Tacrolimus (Page 9 of 16)

7.7 Antimycobacterials

Rifampin [see Clinical Pharmacology (12.3)] and rifabutin are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these antimycobacterial drugs and tacrolimus are used concomitantly.

7.8 Anticonvulsants

Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly. Concomitant administration of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. Thus, frequent monitoring phenytoin plasma concentrations and adjusting the phenytoin dose as needed are recommended when tacrolimus and phenytoin are administered concomitantly.

7.9 St. John’s Wort (Hypericum perforatum)

St. John’s Wort induces CYP3A enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when St. John’s Wort and tacrolimus are co-administered.

7.10 Gastric Acid Suppressors/Neutralizers

Lansoprazole and omeprazole, as CYP2C19 and CYP3A4 substrates, may potentially inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. Cimetidine may also inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations.

Coadministration with magnesium and aluminum hydroxide antacids increase tacrolimus whole blood concentrations [see Clinical Pharmacology (12.3)]. Monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are used concomitantly.

7.11 Others

Bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol, amiodarone and methylprednisolone, and herbal products containing schisandra sphenanthera extracts may inhibit CYP3A metabolism of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when these drugs and tacrolimus are co-administered.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C — There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus given orally to pregnant rabbits at 0.5 to 4.3 times the clinical dose and pregnant rats at 0.8 to 6.9 times the clinical dose was associated with an increased incidence of fetal death in utero , fetal malformations (cardiovascular, skeletal, omphalocele, and gallbladder agenesis) and maternal toxicity. Tacrolimus Capsules USP should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant rabbits, tacrolimus at oral doses of 0.32 and 1.0 mg/kg, 0.5 to 4.3 times the clinical dose range (0.075 – 0.2 mg/kg) based on body surface area, was associated with maternal toxicity as well as an increased incidence of abortions. At the 1 mg/kg dose, fetal rabbits showed an increased incidence of malformations (ventricular hypoplasia, interventricular septal defect, bulbous aortic arch, stenosis of ductus arteriosis, interrupted ossification of vertebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, tacrolimus at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.

8.3 Nursing Mothers

Tacrolimus is excreted in human milk. As the effect of chronic exposure to tacrolimus in healthy infants is not established, patients maintained on tacrolimus should discontinue nursing taking into consideration importance of drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Tacrolimus Capsules USP in pediatric kidney and heart transplant patients have not been established. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Tacrolimus Capsules USP. Two randomized active controlled trials of Tacrolimus Capsules USP in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of Tacrolimus Capsules USP to maintain blood trough concentrations of tacrolimus similar to adult patients [see Dosage and Administration(2.2)].

8.5 Geriatric Use

Clinical trials of Tacrolimus Capsules USP 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 and renal function, and of concomitant disease or other drug therapy.

8.6 Use in 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 Capsules USP 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 (2.3) and Clinical Pharmacology (12.3)].

8.7 Use in 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 Capsules USP 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 (2.3) and Clinical Pharmacology (12.3)].

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 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; (all based on body surface area corrections).

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