Tacrolimus (Page 7 of 10)

8.2 Lactation

Risk Summary

Controlled lactation studies have not been conducted in humans; however tacrolimus has been reported to be present in human milk. The effects of tacrolimus on the breastfed infant, or on milk production have not been assessed. Tacrolimus is excreted in rat milk and in peri-/postnatal rat studies, exposure to tacrolimus during the postnatal period was associated with developmental toxicity in the offspring at clinically relevant doses [ see Pregnancy ( 8.1), and Nonclinical Toxicology ( 13.1) ].

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tacrolimus and any potential adverse effects on the breastfed child from tacrolimus or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Tacrolimus can cause fetal harm when administered to pregnant women. Advise female and male patients of reproductive potential to speak to their healthcare provider on family planning options including appropriate contraception prior to starting treatment with tacrolimus [see Use in Specific Populations ( 8.1), and Nonclinical Toxicology ( 13.1)] .

Infertility

Based on findings in animals, male and female fertility may be compromised by treatment with tacrolimus [see Nonclinical Toxicology ( 13.1)].

8.4 Pediatric Use

Safety and effectiveness have been established in pediatric liver, kidney, and heart transplant patients.

Kidney and heart transplant

Use of tacrolimus capsules in pediatric kidney and heart transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult kidney and heart transplant patients with additional pharmacokinetic data in pediatric kidney and heart transplant patients and safety data in pediatric liver transplant patients [see Dosage and Administration ( 2.3) and Clinical Pharmacology ( 12.3)].

8.5 Geriatric Use

Clinical trials of tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

The pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

The mean clearance of tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology ( 12.3)].

The use of tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole blood trough concentrations of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients [see Dosage and Administration ( 2.5) and Clinical Pharmacology ( 12.3)].

8.8 Race or Ethnicity

African-American patients may need to be titrated to higher dosages to attain comparable trough concentrations compared to Caucasian patients [see Dosage and Administration ( 2.2) and Clinical Pharmacology ( 12.3)].

African-American and Hispanic patients are at increased risk for new onset diabetes after transplant. Monitor blood glucose concentrations and treat appropriately [see Warnings and Precautions ( 5.4)].

10 OVERDOSAGE

Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae. Acute overdosage was sometimes followed by adverse reactions consistent with those listed in Adverse Reactions ( 6) (including tremors, abnormal renal function, hypertension, and peripheral edema); in one case of acute overdosage, transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

In acute oral and IV toxicity studies, mortalities were seen at or above the following doses: in adult rats, 52 times the recommended human oral dose; in immature rats, 16 times the recommended oral dose; and in adult rats, 16 times the recommended human IV dose (all based on body surface area corrections).

11 DESCRIPTION

Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as
[3 S -[3 R *[E( 1S*,3S*,4S*)], 4S*,5R*,8S*,9E,12R* , 14R*, 15S*,16R*,18S*,19S*,26aR* ]] 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26-a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

The chemical structure of tacrolimus is:

chemical structure

Tacrolimus has a molecular formula of C 44 H 69 NO 12 •H 2 O and a formula weight of 822.03. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.

Tacrolimus capsules, USP are available for oral administration containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. In addition, each capsule contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate.

The tacrolimus capsule shell for 0.5 mg strength consists of gelatin, titanium dioxide and yellow iron oxide.

The tacrolimus capsule shell for 1 mg strength consists of black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.

The tacrolimus capsule shell for 5 mg strength consists of red iron oxide, gelatin, and titanium dioxide.

Tacrolimus capsules, USP 0.5 mg, 1 mg and 5 mg are printed with edible black ink. The black ink is comprised of ammonia, black iron oxide, butyl alcohol, potassium hydroxide, propylene glycol, and shellac.

USP Dissolution test 2 and Organic Impurities procedure 2 used.

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