Astellas Pharma

0.5 mg, 1 mg, 3 mg, and 5 mg hard prolonged- 
release capsules tacrolimus

Read all of this leaflet carefully before you start taking this medicine. It contains information that is important to you.

– Save this information, you may need to read it again.

– If you have any further questions, ask your doctor or pharmacist.

– This medicine has been prescribed for you only. Do not give it to others. It can harm them, even if they show signs of illness similar to yours.

– If you get any side effects, talk to your doctor or pharmacist. This also applies to any side effects not mentioned in this information. See section 4.

In this leaflet you will find information about: 
1. What Advagraf is and what it is used for 
2. What you need to know before taking Advagraf 
3. How to take Advagraf 
4. Possible side effects 
5. How to store Advagraf 6. Contents of the pack 
and other ingredients information

1. What Advagraf is and what it is used for

Advagraf contains the active substance tacrolimus. It is an immunosuppressive drug. After an organ transplant (liver, kidney), your body tries to repel the new organ. Advagraf is used to control the immune system in your body, for it to accept the transplanted organ.

You can also be given Advagraf for an ongoing rejection reaction in your transplanted liver, kidney, heart, or another organ when another treatment you have received has not been able to control the immune system after your transplant.

Advagraf is used for adults.

2. What you need to know before taking Advagraf

Do not use Advagraf

  • if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Advagraf (listed in section 6).
  • if you are allergic to sirolimus or any macrolide antibiotic (eg erythromycin, clarithromycin, josamycin).

Warnings and cautions

Prograf and Advagraf both contain the active substance tacrolimus. However, Advagraf is taken once daily, while Prograf is taken twice daily. This is because the Advagraf capsules have delayed-release (slower release for a longer period of time) of tacrolimus. Advagraf and Prograf are not interchangeable.

Tell your doctor if any of the following apply to you:

  • if you are taking any of the medicines mentioned below under the heading Other medicines and Advagraf
  • if you have or have had liver problems
  • if you have diarrhea that lasts more than a day
  • if you experience severe abdominal pain or not accompanied by other symptoms such as chills, fever, nausea, or vomiting
  • if you have a change in heart rate, so-called “QT prolongation”, which is displayed in the ECG.

Contact your doctor immediately if you suffer from:

problems with your vision such as blurred vision, changes in color vision, difficulty seeing details, or if your field of vision becomes limited.

Your doctor may need to adjust the Advagraf dose.

You should have regular contact with your doctor, who may occasionally need tests of blood, urine, heart function, and eyes, to determine the correct dose of Advagraf.

You should limit your exposure to sunlight and UV light (ultraviolet light) while taking Advagraf. This is because immunosuppressive drugs may increase the risk of skin cancer. Wear suitable protective clothing and sunscreen with a high sun protection factor.

Children and young people

Advagraf is not recommended for children and adolescents under 18 years of age.

Other medicines and Advagraf

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription and herbal medicines.

Concomitant treatment with Advagraf and ciclosporin (another medicine used to counteract rejection of transplanted organs) is not recommended.

Blood concentrations of Advagraf may be affected by other medicines you are taking and blood levels of other medicines may be affected by you taking Advagraf, which means that the Advagraf dosage may need to be increased, decreased, or stopped. You should especially tell your doctor if you are taking or have recently taken any medicines such as:

  • medicines for fungal infections and antibiotics, especially so-called macrolide antibiotics used to treat infections, e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole and isavuconazole, erythromycin, clarithromycin, josamycin, and rifampicin
  • letermovir, which is used to prevent diseases caused by CMV ( cytomegalovirus in humans)
  • HIV – protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), and cobicistat booster drug combination tablets used to treat HIV – infection
  • HCV – protease inhibitors (eg telaprevir, boceprevir, and the combination of ombitasvir / paritaprevir/ritonavir with or without dasabuvir), used to treat hepatitis C infection
  • nilotinib and imatinib (used to treat certain cancers)
  • mycophenolic acid, which is used to suppress the immune system to prevent rejection of the transplanted organ
  • medicines for stomach ulcers and acid reflux (eg omeprazole, lansoprazole, or cimetidine)
  • medicines for nausea and vomiting (eg metoclopramide)
  • cisapride or magnesium- aluminum hydroxide, used to treat heartburn
  • birth control pills or other hormone treatments that contain Ethinyl estradiol, hormone treatments with danazol
  • medicines for high blood pressure or heart problems (eg nifedipine, nicardipine, diltiazem, and verapamil)
  • antiarrhythmics ( amiodarone ) drugs used to treat arrhythmias (irregular heartbeat)
  • medicines are known as “statins” used to treat elevated cholesterol and triglyceride s
  • phenytoin and phenobarbital used to treat epilepsy
  • corticosteroids are prednisolone and methylprednisolone, used to treat inflammation s and suppress the immune system (such as the rejection of the transplanted organ)
  • nefazodone used to treat depression
  • an herbal medicine containing St. John’s wort ( Hypericum perforatum ) or extract of Schisandra sphenanthera

Tell your doctor if you are taking or need to take ibuprofen (medicines for fever, inflammation, and pain), amphotericin B (medicines for bacterial infections), or medicines for viral infections (eg aciclovir). These can aggravate kidney problems or problems in the nervous system when taken with Advagraf.

Your doctor must also know if you are taking potassium supplements or certain diuretics, which are used for heart failure, high blood pressure and kidney disease (eg amiloride, triamterene, or spironolactone ), some medicines used for fever, inflammation, and pain (so-called NSAIDs), such as ibuprofen ), blood thinners or oralmedication to treat diabetes while you are taking Advagraf.

If you need to be vaccinated, tell your doctor in advance.

Advagraf with food and drink

Avoid grapefruit (also like grapefruit juice) when you are being treated with Advagraf, as it affects your blood levels.

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Advagraf passes into breast milk. Therefore, you should not breast-feed while taking Advagraf.

Driving and using machines

Do not drive or use any tools or machines if you feel dizzy or sleepy, or have trouble seeing clearly after taking Advagraf. These effects are more common if you also drink alcohol.

Advagraf contains lactose, sodium, and lecithin (soy)

Advagraf contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, ie essentially ‘sodium-free’.

The printing ink used on the Advagraf capsules contains soy lecithin. If you are allergic to peanuts or soy, consult your doctor to determine if you should use this medicine.

3. How to take Advagraf

Always take Advagraf exactly as your doctor has told you. Ask your doctor or pharmacist if you are unsure. This medicine should only be prescribed to you by a doctor who has experience in the treatment of transplant patients.

Make sure you get the same tacrolimus medicine every time you pick up your prescription unless your transplant doctor has decided to switch you to another tacrolimus medicine.

This medicine should be taken once daily. If the appearance of the medicine is not the same as usual, or if the dosing instructions have been changed, talk to your doctor or pharmacist as soon as possible to make sure you have received the correct medicine.

The starting dose to prevent rejection of your transplanted organ is determined by your doctor and is calculated according to your body weight. The starting doses immediately after the transplant are normally within the range

0.10 – 0.30 mg per kg of body weight per day

depending on the organ transplant. In the treatment of rejection, the same dosage can be used.

Dose one depends on your general condition and on which other immunosuppressive drugs (s) you are receiving. After you have started treatment with Advagraf, your doctor will take blood samples frequently to arrive at the correct dose. Then regular blood tests are required for your doctor to determine the correct dose and to adjust the dose from time to time. The dose of Advagraf is usually reduced by your doctor once your condition has stabilized. Your doctor will tell you exactly how many capsules to take.

You will need to take Advagraf every day for as long as you need immunosuppression to prevent rejection of your transplanted organ. You should be in regular contact with your doctor.

Advagraf is taken orally once daily in the morning. Take Advagraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour for the next meal. Take the capsules immediately after removing them from the blister. The capsules should be swallowed whole with a glass of water. Do not swallow the desiccant contained in the aluminum cover.

If you take more Advagraf than you should

If you have accidentally taken too much Advagraf, contact your doctor or nearest hospital emergency department immediately.

If you forget to take Advagraf

If you forget to take your dose of Advagraf capsules in the morning, take them as soon as possible the same day. Do not take a double dose the next morning.

If you stop taking Advagraf

Discontinuing treatment with Advagraf may increase the risk of rejection of your transplanted organ. Do not stop your treatment as long as your doctor does not tell you to.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Advagraf can cause side effects, although not everybody gets them

Advagraf weakens the body’s defense mechanisms (immune system), which makes the body’s ability to fight infection worse. When you take Advagraf, you can therefore get more infections than usual.

Serious side effects have been reported, including allergic and anaphylactic reactions. Benign and malignant tumors have been reported during treatment with Advagraf.

Cases of pure erythrocyte plasma (very severe decrease in red blood cell count ), agranulocytosis (severe decrease in white blood cell count ), hemolytic anemia(decreased red blood cell count due to increased degradation) and febrile neutropenia (a decrease in white blood cells fighting infection, together with fever) have been reported. It is not known exactly how often these side effects occur.

Very common side effects (may affect more than 1 user in 10):

  • Increased blood sugar, diabetes mellitus, increased potassium in the blood
  • Difficulty sleeping
  • Tremors, headaches
  • Increased blood pressure
  • Abnormal liver function tests
  • Diarrhea, nausea
  • Kidney problems

Common side effects (may affect up to 1 in 10 people):

  • Decreased number of blood cells ( platelets, red or white blood cells ), increased number of white blood cells, changes in the number of red blood cells (seen in blood samples)
  • Decreased magnesium, phosphate, potassium, calcium, or sodium in the blood, increased amount of fluid in the body, increased amount of uric acid or fats in the blood, decreased appetite, increased acidity in the blood, other changes in blood salts (seen in blood samples)
  • Anxiety, confusion, and difficulty orienting, depression, mood swings, nightmares, hallucinations, mental illness
  • Seizures, disturbances of consciousness, and crawling or numbness (sometimes painful) in the hands and feet, dizziness, reduced writing ability, disorders of the nervous system
  • Blurred vision, increased photosensitivity, eye diseases
  • Earrings
  • Decreased blood flow in the heart vessels, faster heartbeat
  • Bleeding, partial or complete blockage of blood vessels decreased blood pressure
  • Shortness of breath, changes in the lungs, fluid accumulation around the lungs, inflammation of the throat, cough, flu-like symptoms
  • Stomach problems, such as inflammation or sores that cause abdominal pain or diarrhea, bleeding in the stomach or inflammation or sores in the mouth, fluid accumulation in the abdomen, vomiting, abdominal pain, digestive problems, constipation, flatulence, flatulence, loose stools
  • Bile duct problems, yellowing of the skin due to liver problems, liver tissue damage, and hepatitis
  • Itching, rash, hair loss, acne, increased sweating
  • Pain in joints, limbs, back and feet, muscle twitching
  • Insufficient renal function, decreased urine output, impaired or painful urination
  • General weakness, fever, accumulation of fluid in the body, pain and discomfort, increase in alkaline phosphatases in the blood, weight gain, feeling of disturbed temperature perception
  • The insufficient function of the transplanted organ

Uncommon side effects (may affect up to 1 in 100 people):

  • Changes in blood clotting ability, decrease in the number of all kinds of blood cells(seen in blood samples)
  • Dehydration, inability to throw water
  • Abnormal blood test results: decreased protein or sugar, increased phosphate, increased enzyme, and lactate dehydrogenase
  • Coma, cerebral hemorrhage, stroke, paralysis, brain disease, speech and language difficulties, memory problems
  • Clouding in the lens of the eye, impaired hearing
  • Irregular heartbeat, cardiac arrest, decreased heart rate, heart muscle disease, heart muscle enlargement, heavier heartbeat, abnormal ECG, abnormal heart rate and heart rate
  • A blood clot in a friend in leg or arm, shock
  • Breathing difficulties, respiratory disease, asthma
  • Obstacles in the intestinal passage increased blood level of enzyme et amylase, regurgitation of contents from the stomach to the throat, slowed emptying of the stomach
  • Skin inflammation, burning sensation in the sun
  • Joint diseases
  • Painful menstruation and abnormal menstrual bleeding
  • Impaired function of several organs, flu-like symptoms, increased sensitivity to heat and cold, pressure over the chest, nervousness or abnormal feeling, weight loss

Rare side effects (may affect up to 1 in 1,000 people):

  • Small skin bleeds due to blood clots
  • Increased muscle stiffness
  • Blindness, deafness
  • Accumulation of fluid around the heart
  • Acute breathing difficulties
  • Cyst formation in the pancreas
  • Problems with blood flow in the liver
  • Severe disease with blistering of the skin, mouth, eyes, and genitals, increased hair growth
  • Thirst falls, feeling of pressure over the chest, decreased mobility, sores

Very rare side effects (may affect up to 1 in 10,000 people):

  • Muscle weakness
  • Abnormal echocardiogram ( ECG )
  • Liver failure
  • Painful urination with blood in the urine
  • The increased amount of adipose tissue

In no known frequency (cannot be calculated from the available data):

  • Visual nerve damage ( optic neuropathy )

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly to the Medical Products Agency, www.lakemedelsverket.se. By reporting side effects, you can help increase drug safety information. 

5. How to store Advagraf

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiration date is the last day of the specified month. Use all prolonged-release capsules within one year of opening the aluminum cover.

Store in the original package. Moisture sensitive.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Contents of the packaging and other information

Content declaration

The active substance is tacrolimus.

One Advagraf 0.5 mg capsule contains 0.5 mg tacrolimus (as monohydrate).

One Advagraf 1 mg capsule contains 1 mg tacrolimus (as monohydrate).

One Advagraf 3 mg capsule contains 3 mg tacrolimus (as monohydrate).

One Advagraf 5 mg capsule contains 5 mg tacrolimus (as monohydrate).

Other ingredients are:

Capsule contents: hypromellose, ethylcellulose, lactose, magnesium stearate.

Capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), sodium lauryl sulfate, gelatin.

Printing inks: shellac, lecithin (soy), simethicone, red iron oxide (E 172), hydroxypropyl cellulose.

What the medicine looks like and the contents of the pack

Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules marked with “0.5 mg” in red on the light yellow capsule cap and “* 647” on the orange lower part of the capsule containing white powder.

Advagraf 0.5 mg is supplied in blister cards or perforated unit dose blisters of 10 capsules in a protective foil wrapper containing a desiccant. Packs of 30, 50, and 100 hard prolonged-release capsules are available in blisters, and packs of 30×1, 50×1, and 100×1 hard prolonged-release capsules are available in perforated single-dose blisters.

Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules marked with “1 mg” in red on the white capsule cap and “* 677” on the orange lower part of the capsule, which contains white powder.

Advagraf 1 mg is supplied in blister cards or perforated unit dose blisters with 10 capsules in a protective foil wrapper containing a desiccant. Packs of 30, 50, 60 and 100 hard prolonged-release capsules are available in blisters, and packs of 30×1, 50×1, 60×1, and 100×1 hard prolonged-release capsules are available in perforated single-dose blisters.

Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules marked with “3 mg” in red on the orange capsule cap and “* 637” on the orange lower part of the capsule, which contains white powder.

Advagraf 3 mg is supplied in blister cards or perforated unit dose blisters of 10 capsules in a protective foil wrapper containing a desiccant. Packs of 30, 50, and 100 prolonged-release capsules are available in blisters, and packs of 30×1, 50×1, and 100×1 hard prolonged-release capsules are available in perforated single-dose blisters.

Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules marked with “5 mg” on the gray-red capsule cap and “* 687” on the orange-colored lower part of the capsule, which contains white powder.

Advagraf 5 mg is supplied in blister cards or perforated unit dose blisters of 10 capsules in a protective film wrapper containing a desiccant. Packs of 30, 50, and 100 hard prolonged-release capsules are available in blisters, and packs of 30×1, 50×1, and 100×1 hard prolonged-release capsules are available in perforated single-dose blisters.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorisation Holder:

Astellas Pharma Europe BV

Sylviusweg 62

2333 BE Leiden

Netherlands

Manufacturer:

Astellas Ireland Co., Ltd.

Killorglin, County Kerry, V93FC86

Ireland

Contact the representative of the marketing authorization holder to find out more about this medicine:

Further information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu/.

Muhammad Nadeem

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