has given its OK to this Patient Information.

Made in the USA

Who Sent It Out:

Ajenat Pharmaceuticals LLC

203 North Marion Street,

Tampa, FL 33602 USA

L54I-AJT

R-2302

Rev: 12/19

The main display pannel

NDC 82983-400-10

Tacrolimus Capsules, USP 0.5 mg

Only Rx

Each capsule has 0.5 mg of Tacrolimus USP.

Store at 25°C (77°F), with a range of 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

To find out how much to take, look at the package insert.

100 Capsules

NDC 82983-401-10

Tacrolimus Capsules, USP 1 mg

Only Rx

Tacrolimus USP 1 mg is in each capsule.

Keep at 25°C (77°F), but you can go between 15°C and 30°C (59°F and 86°F) See USP Controlled Room Temperature for more info.
Dosage: See Package Insert for dosage information.

100 Capsule

NDC 82983-402-10

Tacrolimus Capsules, USP 5 mg

Only Rx

Tacrolimus USP 5 mg is in each capsule.

Keep at 25°C (77°F), but you can go between 15°C and 30°C (59°F and 86°F) See USP Controlled Room Temperature for more info.
Dosage: See Package Insert for dosage information.

100 Capsules

Made in the USA

Who Sent It Out:

Ajenat Pharmaceuticals LLC

203 North Marion Street,

Tampa, FL 33602 USA

L54I-AJT

R-2302

Rev: 12/19

Tacrolimus Tacrolimus capsule
Product Information
Product Type	HUMAN PRESCRIPTION DRUG LABEL	Item Code (Source)	NDC:82983-400
Route of Administration	ORAL	DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Tacrolimus (Tacrolimus ANHYDROUS)	Tacrolimus ANHYDROUS	0.5 mg
Inactive Ingredients
Ingredient Name	Strength
ANHYDROUS LACTOSE
HYPROMELLOSE 2208 (100 MPA.S)
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
SHELLAC
FERRIC OXIDE RED
DIMETHICONE
HYDRATED SILICA
Product Characteristics
Color	yellow (yellow opaque body and yellow oaque cap)	Score	no score
Shape	CAPSULE	Size	14mm
Flavor		Imprint Code	05;mg;BP;665
Contains
Packaging
#	Item Code	Package Description
1	NDC:82983-400-10	100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA206651	01/31/2023
Tacrolimus
Tacrolimus capsule
Product Information
Product Type	HUMAN PRESCRIPTION DRUG LABEL	Item Code (Source)	NDC:82983-401
Route of Administration	ORAL	DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Tacrolimus (Tacrolimus ANHYDROUS)	Tacrolimus ANHYDROUS	1 mg
Inactive Ingredients
Ingredient Name	Strength
ANHYDROUS LACTOSE
HYPROMELLOSE 2208 (100 MPA.S)
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
SHELLAC
FERRIC OXIDE RED
DIMETHICONE
HYDRATED SILICA
Product Characteristics
Color	white (white opaque body and white oaque cap)	Score	no score
Shape	CAPSULE	Size	14mm
Flavor		Imprint Code	1;mg;BP;666
Contains
Packaging
#	Item Code	Package Description
1	NDC:82983-401-10	100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA206651	01/31/2023
Tacrolimus
Tacrolimus capsule
Product Information
Product Type	HUMAN PRESCRIPTION DRUG LABEL	Item Code (Source)	NDC:82983-402
Route of Administration	ORAL	DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Tacrolimus (Tacrolimus ANHYDROUS)	Tacrolimus ANHYDROUS	5 mg
Inactive Ingredients
Ingredient Name	Strength
ANHYDROUS LACTOSE
HYPROMELLOSE 2208 (100 MPA.S)
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
GELATIN, UNSPECIFIED
TITANIUM DIOXIDE
SHELLAC
FERRIC OXIDE RED
DIMETHICONE
HYDRATED SILICA
Product Characteristics
Color	red (salmon opaque body and salmon oaque cap)	Score	no score
Shape	CAPSULE	Size	14mm
Flavor		Imprint Code	5;mg;BP;667
Contains
Packaging
#	Item Code	Package Description
1	NDC:82983-402-10	100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA206651	01/31/2023
Labeler – Ajenat Pharmaceuticals LLC (118777896)
Establishment
Name	Address	ID/FEI	Operations
Belcher Pharmaceuticals LLC		965082543	MANUFACTURE(82983-400, 82983-401, 82983-402), ANALYSIS(82983-400, 82983-401, 82983-402)

Ajenat Pharmaceuticals LLC

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