113FM.1 RANOLAZINE FOR USE IN CARDIOLOGY Amber Initiation Guideline
This guideline provides prescribing and monitoring guidance for ranolazine therapy in the treatment of stable angina. It should be read in conjunction with the Summary of Product Characteristics (SPC) available on www.medicines.org.uk/emc and the BNF.
BACKGROUND FOR USE Ranolazine is included on the Bucks Formulary for use in adults with stable angina as add-on treatment only. For treatment of stable angina only in patients whose symptoms are not adequately controlled with (or there is intolerance or contraindications to) four anti-anginal medicines, i.e. beta blockers, calcium channel blockers, long acting nitrates and nicorandil, AND where revascularisation is not appropriate. Initiation by Consultant Cardiologists, continuation by GPs. Patients will be reviewed at one month by the Cardiology team to assess efficacy and decide on continuation (as per the application). Therefore all patients will receive the first 2 months’ supply from hospital. Treatment of stable angina with four drugs is not recommended because there is no evidence for superior outcomes compared to treatment with two or three drugs.2 Ranolazine has a novel mode of action which is thought to be due to selective inhibition of the late inward sodium current in cardiac cells. It has little effect on heart rate and can be useful in patients whose heart rate limits alternative additional treatment. Its overall effects on angina are modest. In the pivotal randomised controlled trial (RCT), when added to standard doses of beta blockers and calcium channel blockers, ranolazine significantly increased exercise duration and reduced the frequency of angina attacks compared to placebo after 12 weeks’ treatment.2
CONTRAINDICATIONS AND PRECAUTIONS
Severe renal impairment Avoid CrCl <30 ml/min Mild to moderate renal Caution is required if creatinine clearance is 30 - 80 ml/min. May require a impairment reduced maintenance dose. Avoid if creatinine clearance is <30 ml/min. Moderate and severe liver Avoid dysfunction Existing QT prolongation or May make QT interval longer, caution and monitor ECG. family history of QT prolongation There are many, some of which have absolute contraindications such as class 1a (e.g. quinidine) and class 3 anti-arrhythmic agents (e.g. sotalol). Interacting drugs (See Drug Interactions section.) Co-administration with amiodarone is acceptable. Moderate and severe left ventricular failure (LVF), NYHA Caution in use and consider lower maintenance doses. Class III - IV Pregnancy and breastfeeding Safe use not established - avoid. Hypersensitivity to active substance or any excipient Avoid (including lactose and E102) In patients whose clinical situation represents several cautions described above, consider a lower maintenance dose and monitor for side effects more frequently.
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DOSAGE
Dose of ranolazine Comments M/R tablets Specialist review at 2 - 4 weeks and, if well, consider increasing to target 375 mg twice daily dose. If inadequate control, can be up-titrated again in some patients. Do not exceed 500 mg twice daily in the elderly, if renal or hepatic 500 mg twice daily impairment, if <60 kg or if taking calcium channel blockers or other interacting drugs.
750 mg twice daily Do not exceed 750 mg twice daily.
At initiation, patients should be given the Patient Alert Card by the pharmacist (see EMC website). Swallow tablets whole. Step down to previous dose if side effects occur. The specialist should review patient at 4 - 6 weeks to assess response to therapy. If a responder, then the specialist can request shared care with the GP.
TIME TO RESPONSE Symptom relief is often seen within the first two weeks of treatment. If a response is seen, it will generally occur within the first 4 - 6 weeks of treatment at the maximum tolerated dose, so a 6 week course constitutes an adequate trial of therapy.
PRE-TREATMENT ASSESSMENT BY THE SPECIALIST ECG – checking for QT prolongation LFTs U&E (including renal function)
ONGOING MONITORING SCHEDULE
By specialist annually. (Note: May cause prolonged QT interval, ECG, U&E reduced renal function affects dose.)
Angina frequency By GP at annual review.
COMMON SIDE EFFECTS AND ACTIONS TO BE TAKEN (for full list of side effects see SPC1)
Side Effects Action Common in first two weeks of treatment, usually resolves. Is usually Dizziness, headache dose related so if very disabling consider dose reduction. GI upset (constipation, Common in first two weeks of treatment, usually resolves. Nausea is nausea, vomiting) usually dose related so if very disabling consider dose reduction.
Asthenia Common in first two weeks of treatment, usually resolves.
May prolong QT Risk of VT with prolonged QT interval. Seek specialist advice. interval on ECG
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NOTABLE DRUG INTERACTIONS (refer to BNF and SPC) Avoid interacting drugs where possible. Ranolazine is a substrate of CYP3A4, and is partially metabolised by CYP2D6.
Drugs that affect ranolazine Effect CYP3A4 inhibitors, e.g. diltiazem, conazoles, Expect increased levels of ranolazine. Avoid the erythromycin, clarithromycin, HIV medicines, combined use where practical. Commonest signs of grapefruit juice. higher levels of ranolazine are nausea and dizziness. P-glycoprotein inhibitors, e.g. verapamil, If diltiazem or verapamil is required with ranolazine, ciclosporin. consider reducing or halving the dose of ranolazine. CYP3A4 inducers, e.g. rifampicin, phenytoin, Reduced effectiveness of ranolazine, avoid combined phenobarbitone, carbamazepine, St John’s use.1 Wort. Class 1a, e.g. quinidine and some class 3 Avoid combination - concern about effects on QT anti-arrhythmics, e.g. sotalol. interval. Dose reduction of ranolazine is not usually required, CYP2D6 inhibitors, e.g. paroxetine, may but if nausea or dizziness occurs consider reducing cause small increases in ranolazine levels. ranolazine dose. Ranolazine may affect the following drug levels: Levels of simvastatin, ciclosporin and tacrolimus may Inhibitor of CYP3A4 or P-Gp, e.g. be increased. Max. simvastatin dose is 20 mg daily1. simvastatin, ciclosporin, tacrolimus. For drugs where monitoring levels is possible, do so and adjust according to desired therapeutic range. Levels of metoprolol, listed anti-arrhythmics, TCAs Inhibitor of CYP2D6, e.g. metoprolol, and antipsychotics may be increased and doses may propafenone, flecainide, tricyclic need to be reduced, e.g. metoprolol dose should be antidepressants (TCAs), antipsychotics. halved and then adjusted according to the pulse. Drugs which are known to prolong QT May have additive effects on QT prolongation with interval e.g. antihistamines, anti-arhythmics, ranolazine – consider alternatives where practical, macrolides, TCAs. check ECG and adjust prescribing if necessary. Metformin levels increased by 1.4 to 1.8 fold, adjust Metformin dose if necessary. Levels of digoxin increase 1.5 fold, adjust if Digoxin necessary.
BACK-UP INFORMATION AND ADVICE Contact Wycombe and Amersham Stoke Mandeville Details Cardiology Dr Piers Clifford 01494 425004 Dr Andrew Money-Kyrle 01296 315543 [email protected] [email protected] Fax: 01494 425908 Dr Punit Ramrakha 01296 315675 [email protected] Fax: 01296 315672 Switchboard Wycombe 01494 526161 01296 315000 Amersham 01494 434411 Medicines 01494 425355 Information
REFERENCES 1. Ranexa® prolonged release tablets. www.medicines.org.uk. Latest revision to text 25 April 2013
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Title of Guideline Ranolazine for Use in Cardiology Guideline Number 113FM Version 1 Effective Date January 2015 Review Date January 2018 Original Version Published January 2015 Approvals: Formulary Management Group 26th February 2014 Area Prescribing Committee 12th November 2014 Clinical Guidelines Subgroup 6th November 2014 Author/s Sarah Crotty, Interface Pharmacist. Aylesbury Vale and Chiltern CCG Dr Piers Clifford, Consultant Cardiologist, BHNHST SDU(s)/Department(s) responsible Cardiology for updating the guideline Pharmacy (Medicines Management Team, Aylesbury Vale and Chiltern CCG and BHNHST) Uploaded to Intranet 5th January 2015 Buckinghamshire Healthcare NHS Trust/Aylesbury Vale and Chiltern Clinical Commissioning Groups
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