Prograf
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Side effects
What Is Tacrolimus (Prograf)?
Tacrolimus is the generic version of the brand name drug Prograf, which is used along with other medicines to prevent organ rejection in people who've had a kidney, liver, or heart transplant.
The drug is also sometimes used to treat Crohn's disease (a condition where the body attacks the lining of the digestive tract).
Prograf (tacrolimus) is an immunosuppressant. It works by blocking the action of certain blood cells that can prompt the body to reject a transplanted organ.
The Food and Drug Administration (FDA) approved tacrolimus in 1994. Prograf is manufactured by Astellas Pharma US.
Tacrolimus Warnings
Tacrolimus contains a black-box warning because it may increase your risk of infection and your chances of developing skin cancer or lymphoma.
Tell your doctor right away if you notice any of the following symptoms while taking tacrolimus:
- Signs of infection, which may include fever, chills, or sore throat
- Unusual growths or lumps
- Any changes in the appearance or size of a mole
- Night sweats
- Unusual tiredness or weakness
- Swollen lymph nodes in the neck, armpits, or groin
- Weight loss
- Trouble breathing
- Chest pain
- Cough
- Pain, swelling, or fullness in the stomach area
To lower your risk of skin cancer, avoid tanning beds and unnecessary exposure to sunlight while taking this drug. Wear protective clothing and sunscreen if you must be outdoors.
This medicine should only be given under the supervision of a physician who is experienced in treating organ transplant patients and administering drugs that decrease the activity of the immune system.
Before taking tacrolimus, tell your doctor if you have or have had:
- Kidney disease
- Heart disease
- Pure red blood cell aplasia (a type of anemia)
- Long QT syndrome (a heart rhythm disorder)
- Liver disease
- A history of infections
- High blood pressure
- Diabetes
- High levels of potassium in the blood
- A weakened immune system
- Skin cancer or a family history of skin cancer
- Allergies to medications
Be sure to tell your physician about all the drugs you take. Some medications may increase your chances of developing QT prolongation (a type of irregular heartbeat).
Also, tell your healthcare provider if you take or if you've recently stopped taking the drug Gengraf, Neoral or Sandimmune (cyclosporine).
Your physician will probably tell you not to start tacrolimus until 24 hours after your last dose of cyclosporine.
Tacrolimus may cause high blood pressure. Your doctor will need to monitor your blood pressure carefully during your treatment.
The medicine may also increase your chances of developing diabetes during treatment. Hispanics and African Americans who've had kidney transplants are at an especially high risk.
Tell your physician if you or anyone in your family has ever had diabetes, and tell your doctor immediately if you experience any of the following symptoms:
- Excessive thirst or hunger
- Frequent urination
- Blurred vision
- Confusion
Let your healthcare provider know you're taking this medicine before having any type of surgery, including a dental procedure.
Don't receive any vaccination while taking tacrolimus without first talking to your doctor.
Continue to take tacrolimus even if you feel well. Don't stop using this medicine without first talking to your doctor.
Keep all appointments with your healthcare provider while taking this drug. Your doctor will want to frequently monitor your body's response to the therapy.
Pregnancy and Tacrolimus
Tacrolimus may cause harm to an unborn baby.
Tell your doctor if you're pregnant or might become pregnant before taking this medicine.
The drug can be found in breast milk. Don't breastfeed a baby while taking tacrolimus.
Indications
Prophylaxis Of Organ Rejection In Kidney Transplant
Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic kidneytransplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].
Prophylaxis Of Organ Rejection In Liver Transplant
Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver transplants. It is recommended that Prograf be used concomitantly with adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].
Prophylaxis Of Organ Rejection In Heart Transplant
Prograf is indicated for the prophylaxis of organ rejection in patients receiving allogeneic heart transplants. It is recommended that Prograf be used concomitantly with azathioprine or mycophenolate mofetil (MMF) and adrenal corticosteroids [see Clinical Studies]. Therapeutic drug monitoring is recommended for all patients receiving Prograf [see DOSAGE AND ADMINISTRATION].
Limitations Of Use
Prograf should not be used simultaneously with cyclosporine [see DOSAGE AND ADMINISTRATION].
Prograf injection should be reserved for patients unable to take Prograf capsules orally [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Use with sirolimus is not recommended in liver and heart transplant. The safety and efficacy of Prograf with sirolimus has not been established in kidney transplant [see WARNINGS AND PRECAUTIONS].
Warnings
Included as part of the PRECAUTIONS section.
Related health
- Eczema
- Hypertensive Kidney Disease
- Inflammatory Bowel Disease (Intestinal Problems of IBD)
- Kidney Failure
Prograf Precautions
Prograf can cause serious side effects, including:
- increased risk of cancer. People who take Prograf have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
- increased risk of infection. Prograf is a medicine that affects your immune system. Prograf can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving Prograf that can cause death. Call your doctor right away if you have symptoms of an infection such as:
- fever
- sweats or chills
- cough or flu-like symptoms
- muscle aches
- warm, red, or painful areas on your skin
- high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take Prograf. Call your doctor right away if you have:
- frequent urination
- increased thirst or hunger
- blurred vision
- confusion
- drowsiness
- loss of appetite
- fruity smell on your breath
- nausea, vomiting, or stomach pain
- kidney problems. Your doctor may do certain tests to check your kidney function while you take Prograf.
- nervous system problems. Call your doctor right away if you get any of these symptoms while taking Prograf. These could be signs of a serious nervous system problem:
- confusion
- coma
- muscle tremors
- numbness and tingling
- headache
- seizures
- vision changes
- high levels of potassium in your blood. Your doctor may do certain tests to check your potassium level while you take Prograf.
- high blood pressure. Your doctor will monitor your blood pressure while you take Prograf.
- heart problems (myocardial hypertrophy). Tell your doctor right away if you get any of these symptoms of heart problems while taking Prograf:
- shortness of breath
- chest pain
- feel lightheaded
- feel faint
- gastrointestinal perforation which is a hole that develops through the wall of the esophagus, stomach, small intestine, large bowel, rectum, or gallbladder.
- severe allergic reactions to the injection. Tell your doctor right away if you get any of these symptoms while taking Prograf:
- ​difficulty breathing
- itching
- rash
Do not take Prograf if you are allergic to Prograf or any of the ingredients in Prograf including HCO-60 (polyoxyl 60 hydrogenated castor oil).
While you take Prograf you should not receive any live vaccines such as:
Avoid exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.
- flu vaccine through your nose
- measles
- mumps
- rubella
- polio by mouth
- BCG (TB vaccine)
- yellow fever
- chicken pox (varicella)
- typhoid
Prograf and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
Prograf falls into category C. No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Prograf may harm your unborn baby. Prograf should be given to a pregnant woman only if clearly needed.
Prograf FDA Warning
BOX WARNING - MALIGNANCIES AND SERIOUS INFECTIONS
- Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression.
- Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections.
- Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
Overdosage
Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in Adverse Reactions (6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.
In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections).
Prograf Description
Prograf is available for oral administration as capsules (tacrolimus capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive ingredients include lactose monohydrate NF, hypromellose USP, croscarmellose sodium NF, and magnesium stearate NF. The 0.5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF, the 1 mg capsule shell contains gelatin NF and titanium dioxide USP, and the 5 mg capsule shell contains gelatin NF, titanium dioxide USP and ferric oxide NF.
Prograf is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by intravenous infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.
Tacrolimus, previously known as FK506, is the active ingredient in Prograf. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [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.
The chemical structure of tacrolimus is:
Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.
Prograf - Clinical Pharmacology
Mechanism of Action
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.
In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.
Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 14).
| * not applicable † AUC0-120 ‡ AUC0-72 § Corrected for individual bioavailability ¶ AUC0-inf # not available Þ AUC0-t ß Determined after the first dose à Median [range] è AUC0-12 | ||||||||
| Population | N | Route (Dose) | Parameters | |||||
| Cmax (ng/mL) | Tmax (hr) | AUC (ng•hr/mL) | t1/2 (hr) | CI (L/hr/kg) | V (L/kg) | |||
| Healthy Volunteers | 8 | IV (0.025 mg/kg/4hr) | * | * | 598† ± 125 | 34.2 ± 7.7 | 0.040 ± 0.009 | 1.91 ± 0.31 |
| 16 | PO (5 mg) | 29.7 ± 7.2 | 1.6 ± 0.7 | 243‡ ± 73 | 34.8 ± 11.4 | 0.041§ ± 0.008 | 1.94§ ± 0.53 | |
| Kidney Transplant Patients | 26 | IV (0.02 mg/kg/12 hr) | * | * | 294¶ ± 262 | 18.8 ± 16.7 | 0.083 ± 0.050 | 1.41 ± 0.66 |
| PO (0.2 mg/kg/day) | 19.2 ± 10.3 | 3.0 | 203¶ ± 42 | # | # | # | ||
| PO (0.3 mg/kg/day) | 24.2 ± 15.8 | 1.5 | 288¶ ± 93 | # | # | # | ||
| Liver Transplant Patients | 17 | IV (0.05 mg/kg/12 hr) | * | * | 3300¶ ± 2130 | 11.7 ± 3.9 | 0.053 ± 0.017 | 0.85 ± 0.30 |
| PO (0.3 mg/kg/day) | 68.5 ± 30.0 | 2.3 ± 1.5 | 519¶ ± 179 | # | # | # | ||
| Heart Transplant Patients | 11 | IV (0.01 mg/kg/day as a continuous infusion) | * | * | 954Þ ± 334 | 23.6 ± 9.22 | 0.051 ± 0.015 | # |
| 11 | PO (0.075 mg/kg/day)ß | 14.7 + 7.79 | 2.1 [0.5-6.0]à | 82.7è ± 63.2 | * | # | # | |
| 14 | PO (0.15 mg/kg/day)ß | 24.5 ± 13.7 | 1.5 [0.4-4.0]à | 142è ± 116 | * | # | # | |
Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.
Absorption
Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), 23±9% in adult heart transplant patients (N=11) and 18±5% in healthy volunteers (N=16).
A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.
In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.
Food Effects
The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.
The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.
In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.
In 11 liver transplant patients, Prograf administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27±18%) and Cmax (50±19%), as compared to a fasted state.
Prograf capsules should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of Prograf [see Dosage and Administration (2.5)].
Distribution
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).
Metabolism
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
Excretion
The mean clearance following IV administration of tacrolimus is 0.040, 0.083, and 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.
In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8±12.7%. Fecal elimination accounted for 92.4±1.0% and the elimination half-life based on radioactivity was 48.1±15.9 hours whereas it was 43.5±11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029±0.015 L/hr/kg and clearance of tacrolimus was 0.029±0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9±30.7%. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1% and the elimination half-life based on radioactivity was 31.9±10.5 hours whereas it was 48.4±12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226±0.116 L/hr/kg and clearance of tacrolimus 0.172±0.088 L/hr/kg.
Specific Populations
Pediatric
Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5±3.8 hours, 2.6±2.1 L/kg and 0.138±0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and Cmax were 337±167 ng·hr/mL and 48.4±27.9 ng/mL, respectively. The absolute bioavailability was 31±24%.
Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Dosage and Administration (2.2)].
Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2±2.4 years of age. Following IV infusion of a 0.06 (range 0.06 – 0.09) mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (range 3.4-25) hours and 0.12±0.04 (range 0.06-0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and Cmax were 181±65 (range 81-300) ng·hr/mL and 30±11 (range 14-49) ng/mL, respectively. The absolute bioavailability was 19±14 (range 5.2-56) %.
Renal and Hepatic Impairment
The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 15.
| * corrected for bioavailability † 1 patient did not receive the PO dose | |||||
| Population (No. of Patients) | Dose | AUC0-t (ng·hr/mL) | t1/2 (hr) | V (L/kg) | CI (L/hr/kg) |
| Renal Impairment (n=12) | 0.02 mg/kg/4hr IV | 393±123 (t=60 hr) | 26.3±9.2 | 1.07 ±0.20 | 0.038 ±0.014 |
| Mild Hepatic Impairment (n=6) | 0.02 mg/kg/4hr IV | 367±107 (t=72 hr) | 60.6±43.8 Range: 27.8 – 141 | 3.1±1.6 | 0.042 ±0.02 |
| 7.7 mg PO | 488±320 (t=72 hr) | 66.1±44.8 Range: 29.5 – 138 | 3.7±4.7* | 0.034 ±0.019* | |
| Severe Hepatic Impairment (n=6, IV) | 0.02 mg/kg/4hr IV (n=2) IV (n=4) | 762±204 (t=120 hr) (t=144 hr) | 198±158 Range: 81-436 | 3.9±1.0 | 0.017 ±0.013 |
| (n=5, PO)† | 8 mg PO (n=1) (n=4) 4 mg PO (n=1) | 658 (t=120 hr) | 119±35 Range: 85-178 | 3.1±3.4* | 0.016 ±0.011* |
Renal Impairment: Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 15) [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
Hepatic Impairment: Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: >10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].
Race
The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Prograf to 10 African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was significantly lower than in Caucasians (40.2±12.6 ng/mL) and the Latino-Americans (36.2±15.8 ng/mL) (p<0.01). Mean AUC0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino-Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was significantly lower than in Caucasians (19±5.8%, p=0.011). There was no significant difference in mean terminal T1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.1)].
Gender
A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver and heart transplant patients indicated no gender-based differences.
Drug Interactions
Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].
Telaprevir: In a single dose study in 9 healthy volunteers, coadministration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.3)].
Boceprevir: In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.3)].
Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of Prograf and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.3)].
Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036±0.008 L/hr/kg vs. 0.053±0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.7)].
Magnesium-aluminum-hydroxide: In a single-dose crossover study in healthy volunteers, co-administration of tacrolimus and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see Drug Interactions (7.10)].
Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole co-administration, although it was highly variable between patients [see Drug Interactions (7.4)].
Voriconazole (see complete prescribing information for VFEND®): Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see Drug Interactions (7.4)].
Posaconazole (see complete prescribing information for Noxafil®): Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see Drug Interactions (7.4)].
Caspofungin (see complete prescribing information for CANCIDAS®): Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see Drug Interactions (7.4)].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 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 in the rat was 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)].
A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2/day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.
The implications of these carcinogenicity studies to the human condition are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals impairing their immune system’s ability to inhibit unrelated carcinogenesis.
No evidence of genotoxicity was seen 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 performed 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, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable 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 associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.