Ranexa prolonged-release tablets

Joint NI and IE PIL created due to Brexit

Section 6 - Change to MAH details (United Kingdom Northern Ireland) and date of revision 

The changes are to update the SmPC to include additional pre-clinical data (sections 4.6 fertility, pregnancy and lactation and 5.3 pre-clinical safety data) and to implement the warning on sodium (section 4.4 special warnings and precautions for use).

4.2       Posology and method of administration

Updated to remove reference to the Patient Alert Card following its removal as an additional Risk Minimization Measure in Risk the Management Plan.

4.4       Special warnings and precautions for use

QT prolongation: 

Information added - Ranolazine blocks I_Kr and prolongs the QTc interval in a dose-related manner. 

The following sections have been updated:

Section 4.8 Undesirable effects

The following paragraph has been added:

An increased incidence of adverse events was seen among ranolazine treated patients in the RIVER-PCI trial (see section 5.1) where patients with incomplete revascularization post-PCI were given ranolazine up to 1000 mg twice daily or placebo for approximately 70 weeks. In this study, there was a higher reporting rate for congestive heart failure in the ranolazine group (2.2% vs 1.0% in placebo). Also, transient ischemic attack occurred more frequently in patients treated with ranolazine 1000 mg twice daily compared with placebo (1.0% vs 0.2%, respectively); however, the incidence of stroke was similar between treatment groups (ranolazine 1.7% vs placebo 1.5%).

Section 5.1 Pharmacodynamic properties

The following paragraph has been added:

In a phase 3, double-blind, placebo-controlled, event-driven trial (RIVER-PCI) in 2604 patients aged ≥18 years with a history of chronic angina and incomplete revascularisation after percutaneous coronary intervention (PCI) patients were up-titrated to 1000 mg twice daily*. No significant difference occurred in the composite primary endpoint (time to first occurrence of ischaemia-driven revascularisation or ischaemia-driven hospitalisation without revascularisation) in the ranolazine group (26.2%) versus the placebo group (28.3%), hazard ratio 0.95, 95% CI 0.82-1.10 p= 0.48. The risk of all cause mortality, CV death or major adverse cardiovascular events (MACE) and heart failure hospitalisation was similar between treatment groups in the overall population; however, MACE were reported more frequently in patients ≥ 75 years treated with ranolazine compared with placebo (17.0% vs 11.3%, respectively); in addition there was a numerical increase in all cause mortality in patients ≥ 75 years (9.2% vs. 5.1%, p = 0.074). 

*dosage not approved in the current SmPC

Section 3 Pharmaceutical Form

Remove CVT 375/500/750 from the tablet descriptions.

Section 4.8 Undesirable effects

Add details on Reporting of suspected adverse reactions

Section 10 Date of Revision of the text

Updated to July 2014

Section 4.8 – Musculoskeletal and connective tissue disorders

add ‘muscular weakness as an uncommon side-effect’

Section 10 – Date of revision updated to 13 November 2013

• Section 4.5 Interactions: update the information on simvastatin, add information on atorvastatin, other statins and drugs transported by Organic Cation Transporter-2 (OCT2) - metformin
• Section 4.7 Effects on ability to drive and use machines: add diplopia and coordination abnormal
• Section 4.8 Undesirable effects: add paresthesia, coordination abnormal, gait disturbance, diplopia, urinary retention.
• Typographical updates to align to current template

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 2. Qualitative and quantative composition

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

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).