A.Menarini Pharma U.K. S.R.L.

Section 4.5 Interactions

Effects of ranolazine on other medicinal products  - new paragraph added:

Dose adjustment of sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, tacrolimus, sirolimus, everolimus) may be required as RANEXA may increase plasma concentrations of these drugs.

Simvastatin: additional information added:

Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranexa. Dose limitation of other statins, metabolised by CYP3A4 (lovastatin), may be considered in patients taking Ranexa.

New paragraph added:

Tacrolimus, ciclosporin, sirolimus, everolimus: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after ranolazine administration. It is recommended that tacrolimus blood levels are monitored when co-administering Ranexa and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, sirolimus, everolimus).

Section 4.6 Fertility, pregnancy and lactation

New paragraph added:

Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is unknown.

 
Section 4.7 Effects on ability to drive and use machines
Confusional state and hallucination added to wording.

Section 4.8 Undesirable effects
Acute renal failure added as a rare side-effect

Section 5.3 Preclinical safety data

New sentence added:

Animal studies do not indicate direct or indirect harmful effects of ranolazine with respect to male or female fertility.

Other sections 4.1, 4.2, 5.1, 5.2, 10 - amendments made for clarification

Section 4.4 Special warnings and precuations

- 500 mg tablet: Azo colouring agent E110 removed as an excipient.

Please note that stock of Ranexa 500 mg tablets containing E110 may still be in the distribution chain.

Section 4.5

• Interactions add information on the effect of Ranolazine 750 mg twice daily on the pharmacokinetics of metoprolol. Add further details regarding other CYP2D6 substrates.
• Delete "quinidine" as it is already included in the section 4.3 Contraindications

 Section 5.1 Pharmacodynamic properties

• Amendment of a mistake as regards the incidence of arrhythmia in the MERLIN-TIMI 36 study

 Section 6.1

• List of excipients updated.

 Section 10

• Date of revision of the text updated.

In section 4.8, two additional statements added regarding acute renal failure:

The adverse event profile was generally similar in the MERLIN-TIMI 36 study. In this long term study, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazine patients.... 

.......

Post-marketing experience: In post-marketing experience, there have been reports of acute renal failure, including in patients with pre-existing mild to moderate renal impairment and/or taking concomitant medications that are known to interact with ranolazine (see section 4.4 and 4.5).

• In section 7 Marketing Authorisation Holder is now Menarini International Operations Luxembourg S.A.
• In section 10 Date of Revision of the Text, updated to 25 February 2009