Prograf: Package Insert and Label Information (Page 7 of 8)

14.2 Liver Transplantation

The safety and efficacy of Prograf-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 Prograf-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 Prograf-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 Prograf-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 Prograf-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 Prograf-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 Prograf 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 one 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 Prograf-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 Prograf or cyclosporine modified for 18 months. In a 3-arm trial conducted in the US, 331 patients received corticosteroids and Prograf plus sirolimus, Prograf 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 Prograf 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 Prograf; 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

Repackaged by Aphena Pharma Solutions — TN.See Repackaging Information for available configurations.

Aphena Pharma Solutions -- TN

16.1 Prograf (tacrolimus) Capsules USP

strength

0.5 mg

(containing the equivalent of 0.5 mg anhydrous tacrolimus USP)

1 mg

(containing the equivalent of 1 mg anhydrous tacrolimus USP)

5 mg

(containing the equivalent of 5 mg anhydrous tacrolimus USP)

shape/color

oblong/light yellow

oblong/white

oblong/grayish red

branding on capsule cap/body

logo2 607

logo3 617

logo4 657

100 count bottle

NDC 0469-0607-73

NDC 0469-0617-73

NDC 0469-0657-73

10 blister cards of 10 capsules

NDC 0469-0617-11

NDC 0469-0657-11

Made in Ireland

Note: Prograf capsules USP are not filled to maximum capsule capacity. Capsule contains labeled amount.
Store and Dispense

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).

16.2 Prograf (tacrolimus) Injection

(for IV infusion only)

NDC 0469-3016-01 Product Code 301601

5 mg/mL (equivalent of 5 mg of anhydrous tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 ampules

Made in Ireland
Store and Dispense

Store between 5°C and 25°C (41°F and 77°F).

17 PATIENT COUNSELING INFORMATION

17.1 Administration

Advise patients to:

Take Prograf at the same 12-hour intervals everyday to achieve consistent blood concentrations.
Take Prograf consistently either with or without food because the presence and composition of food decreases the bioavailability of Prograf.
Not to eat grapefruit or drink grapefruit juice in combination with Prograf [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 Prograf 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 Prograf 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 Prograf 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 Prograf can cause high blood pressure which may require treatment with anti-hypertensive 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 breast-feed their infant [see Use in Specific Populations (8.1, 8.3)]

17.11 Immunizations

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

Rx only


Product of Japan

Manufactured by:
Astellas Ireland Co., Ltd.
Killorglin, County Kerry, Ireland

Marketed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062

Revised: September 2013

13H057-PRG

PATIENT INFORMATION

PROGRAF[PRO-graf]

(tacrolimus) capsules USP

Read this Patient Information before you start taking PROGRAF 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 PROGRAF?


Prograf can cause serious side effects, including:

1.
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).
2.
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

What is PROGRAF?

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

PROGRAF is not for use with a medicine called sirolimus (Rapamune®) in people who have had a liver or heart transplants.

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

It is not known if PROGRAF is safe and effective in children who have had a kidney or heart transplants.
Who Should Not Take PROGRAF?

Do not take PROGRAF if you are allergic to tacrolimus or any of the ingredients in PROGRAF. See the end of this leaflet for a complete list of ingredients in PROGRAF.
What should I tell my doctor before taking PROGRAF?

Before you take PROGRAF, 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. PROGRAF may harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
Are breastfeeding or plan to breastfeed. PROGRAF can pass into your breast milk. You and your doctor should decide if you will take PROGRAF 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 (IncivekTM)
boceprevir (VictrelisTM)
amiodarone (CordaroneTM , NexteroneTM , PaceroneTM)

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

PROGRAF may affect the way other medicines work, and other medicines may affect how PROGRAF works.

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 PROGRAF?

Take PROGRAF exactly as your doctor tells you to take it.
Your doctor will tell you how many PROGRAF to take and when to take them.
Your doctor may change your PROGRAF dose if needed. Do not stop taking or change your dose of PROGRAF without talking to your doctor.
Take PROGRAF with or without food.
Take PROGRAF the same way everyday. For example, if you choose to take PROGRAF with food, you should always take PROGRAF with food.
Take PROGRAF 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 PROGRAF 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 PROGRAF.
If you take too much PROGRAF, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking PROGRAF?

While you take PROGRAF 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 PROGRAF?

PROGRAF may cause serious side effects, including:

See “What the most important information I should know about PROGRAF?”
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

The most common side effects of PROGRAF in people receiving kidney transplant 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 PROGRAF 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 PROGRAF 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 PROGRAF. 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 PROGRAF?

Store PROGRAF at 59º F to 86ºF (15°C to 30º C).
Safely throw away medicine that is out of date or no longer needed.

Keep PROGRAF and all medicines out of reach of children.
General information about the safe and effective use of PROGRAF

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROGRAF for a condition for which it was not prescribed. Do not give PROGRAF to other people, even if they have the same symptoms that you have. It may harm them.
How Does PROGRAF 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”. PROGRAF protects your new organ by slowing down the body’s immune system.

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

For more information, go to www.astellas.com/us or call 1-800-727-7003.
What are the ingredients in PROGRAF?

Active ingredient: tacrolimus

Inactive ingredients: lactose monohydrate, hypromellose, croscarmellose sodium, magnesium stearate, gelatin, titanium dioxide and ferric oxide.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Product of Japan

Manufactured by:
Astellas Ireland Co., Ltd.
Killorglin, County Kerry, Ireland

Marketed by:
Astellas Pharma US, Inc. Northbrook, IL 60062

Revised: September 2013

13H057-PRG-PI

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