Tacrolimus: Package Insert and Label Information (Page 10 of 11)

14.2 Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to the CsA/AZA. In 10 of the 12 sites, the same CsA/AZA protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CsA/AZA. In this trial, each center used its local standard CsA/AZA protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and tacrolimus-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and tacrolimus-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral tacrolimus dosing was 2 days.

Although there is a lack of direct correlation between tacrolimus concentrations and drug efficacy, data from clinical trials of liver transplant patients have shown an increasing incidence of adverse reactions with increasing trough blood concentrations. Most patients are stable when trough whole blood concentrations are maintained between 5 to 20 ng/mL. Long-term post-transplant patients are often maintained at the low end of this target range. Data from the U.S. clinical trial show that the median trough blood concentrations, measured at intervals from the second week to one year post-transplantation, ranged from 9.8 ng/mL to 19.4 ng/mL.

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

14.3 Heart Transplantation

Two open-label, randomized, comparative trials evaluated the safety and efficacy of tacrolimus-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with tacrolimus or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and tacrolimus plus sirolimus, tacrolimus plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year.

In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the tacrolimus plus MMF group and 86% survival in the cyclosporine modified plus MMF group. In the European trial, the cyclosporine trough concentrations were above the pre-defined target range (i.e., 100 to 200 ng/mL) at Day 122 and beyond in 32% to 68% of the patients in the cyclosporine treatment arm, whereas the tacrolimus trough concentrations were within the pre-defined target range (i.e., 5 to 15 ng/mL) in 74% to 86% of the patients in the tacrolimus treatment arm. Data from this European trial indicate that from 1 week to 3 months post-transplant, approximately 80% of patients maintained trough concentrations between 8 to 20 ng/mL and, from 3 months through 18 months post-transplant, approximately 80% of patients maintained trough concentrations between 6 to 18 ng/mL.

The U.S. trial contained a third arm of a combination regimen of sirolimus, 2 mg per day, and full-dose tacrolimus; however, this regimen was associated with increased risk of wound-healing complications, renal function impairment, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Warnings and Precautions (5.10)] .

15 REFERENCES

  1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Tacrolimus Capsules

Tacrolimus Capsules, USP are available containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus, USP.

The 0.5 mg capsules are hard-shell gelatin capsules with a light orange opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2045 in black ink on both the cap and the body. They are available as follows:

NDC 60429-377-01
bottles of 100 capsules

The 1 mg capsules are hard-shell gelatin capsules with a light blue opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2046 in black ink on both the cap and the body. They are available as follows:

NDC 60429-378-01
bottles of 100 capsules

The 5 mg capsules are hard-shell gelatin capsules with a rubine red opaque cap and a gray opaque body filled with white to off-white powder. The capsules are axially printed with MYLAN over 2047 in black ink on both the cap and the body. They are available as follows:

NDC 60429-379-01 bottles of 100 capsules

Store and Dispense: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

16.4 Handling and Disposal

Tacrolimus can cause fetal harm. Tacrolimus capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in tacrolimus capsules. If such contact occurs, wash the skin thoroughly with soap and water; if ocular contact occurs, rinse eyes with water. In case a spill occurs, wipe the surface with a wet paper towel. Follow applicable special handling and disposal procedures 1.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Patient Information).

17.1 Administration

Advise the patient or caregiver to:

  • Inspect their tacrolimus capsules medicine when they receive a new prescription and before taking it. If the appearance of the capsule is not the same as usual, or if dosage instructions have changed, advise patients to contact their healthcare provider as soon as possible to make sure that they have the right medicine. Other tacrolimus products cannot be substituted for tacrolimus capsules.
  • Take tacrolimus capsules at the same 12-hour intervals every day to achieve consistent blood concentrations.
  • Take tacrolimus capsules consistently either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus.
  • Not to eat grapefruit or drink grapefruit juice in combination with tacrolimus capsules [see Drug Interactions (7.2)].

17.2 Development of Lymphoma and Other Malignancies

Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression. Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor [see Boxed Warning and Warnings and Precautions (5.1)] .

17.3 Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection such as fever, sweats or chills, cough or flu-like symptoms, muscle aches, or warm, red, painful areas on the skin [see Boxed Warning and Warnings and Precautions (5.2)] .

17.4 New Onset Diabetes After Transplant

Inform patients that tacrolimus capsules can cause diabetes mellitus and should be advised to contact their physician if they develop frequent urination, increased thirst, or hunger [see Warnings and Precautions (5.4)] .

17.5 Nephrotoxicity

Inform patients that tacrolimus can have toxic effects on the kidney that should be monitored. Advise patients to attend all visits and complete all blood tests ordered by their medical team [see Warnings and Precautions (5.5)] .

17.6 Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic reactions including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, delirium, or tremors [see Warnings and Precautions (5.6)] .

17.7 Hyperkalemia

Inform patients that tacrolimus can cause hyperkalemia. Monitoring of potassium levels may be necessary, especially with concomitant use of other drugs known to cause hyperkalemia [see Warnings and Precautions (5.7)].

17.8 Hypertension

Inform patients that tacrolimus can cause high blood pressure which may require treatment with antihypertensive therapy. Advise patients to monitor their blood pressure [see Warnings and Precautions (5.8)].

17.9 Drug Interactions

Instruct patients to tell their healthcare providers when they start or stop taking any medicines, including prescription medicines and nonprescription medicines, natural or herbal remedies, nutritional supplements, and vitamins. Advise patients to avoid grapefruit and grapefruit juice [see Drug Interactions (7)] .

17.10 Pregnancy, Lactation and Infertility

Inform women of childbearing potential that tacrolimus can harm the fetus. Instruct male and female patients to discuss with their healthcare provider family planning options including appropriate contraception. Also, discuss with pregnant patients the risks and benefits of breastfeeding their infant [see Use in Specific Populations (8.1, 8.2, 8.3)] .

Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy, exposed to immunosuppressants including tacrolimus, to enroll in the voluntary Transplantation Pregnancy Registry International. To enroll or register, patients can call the toll free number 1-877-955-6877 or https://www.transplantpregnancyregistry.org/ [see Use in Specific Populations (8.1)] .

Based on animal studies, tacrolimus may affect fertility in males and females [see Nonclinical Toxicology (13.1)] .

17.11 Myocardial Hypertrophy

Inform patients to report symptoms of tiredness, swelling, and/or shortness of breath (heart failure).

17.12 Immunizations

Inform patients that tacrolimus can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.14)] .

Patient Information

Tacrolimus Capsules, USP, for oral use

(ta kroe′ li mus)

Read this Patient Information before you start taking tacrolimus capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about tacrolimus capsules, ask your healthcare provider or pharmacist.

What is the most important information I should know about tacrolimus capsules?

Tacrolimus capsules can cause serious side effects, including:

  • Increased risk of cancer. People who take tacrolimus capsules have an increased risk of getting some kinds of cancer, including skin and lymph gland cancer (lymphoma).
  • Increased risk of infection. Tacrolimus capsules are a medicine that affect your immune system. Tacrolimus capsules can lower the ability of your immune system to fight infections. Serious infections can happen in people receiving tacrolimus capsules that can cause death. Call your healthcare provider right away if you have any symptoms of an infection, including:
  • fever
  • sweats or chills
  • cough or flu-like symptoms
  • muscle aches
  • warm, red, or painful areas on your skin

What are tacrolimus capsules?

  • Tacrolimus capsules are a prescription medicine used with other medicines to help prevent organ rejection in people who have had a kidney, liver, or heart transplant.
  • Tacrolimus capsules are a type of tacrolimus immediate-release drug and they are not the same as tacrolimus extended-release tablets or tacrolimus extended-release capsules. Your healthcare provider should decide what medicine is right for you.

Who should not take tacrolimus capsules?

Do not take tacrolimus capsules if you are allergic to tacrolimus or any of the ingredients in tacrolimus capsules. See the end of this leaflet for a complete list of ingredients in tacrolimus capsules.

What should I tell my healthcare provider before taking tacrolimus capsules?

Before you take tacrolimus capsules, tell your healthcare provider about all of your medical conditions, including if you:

  • plan to receive any live vaccines. People taking tacrolimus capsules should not receive live vaccines.
  • have or have had liver, kidney, or heart problems.
  • are pregnant or plan to become pregnant. Tacrolimus capsules can harm your unborn baby.
    • If you are able to become pregnant, you should use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.
    • Males who have female partners who are able to become pregnant should also use effective birth control before and during treatment with tacrolimus capsules. Talk to your healthcare provider before starting treatment with tacrolimus capsules about birth control methods that may be right for you.
    • There is a pregnancy registry for females who become pregnant and males who have fathered a pregnancy during treatment with tacrolimus capsules. The purpose of this registry is to collect information about the health of you and your baby. To enroll in this voluntary registry, call 1-877-955-6877 or go to https://www.transplantpregnancyregistry.org/.
  • are breastfeeding or plan to breastfeed. Tacrolimus passes into your breast milk. You and your healthcare provider should decide if you will breastfeed while taking tacrolimus capsules.

Tell your healthcare provider about all the medicines you take, and when you start a new medicine or stop taking a medicine, including prescription and over-the-counter medicines, vitamins, natural, herbal or nutritional supplements.

Especially tell your healthcare provider if you take:

  • sirolimus (RAPAMUNE ®)
  • cyclosporine (GENGRAF ® , NEORAL ® , and SANDIMUNE ®)
  • medicines called aminoglycosides that are used to treat bacterial infections
  • ganciclovir (CYTOVENE ® IV, VALCYTE ®)
  • amphotericin B (ABELCET ® , AMBISOME ®)
  • cisplatin
  • antiviral medicines called nucleoside reverse transcriptase inhibitors
  • antiviral medicines called protease inhibitors
  • water pill (diuretic)
  • medicine to treat high blood pressure
  • nelfinavir (VIRACEPT ®)
  • telaprevir (INCIVEK ®)
  • boceprevir
  • ritonavir (KALETRA ® , NORVIR ® , TECHNIVIE TM , VIEKIRA PAK TM , VIEKIRA, XR TM)
  • letermovir (PREVYMIS TM)
  • ketoconazole
  • itraconazole (ONMEL TM , SPORANOX ®)
  • voriconazole (VFEND ®)
  • clarithromycin (BIAXIN ® , BIAXIN XL ® , PREVPAC ®)
  • rifampin (RIFADIN ® , RIFAMATE ® , RIFATER ® , RIMACTANE ®)
  • rifabutin (MYCOBUTIN ®)
  • amiodarone (NEXTERONE ® , PACERONE ®)

Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above.

Tacrolimus capsules may affect the way other medicines work, and other medicines may affect how tacrolimus capsules work.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take tacrolimus capsules?

  • Take tacrolimus capsules exactly as your healthcare provider tells you to take them.
  • Your healthcare provider will tell you how many tacrolimus capsules to take and when to take them. Your healthcare provider may change your tacrolimus capsules dose if needed. Do not stop taking or change your dose of tacrolimus capsules without talking to your healthcare provider.
  • Take tacrolimus capsules with or without food.
  • Take tacrolimus capsules the same way every day. For example, if you choose to take tacrolimus capsules with food, you should always take tacrolimus capsules with food.
  • Take tacrolimus capsules at the same time each 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 capsules at the same time each day helps to keep the amount of medicine in your body at a steady level.
  • Do not eat grapefruit or drink grapefruit juice while taking tacrolimus capsules.
  • If you take too many tacrolimus capsules, call your healthcare provider or go to the nearest hospital emergency room right away.

Tacrolimus capsules:

  • Do not open or crush tacrolimus capsules.

What should I avoid while taking tacrolimus capsules?

  • While you take tacrolimus capsules you should not receive any live vaccines.
  • Limit the amount of time you spend in sunlight and avoid exposure to ultraviolet (UV) light, such as tanning machines. Wear protective clothing and use a sunscreen with a high sun protection factor (SPF).

What are the possible side effects of tacrolimus capsules?

Tacrolimus capsules may cause serious side effects, including:

  • See “What is the most important information I should know about tacrolimus capsules?”
  • problems from medicine errors. People who take tacrolimus capsules have sometimes been given the wrong type of tacrolimus product. Tacrolimus extended-release medicines are not the same as tacrolimus capsules and cannot be substituted for each other, unless specifically prescribed by your healthcare provider, who will send you to get blood tacrolimus levels at a lab. Check your tacrolimus capsules when you get a new prescription and before you take it to make sure you have received tacrolimus capsules.
  • Check with the pharmacist and call your healthcare provider if you think you were given the wrong medicine.
  • high blood sugar (diabetes). Your healthcare provider may do blood tests to check for diabetes while you take tacrolimus capsules. Call your healthcare provider right away if you have any symptoms of high blood sugar, including:
  • 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. Kidney problems are a serious and common side effect of tacrolimus capsules. Your healthcare provider may do blood tests to check your kidney function while you take tacrolimus capsules.
  • nervous system problems. Nervous system problems are a serious and common side effect of tacrolimus capsules. Call your healthcare provider right away if you get any of these symptoms while taking tacrolimus capsules. These could be signs of a serious nervous system problem:
  • headache
  • confusion
  • seizures
  • changes in your vision
  • changes in behavior
  • coma
  • tremors
  • numbness and tingling
  • high levels of potassium in your blood. Your healthcare provider may do blood tests to check your potassium level while you take tacrolimus capsules.
  • high blood pressure. High blood pressure is a serious and common side effect of tacrolimus capsules. Your healthcare provider will monitor your blood pressure while you take tacrolimus capsules and may prescribe blood pressure medicine for you, if needed. Your healthcare provider may instruct you to check your blood pressure at home.
  • changes in the electrical activity of your heart (QT prolongation).
  • heart problems (myocardial hypertrophy). Tell your healthcare provider right away if you get any of these symptoms of heart problems while taking tacrolimus capsules:
  • shortness of breath
  • chest pain
  • feel lightheaded
  • feel faint
  • severe low red blood cell count (anemia).

The most common side effects of tacrolimus capsules in people who have received a kidney, liver or heart transplant are:

  • infections in general, including cytomegalovirus (CMV) infection
  • tremors (shaking of the body)
  • constipation
  • diarrhea
  • headache
  • stomach pain
  • trouble sleeping
  • nausea
  • high blood sugar (diabetes)
  • low levels of magnesium in your blood
  • low levels of phosphate in your blood
  • swelling of the hands, legs, ankles, or feet
  • weakness
  • pain
  • high levels of fat in your blood
  • high levels of potassium in your blood
  • low red blood cell count (anemia)
  • low white blood cell count
  • fever
  • numbness or tingling in your hands and feet
  • inflammation of your airway (bronchitis)
  • fluid around your heart

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of tacrolimus capsules. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store tacrolimus capsules?

Tacrolimus capsules:

  • Store tacrolimus capsules at room temperature between 20° to 25°C (68° to 77°F).

Keep tacrolimus capsules and all medicines out of the reach of children.

General information about the safe and effective use of tacrolimus capsules.

  • Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tacrolimus capsules for a condition for which they were not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about tacrolimus capsules that is written for health professionals.
  • This Patient Information leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk to your healthcare provider.

What are the ingredients in tacrolimus capsules?

Active ingredient: tacrolimus

Inactive ingredients:

Tacrolimus capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.

The 0.5 mg capsules also contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules also contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules also contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.

The brands listed are trademarks of their respective owners.

For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Additional pediatric use information is approved for Astellas Pharma US, Inc.’s Prograf (tacrolimus) products. However, due to Astellas Pharma US, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 8/2020
TACR:R8ppb/PL:TACR:R6ppb

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