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 two 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 eight 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 often are 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 1 year post-transplantation ranged from 9.8 ng/mL to 19.4 ng/mL.

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 US, 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 to18 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 (5.12)].

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. They are available as follows:

The 0.5 mg capsule is a hard-shell gelatin capsule with a light orange opaque cap and a gray opaque body filled with white to off-white powder, 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 capsule is a hard-shell gelatin capsule with a light blue opaque cap and a gray opaque body filled with white to off-white powder, 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 capsule is a hard-shell gelatin capsule with a rubine red opaque cap and a gray opaque body filled with white to off-white powder, 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

Storage and Handling

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.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

17 PATIENT COUNSELING INFORMATION

17.1 Administration

Advise patients to:

•

Take tacrolimus capsules at the same 12 hour intervals everyday 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 capsules.

•

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 use a sunscreen with a high protection factor [see Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.3, 5.4, 5.5)].

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 (5.6)].

17.5 Nephrotoxicity

Inform patients that tacrolimus capsules 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 (5.7)].

17.6 Neurotoxicity

Inform patients that they are at risk of developing adverse neurologic effects including seizure, altered mental status, and tremor. Advise patients to contact their physician should they develop vision changes, deliriums, or tremors [see Warnings and Precautions (5.8)].

17.7 Hyperkalemia

Inform patients that tacrolimus capsules 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 (5.9)].

17.8 Hypertension

Inform patients that tacrolimus capsules can cause high blood pressure which may require treatment with antihypertensive therapy [see Warnings and Precautions (5.10)].

17.9 Drug Interactions

Instruct patients to tell their health care providers when they start or stop taking all the medicines, including prescription medicines and non-prescription medicines, natural or herbal remedies, nutritional supplements and vitamins [see Drug Interactions (7)].

17.10 Pregnant Women and Nursing Mothers

Instruct patients to tell their healthcare provider if they plan to become pregnant or breastfeed their infant [see Use in Specific Populations (8.1, 8.3)].

17.11 Immunizations

Inform patients that tacrolimus capsules can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.16)].

PATIENT INFORMATION LEAFLET

TACROLIMUS CAPSULES, USP
(ta kroe′ li mus)
0.5 mg, 1 mg and 5 mg

Read this Patient Information Leaflet 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 doctor about your medical condition or your treatment.

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 capsule is a medicine that affects 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 doctor right away if you have symptoms of an infection such as:

1.

fever

2.

sweats or chills

3.

cough or flu-like symptoms

4.

muscle aches

5.

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 and tacrolimus capsules are not for use with medicines called cyclosporines (Gengraf^®* , Neoral^®* , and Sandimune^®*).

Tacrolimus capsules are not for use with a medicine called sirolimus (Rapamune^®*) in people who have had a liver or heart transplants.

It is not known if tacrolimus capsules are safe and effective when used with sirolimus in people who have had kidney transplants.

It is not known if tacrolimus capsules are safe and effective in children who have had a kidney or heart transplants.

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 doctor before taking tacrolimus capsules?

Before you take tacrolimus capsules, tell your doctor if you:

•

plan to receive any live vaccines

•

have or have had liver, kidney or heart problems

•

are pregnant or plan to become pregnant. Tacrolimus capsules may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.

•

are breastfeeding or plan to breastfeed. Tacrolimus can pass into your breast milk. You and your doctor should decide if you will take tacrolimus or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Especially tell your doctor if you take:

•

cyclosporine (Gengraf^®* , Neoral^®* , and Sandimune^®*)

•

sirolimus (Rapamune^®*)

•

nelfinavir (Viracept^®*)

•

telaprevir (Incivek^TM*)

•

boceprevir (Victrelis^TM*)

•

amiodarone (Cordarone^TM* , Nexterone^TM* , Pacerone^TM*)

Ask your doctor 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 doctor and pharmacist when you get a new medicine.

How should I take tacrolimus capsules?

•

Take tacrolimus capsules exactly as your doctor tells you to take it.

•

Your doctor will tell you how many tacrolimus capsules to take and when to take them.

•

Your doctor may change your tacrolimus capsules dose if needed. Do not stop taking or change your dose of tacrolimus capsules without talking to your doctor.

•

Take tacrolimus capsules with or without food.

•

Take tacrolimus capsules the same way everyday. 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 enough medicine in your body to give your transplanted organ the around-the-clock medicine it needs.

•

Do not eat grapefruit or drink grapefruit juice while taking tacrolimus capsules.

•

If you take too many tacrolimus capsules, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking tacrolimus capsules?

•

While you take tacrolimus capsules you should not receive any live vaccines such as:

•

flu vaccine through your nose

•

measles

•

mumps

•

rubella

•

polio by mouth

•

BCG (TB vaccine)

•

yellow fever

•

chicken pox (varicella)

•

typhoid

•

Avoid exposure to sunlight and UV light such as tanning machines. Wear protective clothing and use a sunscreen.

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?”

•

high blood sugar (diabetes). Your doctor may do certain tests to check for diabetes while you take tacrolimus capsules. 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 tacrolimus capsules.

•

nervous system problems. Call your doctor right away if you get any of these symptoms while taking tacrolimus capsules. 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 tacrolimus capsules.

•

high blood pressure. Your doctor will monitor your blood pressure while you take tacrolimus capsules.

•

heart problems (myocardial hypertrophy). Tell your doctor 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

The most common side effects of tacrolimus capsules in people receiving kidney transplants are:

•

infection

•

tremors (shaking of the body)

•

high blood pressure

•

kidney problems

•

constipation

•

diarrhea

•

headache

•

stomach pain

•

trouble sleeping

•

nausea

•

low levels of phosphate in your blood

•

swelling of the hands, ankles, or legs

•

weakness

•

pain

•

high levels of fat in your blood

•

high levels of potassium in your blood

•

low red blood cell count (anemia)

The most common side effects of tacrolimus capsules in people receiving liver transplants are:

•

shaking of the body tremors

•

headache

•

diarrhea

•

high blood pressure

•

nausea

•

kidney problems

•

stomach pain

•

trouble sleeping

•

numbness or tingling in your hands or feet

•

anemia

•

pain

•

fever

•

weakness

•

high levels of potassium in the blood

•

low levels of magnesium in the blood

The most common side effects of tacrolimus capsules for heart transplant patients are:

•

kidney problems

•

high blood pressure

Tell your doctor 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 doctor or pharmacist.

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

How should I store tacrolimus capsules?

•

Store tacrolimus capsules at 20° to 25°C (68° to 77°F).

•

Safely throw away medicine that is out of date or no longer needed.

Keep tacrolimus capsules and all medicines out of 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 it was not prescribed. Do not give tacrolimus capsules to other people, even if they have the same symptoms that you have. It may harm them.

How do tacrolimus capsules protect my new organ?

The body’s immune system protects the body against anything that it does not recognize as part of the body. For example, when the immune system detects a virus or bacteria it tries to get rid of it to prevent infection. When a person has a liver, kidney, or heart transplant, the immune system does not recognize the new organ as a part of the body and tries to get rid of it, too. This is called “rejection”. Tacrolimus capsules protects your new organ by slowing down the body’s immune system.

This Patient Information Leaflet summarizes the most important information about tacrolimus capsules. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about tacrolimus capsules that is written for health professionals.

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

What are the ingredients in tacrolimus capsules, USP?

Active ingredient: tacrolimus

Inactive ingredients: 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. In addition, the 0.5 mg capsules contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

The imprinting ink contains the following: 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.

^* The brands listed are trademarks of their respective owners.

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

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

Marketed/ Packaged by:
GSMS, Inc.
Camarillo, CA 93012 USA

REVISED AUGUST 2015TACR:R3ppbpt