4.4 Special warnings and precautions for use
The following paragraphs have been added:
Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or efficacy.
When substances with a potential for interaction (see section 4.5) - particularly strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) – are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.
High potassium intake or potassium-sparing diuretics should be avoided (see section 4.5).
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).
Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.
Dose reduction may be necessary in patients with sever liver impairment (see section 4.2)
The printing ink used to mark Advagraf capsules contains soya lecithin. In patients who are hypersensitive to peanut or soya, the risk and severity of hypersensitivity should be weighed against the benefit of using Advagraf.
4.6 Pregnancy and lactation
The following sentence has been updated and added to:
There is a risk for premature delivery (<37 week) (incidence of 66 of 123 births, i.e. 53.7%; however, data showed that the majority of the newborns had normal birth weight for their gestational age) as well as for hyperkalaemia in the newborn (incidence 8 of 111 neonates, i.e. 7.2 %) which, however normalises spontaneously.
The following paragraph has been added:
Fertility
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).
4.8 Undesirable effects
The following paragraph has been added:
The most commonly reported adverse drug reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
The following section has been updated and added to:
Hepatobiliary disorders
very common: liver function tests abnormal
common: bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
rare: venoocclusive liver disease, hepatitic artery thrombosis
very rare: hepatic failure
5.1 Pharmacodynamic properties
The following has been added:
Clinical efficacy and safety of Prograf capsules bid in primary organ transplantation
And the following deleted:
Results from published data of tacrolimus administered twice daily as Prograf capsules in other primary organ transplantation
Prograf has evolved into an accepted treatment as primary immunosuppressive medicinal product following pancreas, lung and intestinal transplantation.
6.1 List of excipients
Sodium laurilsulfate has been added to the list of excipients for the capsule shell.
6.2 Incompatibilities
The following paragraph has been updated and added to with the emphasis changing from “should not...” to “…must not contain PVC”:
Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used to prepare a suspension of Advagraf capsule contents must not contain PVC.
6.4 Special precautions for storage
The following sentence has been updated:
Store in the original package in order to protect from moisture.