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 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.

USE IN SPECIFIC POPULATIONS

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 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  to 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 ver