Astagraf XL oral and injection

Tacrolimus lowers your body's immune system. The immune system helps your body fight infections. The immune system can also fight or "reject" a transplanted organ such as a liver or kidney. This is because the immune system treats the new organ as an invader.

Tacrolimus is used together with other medicines to prevent your body from rejecting a heart, liver, or kidney transplant.

The Astragraf XL and Envarsus XR brands of tacrolimus is generally not used for liver transplants.

Tacrolimus may also be used for purposes not listed in this medication guide.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may receive an injection of tacrolimus shortly after your transplant. Tacrolimus injection is given until you are ready to take the pill form of tacrolimus.

Take your medicine at the same time each day. The regular tacrolimus capsule (Prograf or Hecoria) is usually taken every 12 hours. Extended-release tacrolimus (Astragraf XL, Envarsus XR) is taken only 1 time per day, usually in the morning.

Do not crush, chew, break, or dissolve an extended-release capsule or tablet (Astragraf XL, Envarsus XR). Swallow it whole.

You may take Prograf or Hecoria with or without food, but take it the same way each time.

Take Astragraf XL or Envarsus XR on an empty stomach, at least 1 hour before or 2 hours after a meal.

If your doctor changes your brand, strength, or type of tacrolimus, your dosage needs may change. The regular and extended-release forms of tacrolimus are not equivalent and may not have the same dose or schedule. Ask your pharmacist if you have any questions about the new kind of tacrolimus you receive at the pharmacy.

While using tacrolimus, you may need frequent blood tests. Your blood pressure will need to be checked often.

Store at room temperature away from moisture and heat.

For Prograf or Hecoria: Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

For Astragraf XL or Envarsus XR: If you are more than 14 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Applies to tacrolimus: oral capsule, oral capsule extended release, oral tablet extended release

Other dosage forms:

• intravenous solution

Along with its needed effects, tacrolimus (the active ingredient contained in Astagraf XL) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking tacrolimus:

• Abdominal or stomach pain
• abnormal dreams
• agitation
• chills
• confusion
• convulsions (seizures)
• diarrhea
• dizziness
• fever and sore throat
• flu-like symptoms
• frequent urination
• headache
• itching
• loss of appetite
• loss of energy or weakness
• mental depression
• muscle trembling or twitching
• nausea
• pale skin
• seeing or hearing things that are not there
• shortness of breath
• skin rash
• swelling of the feet or lower legs
• tingling
• trembling and shaking of the hands
• trouble sleeping
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

• Blurred vision
• chest pain
• increased sensitivity to pain
• muscle cramps
• numbness or pain in the legs
• ringing in the ears
• sweating

• Enlarged heart
• flushing of the face or neck
• general feeling of discomfort or illness
• weight loss

• Black, tarry stools
• blistering, peeling, loosening of the skin
• bloating
• bloody urine
• constipation
• cough
• drowsiness
• fainting
• fast, slow, or irregular heartbeat
• heartburn
• increased thirst
• indigestion
• joint or muscle pain
• lightheadedness
• lower back or side pain
• pinpoint red spots on the skin
• pounding or rapid pulse
• red skin lesions, often with a purple center
• red, irritated eyes
• skin sores
• ulcers or white spots in the mouth or on the lips
• weakness
• weight gain
• yellow eyes or skin

Some side effects of tacrolimus may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• difficulty with moving
• lack or loss of strength
• muscle pain or stiffness

• Body aches or pain
• burning or stinging of the skin
• cracks in the skin
• crying
• delusions
• dementia
• depersonalization
• dysphoria
• euphoria
• excessive muscle tone
• feeling of constant movement of self or surroundings
• feeling that others are watching you or controlling your behavior
• feeling that others can hear your thoughts
• increased sensitivity of the skin to sunlight
• large, flat, blue or purplish patches in the skin
• loss of strength or energy
• muscle tension or tightness
• painful blisters on the trunk of the body
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• paranoia
• quick to react or overreact emotionally
• rapidly changing moods
• redness or other discoloration of the skin
• restlessness
• scaly skin
• sensation of spinning
• severe mood or mental changes
• severe sunburn
• sleepiness or unusual drowsiness
• sore mouth or tongue
• sores on the skin
• swelling or inflammation of the mouth
• tender, swollen glands in the neck
• unusual behavior
• white patches in the mouth, tongue, or throat

• Change in color vision
• decreased weight
• difficulty seeing at night
• feeling hot and cold
• hearing loss
• sudden sweating

Summary of Use during Lactation

Limited data indicate that amounts of systemically administered tacrolimus are low in breastmilk and probably do not adversely affect the breastfed infant. European experts consider tacrolimus to be probably safe to use for inflammatory bowel disease during breastfeeding.[1] U.S. investigators and clinicians from the National Transplantation Pregnancy Registry and other experts consider tacrolimus acceptable to use during breastfeeding following transplant.[2][3][4][5][6][7] Exclusively breastfed infants should be monitored if this drug is used during lactation, possibly including measurement of serum levels to rule out toxicity if there is a concern.

Topical tacrolimus presents a low risk to the nursing infant because it is poorly absorbed after topical application and peak blood concentrations are less than 2 mcg/L in most patients. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. If the breast is to be treated, an alternate drug is preferred; do not apply to the nipple area while nursing.[8][9][10]

Drug Levels

Maternal Levels. Random tacrolimus colostrum levels in 10 samples from 6 mothers averaged 1.7 mcg/L (range 0.3 to 1.9 mcg/L) which was about 50% of maternal serum levels. Tacrolimus dosages in these mothers were not reported.[11]

One mother taking 3 mg twice daily (0.1 mg/kg per day), had a peak milk level of 0.57 mcg/L one hour after the dose. The half-life in milk was estimated to be 12.85 hours. The authors estimated that her breastfed infant would receive 0.06% of the maternal weight-adjusted dosage or 0.06 mcg/kg daily, which is 0.03 to 0.04% of the oral starting dosage for pediatric patients.[12]

One mother who had been taking tacrolimus for a kidney transplant 5 years earlier was 3 months postpartum and exclusively breastfeeding her infant. She had been taking a dosage of 2 mg orally twice daily (0.05 mg/kg per day) for at least 2 months. She was also taking atenolol 100 mg, azathioprine 100 mg, diltiazem 180 mg, furosemide 20 mg, and prednisone 5 mg daily. Milk samples obtained over a 12-hour dosage interval found little change throughout the day, with the highest levels of 2.1 mcg/L at 4 and 8.5 hours after the dose. The average milk concentration was 1.8 mcg/L. The authors calculated that an exclusively breastfed infant would receive a daily dosage of 0.27 mcg/kg which is about 0.5% of the maternal weight-adjusted dosage and less than 0.2% of the pediatric dosage for organ transplant rejection.[13]

Eleven women who took tacrolimus (exact dosages not specified, but assumed to be 6 mg daily) during pregnancy and postpartum donated 22 breastmilk samples (times unspecified) for analysis. The median breastmilk concentration was 0.8 mcg/L (range 0.1 to 1.6 mcg/L). Two women took samples before and 4 or more hours after a dose; no difference in milk levels was seen. The authors estimated that the maximum dosage that an exclusively breastfed infant would receive would be 0.56 mg daily, equivalent to 0.23% of the maternal weight-adjusted dosage. Additionally, comparing infants who were breastfed to those who were not, the serum tacrolimus concentrations fell at about the same rate over the first 2 weeks postpartum, regardless of breastfeeding status, indicating that breastfeeding did not prolong infant tacrolimus levels[14]

Eleven breastmilk samples were obtained via breast pump over a 12-hour dosage interval in a nursing mother who was 45 weeks postpartum and receiving tacrolimus 1.5 mg twice daily after a liver transplant. The peak tacrolimus milk level of 1.11 mcg/L occurred 6 hours after the dose. The average tacrolimus level in milk was 0.93 mcg/L. The milk concentration of the active metabolite, 13-demethyl tacrolimus, averaged 0.03 mcg/L (range 0.01 to 0.04 mcg/L). The authors estimated that a fully breastfed infant would receive 0.14 mcg/kg daily or 0.3 % of the maternal weight-adjusted dosage.[2]

Infant Levels. Four breastfed (3 exclusive, 1 partial) infants whose mothers took tacrolimus during breastfeeding had serum tacrolimus concentrations measured between day 15 and 27 of age. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Tacrolimus was undetectable (<1.9 mcg/L) in all of the infants.[15]

A woman was taking tacrolimus 6 mg twice daily during pregnancy to prevent rejection of an small intestine transplant. Her dosage was adjusted to maintain an optimal tacrolimus blood level postpartum, although the exact dosage was not stated. She breastfed (extent not stated) her infant and at 1 week of age, the infant's tacrolimus blood level was less than 1 mcg/L.[16]

Twelve infants were exclusively breastfed by mothers taking tacrolimus (exact dosages not specified) during pregnancy and postpartum. Twenty-four infant blood samples were obtained from the infants at various times. The median infant blood tacrolimus concentration was 1.3 mcg/L (range 0.0-4.0 mcg/L). In infants in whom serial blood levels were obtained, levels declined at about 15% daily. Blood tacrolimus levels in breastfed infants were no higher than those in 3 additional infants who were not breastfed. Eight breast-fed infants with serial blood samples had undetectable (<0.1 mcg/L) tacrolimus blood levels at a median of day 14 (interquartile range day 11-22) postpartum.[14]

Two mothers with systemic lupus erythematosus were reported who took tacrolimus during pregnancy and lactation. One took tacrolimus 3 mg and prednisolone 40 mg daily and the other took tacrolimus 3 mg and prednisolone 30 mg daily during breastfeeding. The infants' blood tacrolimus levels measured 1 hour after breastfeeding were 0.2 mcg/L in the first infant at 10 days of age, and 0.5 mcg/L in the second at 7 days of age.[17]

Effects in Breastfed Infants

One infant was exclusively breastfed during maternal tacrolimus therapy throughout gestation to at least 2.5 months of age at which time the infant was developing normally physically and neurologically. An ultrasound examination of the infant's thymus was normal.[12]

The National Transplantation Pregnancy Registry reported data gathered from 1991 to 2011 on mothers who breastfed their infants following organ transplantation. A total of 68 mothers with transplants (mostly kidney or liver) used tacrolimus while breastfeeding a total of 83 infants. Duration of nursing ranged from 1 week to 1.5 years and follow-up of the children ranged from weeks to 16 years. There were no reports of problems in any of the infants or children.[4] As of December 2013, a total of 92 mothers had breastfed 125 infants for as long as 26 months with no apparent adverse effects in infants.[5]

The breastfed infants of six women who took tacrolimus during pregnancy for organ transplantation were breastfed (4 exclusive, 2 partial) for 45 to 180 days and followed for periods of 2 to 30 months. The mothers' mean daily tacrolimus dosage during breastfeeding was 9.6 mg daily (range 4.5 to 15 mg daily). Four mothers were also taking azathioprine 100 to 150 mg daily, one was taking diltiazem, and one was taking prednisolone 15 mg and aspirin 75 mg daily. None of the infants had any clear tacrolimus-related side effects, although one had transient thrombocytosis that resolved despite continued breastfeeding. Developmental milestones were normal and no pattern of infections was noted.[15]

Two mothers with systemic lupus erythematosus were reported who took tacrolimus 3 mg daily during pregnancy and lactation as well as prednisolone 30 or 40 mg daily. Three years after birth, both children were healthy. The durations of lactation were not stated.[17]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

(Immunosupressant) Azathioprine, Cyclosporine, (Topical) Pimecrolimus

References

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2. Zheng S, Easterling TR, Hays K et al. Tacrolimus placental transfer at delivery and neonatal exposure through breast milk. Br J Clin Pharmacol. 2013;76:988-96. PMID: 23528073

3. Armenti VT, Moritz MJ, Davison JM. Breastfeeding and tacrolimus: is it a reasonable approach? Expert Rev Clin Immunol. 2013;9:623-6. PMID: 23899232

4. Thiagarajan KM, Arakali SR, Mealey KJ et al. Safety considerations: breastfeeding after transplant. Prog Transplant. 2013;23:137-46. PMID: 23782661

5. Constantinescu S, Pai A, Coscia LA et al. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28:1163-73. PMID: 25271063

6. Flint J, Panchal S, Hurrell A et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55:1693-7. PMID: 26750124

7. Gotestam Skorpen C, Hoeltzenbein M, Tincani A et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795-810. PMID: 26888948

8. Strober B, Berger E, Cather J et al. A series of critically challenging case scenarios in moderate to severe psoriasis: a Delphi consensus approach. J Am Acad Dermatol. 2009;61 (Suppl 1):S1-S46. PMID: 19527820

9. Barrett ME, Heller MM, Fullerton Stone H, Murase JE. Dermatoses of the breast in lactation. Dermatol Ther. 2013;26:331-6. PMID: 23914890

10. Butler DC, Heller MM, Murase JE. Safety of dermatologic medications in pregnancy and lactation: Part II Lactation. J Am Acad Dermatol. 2014;70:417.e1-417.e10. PMID: 24528912

11. Jain A, Venkataramanan R et al. Pregnancy after liver transplantation under tacrolimus. Transplantation. 1997;64:559-65. PMID: 9293865

12. French AE, Soldin SJ et al. Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother. 2003;37:815-8. PMID: 12773068

13. Gardiner SJ, Begg EJ. Breastfeeding during tacrolimus therapy. Obstet Gynecol. 2006;107 (2 pt. 2):453-5. PMID: 16449146

14. Bramham K, Chusney G, Lee J et al C. Breastfeeding and tacrolimus: Serial monitoring in breast-fed and bottle-fed infants. Clin J Am Soc Nephrol. 2013;8:563-7. PMID: 23349333

15. Gouraud A, Bernard N, Millaret A et al. Follow-up of tacrolimus breastfed babies. Transplantation. 2012;94:e38-40. PMID: 22996303

16. Gomez-Lobo V, Landy HJ, Matsumoto C, Fishbein TM. Pregnancy in an intestinal transplant recipient. Obstet Gynecol. 2012;120 (2 Pt 2):497-500. PMID: 22825278

17. Izumi Y, Miyashita T, Migita K. Safety of tacrolimus treatment during pregnancy and lactation in systemic lupus erythematosus: A report of two patients. Tohoku J Exp Med. 2014;234:51-6. PMID: 25175032