ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Ranexa 375 mg prolonged-release tablets
2.
Each tablet contains 375 mg of ranolazine.
For a full list of excipients see section 6.1.
3.
Prolonged-release tablet
Pale blue oval-shaped tablet engraved with CVT375 on one side.
4.
4.1
Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina
pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-
blockers and/or calcium antagonists).
4.2
Patients should be given the Ranexa package leaflet and the Patient Alert Card and instructed to
present their Patient Alert Card and medication list to their health care professional at each visit.
Ranexa is available as 375 mg, 500 mg, and 750 mg prolonged-release tablets.
Adults: The recommended initial dose of Ranexa is 375 mg twice daily. After 2–4 weeks, the dose
should be titrated to 500 mg twice daily and, according to the patient’s response, further titrated to a
recommended maximum dose of 750 mg twice daily (see section 5.1).
If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-
titration of Ranexa to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after
dose reduction, treatment should be discontinued.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is
recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole,
erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).
Concomitant administration of potent CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).
Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal
impairment (creatinine clearance 30–80 ml/min) (see sections 4.4, 4.8, and 5.2). Ranexa is
contraindicated in patients with severe renal impairment (creatinine clearance
<
30 ml/min) (see
sections 4.3 and 5.2).
Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment
(see sections 4.4 and 5.2). Ranexa is contraindicated in patients with moderate or severe hepatic
impairment (see sections 4.3 and 5.2).
2
Elderly: Dose titration in elderly patients should be exercised with caution (see section 4.4). Elderly
may have increased ranolazine exposure due to age-related decrease in renal function (see section 5.2).
The incidence of adverse events was higher in the elderly (see section 4.8).
60 kg). Dose
titration in patients with low weight should be exercised with caution (see sections 4.4, 4.8, and 5.2).
£
Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA
Class III–IV) should be exercised with caution (see sections 4.4 and 5.2).
Paediatric patients: Ranexa is not recommended for use in children below the age of 18 years due to a
lack of data on safety and efficacy.
Ranexa tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken
with or without food.
4.3
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.2 and 5.2).
Moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole,
voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see
sections 4.2 and 4.5).
Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol)
antiarrhythmics other than amiodarone.
4.4
Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an
increased exposure is expected:
·
Concomitant administration of moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).
·
Concomitant administration of P-gp inhibitors (see sections 4.2 and 4.5).
·
Mild hepatic impairment (see sections 4.2 and 5.2).
·
Mild to moderate renal impairment (creatinine clearance 30–80 ml/min) (see sections 4.2, 4.8,
and 5.2).
·
Elderly (see sections 4.2, 4.8, and 5.2).
·
Patients with low weight (
£
60 kg) (see sections 4.2, 4.8, and 5.2).
·
Patients with moderate to severe CHF (NYHA Class III–IV) (see sections 4.2 and 5.2).
In patients with a combination of these factors, additional exposure increases are expected. Dose-
dependent side effects are likely to occur. If Ranexa is used in patients with a combination of several
of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment
discontinued, if needed.
The risk for increased exposure leading to adverse events in these different subgroups is higher in
patients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolising
capacity (extensive metabolisers, EM) (see section 5.2). The above precautions are based on the risk in
a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower need
for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been
determined (e.g. by genotyping) or is previously known to be EM, Ranexa can be used with caution in
these patients when they have a combination of several of the above risk factors.
QT prolongation
: A population-based analysis of combined data from patients and healthy volunteers
demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be
2.4 msec per 1000 ng/ml, which is approximately equal to a 2- to 7-msec increase over the plasma
concentration range for ranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed
3
Low weight: The incidence of adverse events was higher in patients with low weight (
when treating patients with a history of congenital or a family history of long QT syndrome, in
patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the
QTc interval (see section 4.5 also).
Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of
efficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin,
phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see section 4.5).
Renal impairment: Renal function decreases with age and it is therefore important to check renal
function at regular intervals during treatment with ranolazine (see sections 4.2, 4.3, 4.8, and 5.2).
4.5
Effects of other medicinal products on ranolazine
CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4
increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g.
nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment
with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3.0- to 3.9-fold during
ranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole,
ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin,
nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a potent CYP3A4 inhibitor.
Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent
increases in average ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of
Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4
inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required (see sections
4.2 and 4.4).
Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma
levels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-state
concentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gp
inhibitors. Down-titration of Ranexa may be required (see sections 4.2 and 4.4).
CYP3A4 inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations
by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of
inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see
section 4.4).
CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of this
enzyme may increase plasma concentrations of ranolazine. The potent CYP2D6 inhibitor paroxetine,
at a dose of 20 mg once daily, increased steady-state plasma concentrations of ranolazine 1000 mg
twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice
daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine
AUC of about 62%.
Effects of ranolazine on other medicinal products
Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may
increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are
transported by P-gp may be increased.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily
increased plasma concentrations of metoprolol by 1.8-fold. Therefore the exposure to metoprolol or
other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic
antidepressants and antipsychotics) may be increased during co-administration with Ranexa, and lower
doses of these medicinal products may be required.
4
The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during
co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported
when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored
following initiation and termination of Ranexa therapy.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa
1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, and the
HMG-CoA reductase inhibitor activity by 1.4- to 1.6-fold.
There is a theoretical risk that concomitant treatment of ranolazine with other drugs known to prolong
the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of
ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine,
astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide),
erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).
4.6
Pregnancy: There are no adequate data from the use of ranolazine in pregnant women. Animal studies
are insufficient with respect to effects on pregnancy and embryofoetal development (see section 5.3).
The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly
necessary.
Lactation: It is unknown whether ranolazine is excreted in human breast milk. The excretion of
ranolazine in milk has not been studied in animals. Ranexa should not be used during breast-feeding.
4.7
No studies on the effects of Ranexa on the ability to drive and use machines have been performed.
Ranexa may cause dizziness and blurred vision (see section 4.8), which may affect the ability to drive
and use machines.
4.8
Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and often
develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical
development programme, which included a total of 1,030 chronic angina patients treated with Ranexa.
The adverse events, considered to be at least possibly related to treatment, are listed below by body
system, organ class, and absolute frequency. Frequencies are defined as very common (
³
1/10),
common (
³
1/100 to
<
1/10), uncommon (
³
1/1,000 to < 1/100), rare (
³
1/10,000 to < 1/1,000), and
very rare (< 1/10,000).
Metabolism and nutrition disorders
Uncommon:
anorexia, decreased appetite, dehydration.
Psychiatric disorders
Uncommon:
anxiety, insomnia.
Rare:
disorientation.
Nervous system disorders
Common:
dizziness, headache.
Uncommon:
lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness.
Rare:
amnesia, depressed level of consciousness, loss of consciousness, parosmia.
5
Eye disorders
Uncommon:
blurred vision, visual disturbance.
Ear and labyrinth disorders
Uncommon:
vertigo, tinnitus.
Rare:
impaired hearing.
Vascular disorders
Uncommon:
hot flush, hypotension.
Rare:
peripheral coldness, orthostatic hypotension.
Respiratory, thoracic, and mediastinal disorders
Uncommon:
dyspnoea, cough, epistaxis.
Rare:
throat tightness.
Gastrointestinal disorders
Common:
constipation, vomiting, nausea.
Uncommon:
abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
Rare:
pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders
Uncommon:
pruritus, hyperhydrosis.
Rare:
allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders
Uncommon:
pain in extremity, muscle cramp, joint swelling.
Renal and urinary disorders
Uncommon:
dysuria, haematuria, chromaturia.
Reproductive system and breast disorders
Rare:
erectile dysfunction.
General disorders and administration site conditions
Common:
asthenia.
Uncommon:
fatigue, peripheral oedema.
Investigations
Uncommon:
increased blood creatinine, increased blood urea, prolonged QT corrected interval,
increased platelet or white blood cell count, decreased weight.
Rare:
elevated levels of hepatic enzyme.
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. Evaluations in patients who may be considered at higher risk of adverse events when treated
with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or
obstructive airway disease, confirmed that these conditions were not associated with clinically
meaningful increases in the incidence of adverse events.
Elderly, renal impairment, and low weight
: In general, adverse events occurred more frequently
among elderly patients and patients with renal impairment; however, the types of events in these
subgroups were similar to those observed in the general population. Of the most commonly reported,
the following events occurred more often with Ranexa (placebo-corrected frequencies) in elderly
(
6
75 years of age) than younger patients (< 75 years of age): constipation (8% versus 5%), nausea
(6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
³
In patients with mild or moderate renal impairment (creatinine clearance ³ 30–80 ml/min) compared
to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported
events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7%
versus 5%), and nausea (4% versus 2%).
60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-
corrected frequencies of the following common adverse events were higher in low body weight than
heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus
2%).
Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels
have been observed in healthy subjects and patients treated with Ranexa. There was no renal toxicity
related to these findings. A renal function study in healthy volunteers demonstrated a reduction in
creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal
tubular secretion of creatinine.
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).
4.9
In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, and
vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia,
lethargy, and syncope were observed in an intravenous overdose study in healthy volunteers. In the
event of overdose, the patient should be closely monitored and the treatment should be symptomatic
and supportive.
Approximately 62% of ranolazine is bound to plasma proteins, and therefore, complete clearance by
haemodialysis is unlikely.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other cardiac preparations, ATC code: C01EB18
Mechanism of action: The mechanism of action of ranolazine is largely unknown. Ranolazine may
have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces
intracellular sodium accumulation and consequently decreases intracellular calcium overload.
Ranolazine, via its action to decrease the late sodium current, is considered to reduce these
intracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload is
expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness.
Clinical evidence of inhibition of the late sodium current by ranolazine is provided by a significant
shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of
5 patients with a long QT syndrome (LQT3 having the SCN5A ∆KPQ gene mutation).
These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
Pharmacodynamic effects
Haemodynamic effects: Minimal decreases in mean heart rate (< 2 beats per minute) and mean
systolic blood pressure (< 3 mm Hg) were observed in patients treated with ranolazine either alone or
in combination with other antianginal medicinal products in controlled studies.
7
In general, the type and frequency of adverse events reported in patients with low body weight
(
£
Electrocardiographic effects: Dose and plasma concentration-related increases in the QTc interval
(about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched
T waves, have been observed in patients treated with Ranexa. These effects of ranolazine on the
surface electrocardiogram are believed to result from inhibition of the fast-rectifying potassium
current, which prolongs the ventricular action potential, and from inhibition of the late sodium current,
which shortens the ventricular action potential. A population analysis of combined data from
1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msec
per 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotal
clinical studies, where mean changes from baseline in QTcF (Fridericia’s correction) after doses of
500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients with
clinically significant hepatic impairment.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference between Ranexa and placebo in the risk of all-cause mortality (relative risk
ranolazine:placebo 0.99), sudden cardiac death (relative risk ranolazine:placebo 0.87), or the
frequency of symptomatic documented arrhythmias (3.0% versus 3.1%).
No proarrhythmic effects were observed in 3,162 patients treated with Ranexa based on 7-day Holter
monitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmias
in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia
³
Clinical efficacy: Clinical studies have demonstrated the efficacy and safety of Ranexa in the
treatment of patients with chronic angina, either alone or when the benefit from other antianginal
medicinal products was sub-optimal.
In the pivotal study, CARISA, Ranexa was added to treatment with atenolol 50 mg once daily,
amlodipine 5 mg once daily, or diltiazem 180 mg once daily. Eight-hundred and twenty-three patients
(23% women) were randomised to receive 12 weeks of treatment with Ranexa 750 mg twice daily,
1000 mg twice daily, or placebo. Ranexa demonstrated greater efficacy than placebo in prolonging
exercise time at trough at 12 weeks for both doses studied when used as an add-on therapy. However,
there was no difference in exercise duration between the two doses (24 seconds compared to placebo;
p
0.03).
Ranexa resulted in significant decreases in the number of angina attacks per week and consumption of
short-acting nitroglycerin compared to placebo. Tolerance to ranolazine did not develop during
treatment and a rebound increase in angina attacks was not observed following abrupt discontinuation.
The improvement in exercise duration in women was about 33% of the improvement in men at the
1000 mg twice-daily dose level. However, men and women had similar reductions in frequency of
angina attacks and nitroglycerin consumption. Given the dose-dependent side effects and similar
efficacy at 750 and 1000 mg twice daily, a maximum dose of 750 mg twice daily is recommended.
In a second study, ERICA, Ranexa was added to treatment with amlodipine 10 mg once daily (the
maximum labelled dose). Five-hundred and sixty-five patients were randomised to receive an initial
dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with
Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg
once daily. Additionally, 45% of the study population also received long-acting nitrates. Ranexa
resulted in significant decreases in the number of angina attacks per week (p = 0.028) and
consumption of short-acting nitroglycerin (p = 0.014) compared to placebo. Both the average number
of angina attacks and nitroglycerin tablets consumed decreased by approximately one per week.
In the main dose-finding study, MARISA, ranolazine was used as monotherapy. One-hundred and
ninety-one patients were randomised to treatment with Ranexa 500 mg twice daily, 1000 mg twice
daily, 1500 mg twice daily, and matching placebo, each for 1 week in a crossover design. Ranexa was
significantly superior to placebo in prolonging exercise time, time to angina, and time to 1 mm ST
segment depression at all doses studied with an observed dose-response relationship. Improvement of
8
8 beats (5% versus 8%).
£
exercise duration was statistically significant compared to placebo for all three doses of ranolazine
from 24 seconds at 500 mg twice daily to 46 seconds at 1500 mg twice daily, showing a dose-related
response. In this study, exercise duration was longest in the 1500 mg group; however, there was a
disproportional increase in side effects, and the 1500 mg dose was not studied further.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99), sudden cardiac
death (relative risk ranolazine:placebo 0.87), or the frequency of symptomatic documented
arrhythmias (3.0% versus 3.1%) between Ranexa and placebo when added to standard medical therapy
(including beta-blockers, calcium channel blockers, nitrates, anti-platelet agents, lipid-lowering
medicinal products, and ACE inhibitors). Approximately one-half of the patients in MERLIN-TIMI 36
had a history of angina. The results showed that exercise duration was 31 seconds longer in ranolazine
patients versus placebo patients (p = 0.002). The Seattle Angina Questionnaire showed significant
effects on several dimensions, including angina frequency (p
<
0.001), compared to placebo-treated
patients.
A small proportion of non-Caucasians was included in the controlled clinical studies; therefore, no
conclusions can be drawn regarding the effect and safety in non-Caucasians.
5.2
Pharmacokinetic properties
After oral administration of Ranexa, peak plasma concentrations (C
max
) are typically observed between
2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.
Absorption: The mean absolute bioavailability of ranolazine after oral administration of immediate-
release ranolazine tablets ranged from 35−50%, with large inter-individual variability. Ranexa
exposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state
AUC as the dose was increased from 500 mg to 1000 mg twice daily. In a pharmacokinetic study in
healthy volunteers, steady-state C
max
was, on average, approximately 1770 (SD 1040) ng/ml, and
steady-state AUC
0-12
was, on average, 13,700 (SD 8290) ng x h/ml following a dose of 500 mg twice
daily. Food does not affect the rate and extent of absorption of ranolazine.
Distribution: Approximately 62% of ranolazine is bound to plasma proteins, mainly alpha-1 acid
glycoprotein and weakly to albumin. The mean steady-state volume of distribution (V
ss
) is about 180 l.
Elimination: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted
unchanged in the urine and faeces. Following oral administration of a single 500 mg dose of
[
14
C]-ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% in
faeces.
Clearance of ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life is
about 2−3 hours after intravenous administration. The terminal half-life at steady state after oral
administration of ranolazine is about 7 hours, due to the absorption rate-limited elimination.
100 metabolites), and faeces (25 metabolites). Fourteen primary pathways
have been identified of which O-demethylation and N-dealkylation are the most important.
In vitro
studies using human liver microsomes indicate that ranolazine is metabolised primarily by CYP3A4,
but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolisers,
PM) had 62% higher AUC than subjects with CYP2D6 metabolising capacity (extensive metabolisers,
EM). The corresponding difference at the 1000 mg twice-daily dose was 25%.
>
Special populations
9
Biotransformation: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults,
ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral
500 mg dose of [
14
C]-ranolazine. A large number of metabolites has been identified in human plasma
(47 metabolites), urine (
The influence of various factors on the pharmacokinetics of ranolazine was assessed in a population
pharmacokinetic evaluation in 928 angina patients and healthy subjects.
Gender effects: Gender had no clinically relevant effect on pharmacokinetic parameters.
Elderly patients: Age alone had no clinically relevant effect on pharmacokinetic parameters.
However, the elderly may have increased ranolazine exposure due to age-related decrease in renal
function.
Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold
higher in subjects weighing 40 kg.
CHF
: CHF NYHA Class III and IV were estimated to have about 1.3-fold higher plasma
concentrations.
Renal impairment: In a study evaluating the influence of renal function on ranolazine
pharmacokinetics, ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild,
moderate, and severe renal impairment compared with subjects with normal renal function. There was
a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites
increased with decreased renal function. The AUC of one pharmacologically active ranolazine
metabolite was 5-fold increased in patients with severe renal impairment.
In the population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was estimated
in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal
impairment (creatinine clearance 10–30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure
was estimated.
The influence of dialysis on the pharmacokinetics of ranolazine has not been evaluated.
Hepatic impairment: The pharmacokinetics of ranolazine have been evaluated in patients with mild or
moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in
patients with moderate impairment. QT prolongation was more pronounced in these patients.
Paediatrics: The pharmacokinetic parameters of ranolazine have not been studied in the paediatric
population (< 18 years).
5.3
Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinical
exposure, were as follows: Ranolazine was associated with convulsions and increased mortality in rats
and dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinical
dose.
Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes at
exposures slightly greater than those seen in clinical patients. This effect is associated with increased
plasma cholesterol concentrations. No similar changes have been identified in humans. No effect on
the adreno-cortical axis was noted in humans.
In long-term carcinogenicity studies at doses of ranolazine up to 50 mg/kg/day (150 mg/m
2
/day) in
mice and 150 mg/kg/day (900 mg/m
2
/day) in rats, no relevant increases in the incidence of any tumour
types were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximum
recommended human dose of 2 grams on a mg/m
2
basis, and represent the maximum tolerated doses in
these species.
10
Signs of embryonal and maternal toxicity, but not teratogenicity, were seen at doses of ranolazine up
to 400 mg/kg/day (2400 mg/m
2
/day) in rats and 150 mg/kg/day (1275 mg/m
2
/day) in rabbits. These
doses represent 2 and 1 times, respectively, the maximum recommended human dose.
6.
6.1
List of excipients
Excipients for all ranolazine prolonged-release tablets:
Carnauba wax
Hypromellose
Magnesium stearate
Methacrylic acid-ethyl acrylate copolymer (1:1)
Microcrystalline cellulose
Sodium hydroxide
Titanium dioxide
Additional excipients for 375 mg tablet
:
Macrogol
Polysorbate 80
Blue #2/Indigo Carmine Aluminium Lake (E132)
6.2
Incompatibilities
Not applicable
6.3
Shelf life
4 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVDC/Aluminium blisters of 10 tablets per blister card. Each carton contains 3, 6, or 10 blister
cards (30, 60, or 100 tablets) or one HDPE bottle containing 60 tablets.
Not all pack-sizes may be marketed.
6.6
Special precautions for disposal
No special requirements
7.
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
8.
EU/1/08/462/001 60 tablets in blister pack
11
EU/1/08/462/002 60 tablets in bottle
EU/1/08/462/007 30 tablets in blister pack
EU/1/08/462/008 100 tablets in blister pack
9.
Date of first authorisation: 09 July 2008
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
12
1.
Ranexa 500 mg prolonged-release tablets
2.
Each tablet contains 500 mg of ranolazine.
For a full list of excipients see section 6.1.
3.
Prolonged-release tablet
Light orange oval-shaped tablet engraved with CVT500 on one side.
4.
4.1
Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina
pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-
blockers and/or calcium antagonists).
4.2
Patients should be given the Ranexa package leaflet and the Patient Alert Card and instructed to
present their Patient Alert Card and medication list to their health care professional at each visit.
Ranexa is available as 375 mg, 500 mg, and 750 mg prolonged-release tablets.
Adults: The recommended initial dose of Ranexa is 375 mg twice daily. After 2–4 weeks, the dose
should be titrated to 500 mg twice daily and, according to the patient’s response, further titrated to a
recommended maximum dose of 750 mg twice daily (see section 5.1).
If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-
titration of Ranexa to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after
dose reduction, treatment should be discontinued.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is
recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole,
erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).
Concomitant administration of potent CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).
Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal
impairment (creatinine clearance 30–80 ml/min) (see sections 4.4, 4.8, and 5.2). Ranexa is
contraindicated in patients with severe renal impairment (creatinine clearance
<
30 ml/min) (see
sections 4.3 and 5.2).
Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment
(see sections 4.4 and 5.2). Ranexa is contraindicated in patients with moderate or severe hepatic
impairment (see sections 4.3 and 5.2).
13
Elderly: Dose titration in elderly patients should be exercised with caution (see section 4.4). Elderly
may have increased ranolazine exposure due to age-related decrease in renal function (see section 5.2).
The incidence of adverse events was higher in the elderly (see section 4.8).
60 kg). Dose
titration in patients with low weight should be exercised with caution (see sections 4.4, 4.8, and 5.2).
£
Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA
Class III–IV) should be exercised with caution (see sections 4.4 and 5.2).
Paediatric patients: Ranexa is not recommended for use in children below the age of 18 years due to a
lack of data on safety and efficacy.
Ranexa tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken
with or without food.
4.3
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.2 and 5.2).
Moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole,
voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see
sections 4.2 and 4.5).
Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol)
antiarrhythmics other than amiodarone.
4.4
Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an
increased exposure is expected:
·
Concomitant administration of moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).
·
Concomitant administration of P-gp inhibitors (see sections 4.2 and 4.5).
·
Mild hepatic impairment (see sections 4.2 and 5.2).
·
Mild to moderate renal impairment (creatinine clearance 30–80 ml/min) (see sections 4.2, 4.8,
and 5.2).
·
Elderly (see sections 4.2, 4.8, and 5.2).
·
Patients with low weight (
£
60 kg) (see sections 4.2, 4.8, and 5.2).
·
Patients with moderate to severe CHF (NYHA Class III–IV) (see sections 4.2 and 5.2).
In patients with a combination of these factors, additional exposure increases are expected. Dose-
dependent side effects are likely to occur. If Ranexa is used in patients with a combination of several
of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment
discontinued, if needed.
The risk for increased exposure leading to adverse events in these different subgroups is higher in
patients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolising
capacity (extensive metabolisers, EM) (see section 5.2). The above precautions are based on the risk in
a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower need
for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been
determined (e.g. by genotyping) or is previously known to be EM, Ranexa can be used with caution in
these patients when they have a combination of several of the above risk factors.
QT prolongation
: A population-based analysis of combined data from patients and healthy volunteers
demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be
2.4 msec per 1000 ng/ml, which is approximately equal to a 2- to 7-msec increase over the plasma
concentration range for ranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed
14
Low weight: The incidence of adverse events was higher in patients with low weight (
when treating patients with a history of congenital or a family history of long QT syndrome, in
patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the
QTc interval (see section 4.5 also).
Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of
efficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin,
phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see section 4.5).
Renal impairment: Renal function decreases with age and it is therefore important to check renal
function at regular intervals during treatment with ranolazine (see sections 4.2, 4.3, 4.8, and 5.2).
4.5
Effects of other medicinal products on ranolazine
CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4
increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g.
nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment
with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3.0- to 3.9-fold during
ranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole,
ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin,
nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a potent CYP3A4 inhibitor.
Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent
increases in average ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of
Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4
inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required (see sections
4.2 and 4.4).
Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma
levels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-state
concentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gp
inhibitors. Down-titration of Ranexa may be required (see sections 4.2 and 4.4).
CYP3A4 inducers
: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations
by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of
inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see
section 4.4).
CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of this
enzyme may increase plasma concentrations of ranolazine. The potent CYP2D6 inhibitor paroxetine,
at a dose of 20 mg once daily, increased steady-state plasma concentrations of ranolazine 1000 mg
twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice
daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine
AUC of about 62%.
Effects of ranolazine on other medicinal products
Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may
increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are
transported by P-gp may be increased.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily
increased plasma concentrations of metoprolol by 1.8-fold. Therefore the exposure to metoprolol or
other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic
15
antidepressants and antipsychotics) may be increased during co-administration with Ranexa, and lower
doses of these medicinal products may be required.
The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during
co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported
when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored
following initiation and termination of Ranexa therapy.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa
1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, and the
HMG-CoA reductase inhibitor activity by 1.4- to 1.6-fold.
There is a theoretical risk that concomitant treatment of ranolazine with other drugs known to prolong
the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of
ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine,
astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide),
erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).
4.6
Pregnancy: There are no adequate data from the use of ranolazine in pregnant women. Animal studies
are insufficient with respect to effects on pregnancy and embryofoetal development (see section 5.3).
The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly
necessary.
Lactation: It is unknown whether ranolazine is excreted in human breast milk. The excretion of
ranolazine in milk has not been studied in animals. Ranexa should not be used during breast-feeding.
4.7
No studies on the effects of Ranexa on the ability to drive and use machines have been performed.
Ranexa may cause dizziness and blurred vision (see section 4.8), which may affect the ability to drive
and use machines.
4.8
Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and often
develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical
development programme, which included a total of 1,030 chronic angina patients treated with Ranexa.
The adverse events, considered to be at least possibly related to treatment, are listed below by body
system, organ class, and absolute frequency. Frequencies are defined as very common (
³
1/10),
common (
³
1/100 to
<
1/10), uncommon (
³
1/1,000 to < 1/100), rare (
³
1/10,000 to < 1/1,000), and
very rare (< 1/10,000).
Metabolism and nutrition disorders
Uncommon:
anorexia, decreased appetite, dehydration.
Psychiatric disorders
Uncommon:
anxiety, insomnia.
Rare:
disorientation.
16
Nervous system disorders
Common:
dizziness, headache.
Uncommon:
lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness.
Rare:
amnesia, depressed level of consciousness, loss of consciousness, parosmia.
Eye disorders
Uncommon:
blurred vision, visual disturbance.
Ear and labyrinth disorders
Uncommon:
vertigo, tinnitus.
Rare:
impaired hearing.
Vascular disorders
Uncommon:
hot flush, hypotension.
Rare:
peripheral coldness, orthostatic hypotension.
Respiratory, thoracic, and mediastinal disorders
Uncommon:
dyspnoea, cough, epistaxis.
Rare:
throat tightness.
Gastrointestinal disorders
Common:
constipation, vomiting, nausea.
Uncommon:
abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
Rare:
pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders
Uncommon:
pruritus, hyperhydrosis.
Rare:
allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders
Uncommon:
pain in extremity, muscle cramp, joint swelling.
Renal and urinary disorders
Uncommon:
dysuria, haematuria, chromaturia.
Reproductive system and breast disorders
Rare:
erectile dysfunction.
General disorders and administration site conditions
Common:
asthenia.
Uncommon:
fatigue, peripheral oedema.
Investigations
Uncommon:
increased blood creatinine, increased blood urea, prolonged QT corrected interval,
increased platelet or white blood cell count, decreased weight.
Rare:
elevated levels of hepatic enzyme.
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. Evaluations in patients who may be considered at higher risk of adverse events when treated
with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or
obstructive airway disease, confirmed that these conditions were not associated with clinically
meaningful increases in the incidence of adverse events.
Elderly, renal impairment, and low weight: In general, adverse events occurred more frequently
among elderly patients and patients with renal impairment; however, the types of events in these
subgroups were similar to those observed in the general population. Of the most commonly reported,
17
75 years of age) than younger patients (< 75 years of age): constipation (8% versus 5%), nausea
(6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
30–80 ml/min) compared
to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported
events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7%
versus 5%), and nausea (4% versus 2%).
³
60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-
corrected frequencies of the following common adverse events were higher in low body weight than
heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus
2%).
Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels
have been observed in healthy subjects and patients treated with Ranexa. There was no renal toxicity
related to these findings. A renal function study in healthy volunteers demonstrated a reduction in
creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal
tubular secretion of creatinine.
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).
4.9
In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, and
vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia,
lethargy, and syncope were observed in an intravenous overdose study in healthy volunteers. In the
event of overdose, the patient should be closely monitored and the treatment should be symptomatic
and supportive.
Approximately 62% of ranolazine is bound to plasma proteins, and therefore, complete clearance by
haemodialysis is unlikely.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other cardiac preparations, ATC code: C01EB18
Mechanism of action: The mechanism of action of ranolazine is largely unknown. Ranolazine may
have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces
intracellular sodium accumulation and consequently decreases intracellular calcium overload.
Ranolazine, via its action to decrease the late sodium current, is considered to reduce these
intracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload is
expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness.
Clinical evidence of inhibition of the late sodium current by ranolazine is provided by a significant
shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of
5 patients with a long QT syndrome (LQT3 having the SCN5A ∆KPQ gene mutation).
These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
Pharmacodynamic effects
18
the following events occurred more often with Ranexa (placebo-corrected frequencies) in elderly
(
³
In patients with mild or moderate renal impairment (creatinine clearance
In general, the type and frequency of adverse events reported in patients with low body weight
(
£
Haemodynamic effects: Minimal decreases in mean heart rate (< 2 beats per minute) and mean
systolic blood pressure (< 3 mm Hg) were observed in patients treated with ranolazine either alone or
in combination with other antianginal medicinal products in controlled studies.
Electrocardiographic effects: Dose and plasma concentration-related increases in the QTc interval
(about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched
T waves, have been observed in patients treated with Ranexa. These effects of ranolazine on the
surface electrocardiogram are believed to result from inhibition of the fast-rectifying potassium
current, which prolongs the ventricular action potential, and from inhibition of the late sodium current,
which shortens the ventricular action potential. A population analysis of combined data from
1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msec
per 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotal
clinical studies, where mean changes from baseline in QTcF (Fridericia’s correction) after doses of
500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients with
clinically significant hepatic impairment.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference between Ranexa and placebo in the risk of all-cause mortality (relative risk
ranolazine:placebo 0.99), sudden cardiac death (relative risk ranolazine:placebo 0.87), or the
frequency of symptomatic documented arrhythmias (3.0% versus 3.1%).
No proarrhythmic effects were observed in 3,162 patients treated with Ranexa based on 7-day Holter
monitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmias
in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia
³
Clinical efficacy
: Clinical studies have demonstrated the efficacy and safety of Ranexa in the
treatment of patients with chronic angina, either alone or when the benefit from other antianginal
medicinal products was sub-optimal.
In the pivotal study, CARISA, Ranexa was added to treatment with atenolol 50 mg once daily,
amlodipine 5 mg once daily, or diltiazem 180 mg once daily. Eight-hundred and twenty-three patients
(23% women) were randomised to receive 12 weeks of treatment with Ranexa 750 mg twice daily,
1000 mg twice daily, or placebo. Ranexa demonstrated greater efficacy than placebo in prolonging
exercise time at trough at 12 weeks for both doses studied when used as an add-on therapy. However,
there was no difference in exercise duration between the two doses (24 seconds compared to placebo;
p
0.03).
Ranexa resulted in significant decreases in the number of angina attacks per week and consumption of
short-acting nitroglycerin compared to placebo. Tolerance to ranolazine did not develop during
treatment and a rebound increase in angina attacks was not observed following abrupt discontinuation.
The improvement in exercise duration in women was about 33% of the improvement in men at the
1000 mg twice-daily dose level. However, men and women had similar reductions in frequency of
angina attacks and nitroglycerin consumption. Given the dose-dependent side effects and similar
efficacy at 750 and 1000 mg twice daily, a maximum dose of 750 mg twice daily is recommended.
In a second study, ERICA, Ranexa was added to treatment with amlodipine 10 mg once daily (the
maximum labelled dose). Five-hundred and sixty-five patients were randomised to receive an initial
dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with
Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg
once daily. Additionally, 45% of the study population also received long-acting nitrates. Ranexa
resulted in significant decreases in the number of angina attacks per week (p = 0.028) and
consumption of short-acting nitroglycerin (p = 0.014) compared to placebo. Both the average number
of angina attacks and nitroglycerin tablets consumed decreased by approximately one per week.
In the main dose-finding study, MARISA, ranolazine was used as monotherapy. One-hundred and
ninety-one patients were randomised to treatment with Ranexa 500 mg twice daily, 1000 mg twice
19
8 beats (5% versus 8%).
£
daily, 1500 mg twice daily, and matching placebo, each for 1 week in a crossover design. Ranexa was
significantly superior to placebo in prolonging exercise time, time to angina, and time to 1 mm ST
segment depression at all doses studied with an observed dose-response relationship. Improvement of
exercise duration was statistically significant compared to placebo for all three doses of ranolazine
from 24 seconds at 500 mg twice daily to 46 seconds at 1500 mg twice daily, showing a dose-related
response. In this study, exercise duration was longest in the 1500 mg group; however, there was a
disproportional increase in side effects, and the 1500 mg dose was not studied further.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99), sudden cardiac
death (relative risk ranolazine:placebo 0.87), or the frequency of symptomatic documented
arrhythmias (3.0% versus 3.1%) between Ranexa and placebo when added to standard medical therapy
(including beta-blockers, calcium channel blockers, nitrates, anti-platelet agents, lipid-lowering
medicinal products, and ACE inhibitors). Approximately one-half of the patients in MERLIN-TIMI 36
had a history of angina. The results showed that exercise duration was 31 seconds longer in ranolazine
patients versus placebo patients (p = 0.002). The Seattle Angina Questionnaire showed significant
effects on several dimensions, including angina frequency (p
<
0.001), compared to placebo-treated
patients.
A small proportion of non-Caucasians was included in the controlled clinical studies; therefore, no
conclusions can be drawn regarding the effect and safety in non-Caucasians.
5.2
Pharmacokinetic properties
After oral administration of Ranexa, peak plasma concentrations (C
max
) are typically observed between
2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.
Absorption: The mean absolute bioavailability of ranolazine after oral administration of immediate-
release ranolazine tablets ranged from 35−50%, with large inter-individual variability. Ranexa
exposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state
AUC as the dose was increased from 500 mg to 1000 mg twice daily. In a pharmacokinetic study in
healthy volunteers, steady-state C
max
was, on average, approximately 1770 (SD 1040) ng/ml, and
steady-state AUC
0-12
was, on average, 13,700 (SD 8290) ng x h/ml following a dose of 500 mg twice
daily. Food does not affect the rate and extent of absorption of ranolazine.
Distribution: Approximately 62% of ranolazine is bound to plasma proteins, mainly alpha-1 acid
glycoprotein and weakly to albumin. The mean steady-state volume of distribution (V
ss
) is about 180 l.
Elimination: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted
unchanged in the urine and faeces. Following oral administration of a single 500 mg dose of
[
14
C]-ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% in
faeces.
Clearance of ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life is
about 2−3 hours after intravenous administration. The terminal half-life at steady state after oral
administration of ranolazine is about 7 hours, due to the absorption rate-limited elimination.
100 metabolites), and faeces (25 metabolites). Fourteen primary pathways
have been identified of which O-demethylation and N-dealkylation are the most important.
In vitro
studies using human liver microsomes indicate that ranolazine is metabolised primarily by CYP3A4,
but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolisers,
PM) had 62% higher AUC than subjects with CYP2D6 metabolising capacity (extensive metabolisers,
EM). The corresponding difference at the 1000 mg twice-daily dose was 25%.
>
20
Biotransformation: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults,
ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral
500 mg dose of [
14
C]-ranolazine. A large number of metabolites has been identified in human plasma
(47 metabolites), urine (
Special populations
The influence of various factors on the pharmacokinetics of ranolazine was assessed in a population
pharmacokinetic evaluation in 928 angina patients and healthy subjects.
Gender effects: Gender had no clinically relevant effect on pharmacokinetic parameters.
Elderly patients: Age alone had no clinically relevant effect on pharmacokinetic parameters.
However, the elderly may have increased ranolazine exposure due to age-related decrease in renal
function.
Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold
higher in subjects weighing 40 kg.
CHF: CHF NYHA Class III and IV were estimated to have about 1.3-fold higher plasma
concentrations.
Renal impairment: In a study evaluating the influence of renal function on ranolazine
pharmacokinetics, ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild,
moderate, and severe renal impairment compared with subjects with normal renal function. There was
a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites
increased with decreased renal function. The AUC of one pharmacologically active ranolazine
metabolite was 5-fold increased in patients with severe renal impairment.
In the population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was estimated
in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal
impairment (creatinine clearance 10–30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure
was estimated.
The influence of dialysis on the pharmacokinetics of ranolazine has not been evaluated.
Hepatic impairment: The pharmacokinetics of ranolazine have been evaluated in patients with mild or
moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in
patients with moderate impairment. QT prolongation was more pronounced in these patients.
Paediatrics: The pharmacokinetic parameters of ranolazine have not been studied in the paediatric
population (< 18 years).
5.3
Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinical
exposure, were as follows: Ranolazine was associated with convulsions and increased mortality in rats
and dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinical
dose.
Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes at
exposures slightly greater than those seen in clinical patients. This effect is associated with increased
plasma cholesterol concentrations. No similar changes have been identified in humans. No effect on
the adreno-cortical axis was noted in humans.
In long-term carcinogenicity studies at doses of ranolazine up to 50 mg/kg/day (150 mg/m
2
/day) in
mice and 150 mg/kg/day (900 mg/m
2
/day) in rats, no relevant increases in the incidence of any tumour
types were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximum
recommended human dose of 2 grams on a mg/m
2
basis, and represent the maximum tolerated doses in
these species.
21
Signs of embryonal and maternal toxicity, but not teratogenicity, were seen at doses of ranolazine up
to 400 mg/kg/day (2400 mg/m
2
/day) in rats and 150 mg/kg/day (1275 mg/m
2
/day) in rabbits. These
doses represent 2 and 1 times, respectively, the maximum recommended human dose.
6.
6.1
List of excipients
Excipients for all ranolazine prolonged-release tablets:
Carnauba wax
Hypromellose
Magnesium stearate
Methacrylic acid-ethyl acrylate copolymer (1:1)
Microcrystalline cellulose
Sodium hydroxide
Titanium dioxide
Additional excipients for 500 mg tablet
:
Macrogol
Polyvinyl alcohol-part hydrolyzed
Iron oxide yellow (E172)
Iron oxide red (E172)
Talc
6.2
Incompatibilities
Not applicable
6.3
Shelf life
4 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVDC/Aluminium blisters of 10 tablets per blister card. Each carton contains 3, 6, or 10 blister
cards (30, 60, or 100 tablets) or one HDPE bottle containing 60 tablets.
Not all pack-sizes may be marketed.
6.6
Special precautions for disposal
No special requirements
7.
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
22
8.
EU/1/08/462/003 60 tablets in blister pack
EU/1/08/462/004 60 tablets in bottle
EU/1/08/462/009 30 tablets in blister pack
EU/1/08/462/010 100 tablets in blister pack
9.
Date of first authorisation: 09 July 2008
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
23
1.
Ranexa 750 mg prolonged-release tablets
2.
Each tablet contains 750 mg of ranolazine.
Excipients: Each tablet contains 0.04 mg azo colouring agent E102 and 12.0 mg lactose monohydrate.
For a full list of excipients see section 6.1.
3.
Prolonged-release tablet
Pale green oval-shaped tablet engraved with CVT750 on one side.
4.
4.1
Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina
pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-
blockers and/or calcium antagonists).
4.2
Patients should be given the Ranexa package leaflet and the Patient Alert Card and instructed to
present their Patient Alert Card and medication list to their health care professional at each visit.
Ranexa is available as 375 mg, 500 mg, and 750 mg prolonged-release tablets.
Adults: The recommended initial dose of Ranexa is 375 mg twice daily. After 2–4 weeks, the dose
should be titrated to 500 mg twice daily and, according to the patient’s response, further titrated to a
recommended maximum dose of 750 mg twice daily (see section 5.1).
If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-
titration of Ranexa to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after
dose reduction, treatment should be discontinued.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is
recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole,
erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).
Concomitant administration of potent CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).
Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal
impairment (creatinine clearance 30–80 ml/min) (see sections 4.4, 4.8, and 5.2). Ranexa is
contraindicated in patients with severe renal impairment (creatinine clearance
<
30 ml/min) (see
sections 4.3 and 5.2).
Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment
(see sections 4.4 and 5.2). Ranexa is contraindicated in patients with moderate or severe hepatic
impairment (see sections 4.3 and 5.2).
24
Elderly: Dose titration in elderly patients should be exercised with caution (see section 4.4). Elderly
may have increased ranolazine exposure due to age-related decrease in renal function (see section 5.2).
The incidence of adverse events was higher in the elderly (see section 4.8).
60 kg). Dose
titration in patients with low weight should be exercised with caution (see sections 4.4, 4.8, and 5.2).
£
Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA
Class III–IV) should be exercised with caution (see sections 4.4 and 5.2).
Paediatric patients: Ranexa is not recommended for use in children below the age of 18 years due to a
lack of data on safety and efficacy.
Ranexa tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken
with or without food.
4.3
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.2 and 5.2).
Moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole,
voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see
sections 4.2 and 4.5).
Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol)
antiarrhythmics other than amiodarone.
4.4
Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an
increased exposure is expected:
·
Concomitant administration of moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).
·
Concomitant administration of P-gp inhibitors (see sections 4.2 and 4.5).
·
Mild hepatic impairment (see sections 4.2 and 5.2).
·
Mild to moderate renal impairment (creatinine clearance 30–80 ml/min) (see sections 4.2, 4.8,
and 5.2).
·
Elderly (see sections 4.2, 4.8, and 5.2).
·
Patients with low weight (
£
60 kg) (see sections 4.2, 4.8, and 5.2).
·
Patients with moderate to severe CHF (NYHA Class III–IV) (see sections 4.2 and 5.2).
In patients with a combination of these factors, additional exposure increases are expected. Dose-
dependent side effects are likely to occur. If Ranexa is used in patients with a combination of several
of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment
discontinued, if needed.
The risk for increased exposure leading to adverse events in these different subgroups is higher in
patients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolising
capacity (extensive metabolisers, EM) (see section 5.2). The above precautions are based on the risk in
a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower need
for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been
determined (e.g. by genotyping) or is previously known to be EM, Ranexa can be used with caution in
these patients when they have a combination of several of the above risk factors.
QT prolongation
: A population-based analysis of combined data from patients and healthy volunteers
demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be
2.4 msec per 1000 ng/ml, which is approximately equal to a 2- to 7-msec increase over the plasma
concentration range for ranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed
25
Low weight: The incidence of adverse events was higher in patients with low weight (
when treating patients with a history of congenital or a family history of long QT syndrome, in
patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the
QTc interval (see section 4.5 also).
Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of
efficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin,
phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see section 4.5).
Renal impairment: Renal function decreases with age and it is therefore important to check renal
function at regular intervals during treatment with ranolazine (see sections 4.2, 4.3, 4.8, and 5.2).
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this
medicinal product.
Azo colouring agent E102: This medicinal product contains the azo colouring agent E102 which may
cause allergic reactions.
4.5
Effects of other medicinal products on ranolazine
CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4
increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g.
nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment
with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3.0- to 3.9-fold during
ranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole,
ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin,
nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a potent CYP3A4 inhibitor.
Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent
increases in average ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of
Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4
inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required (see sections
4.2 and 4.4).
Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma
levels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-state
concentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gp
inhibitors. Down-titration of Ranexa may be required (see sections 4.2 and 4.4).
CYP3A4 inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations
by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of
inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see
section 4.4).
CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of this
enzyme may increase plasma concentrations of ranolazine. The potent CYP2D6 inhibitor paroxetine,
at a dose of 20 mg once daily, increased steady-state plasma concentrations of ranolazine 1000 mg
twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice
daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine
AUC of about 62%.
26
Effects of ranolazine on other medicinal products
Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may
increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are
transported by P-gp may be increased.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily
increased plasma concentrations of metoprolol by 1.8-fold. Therefore the exposure to metoprolol or
other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent,. tricyclic
antidepressants and antipsychotics) may be increased during co-administration with Ranexa, and lower
doses of these medicinal products may be required.
The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during
co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported
when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored
following initiation and termination of Ranexa therapy.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa
1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, and the
HMG-CoA reductase inhibitor activity by 1.4- to 1.6-fold.
There is a theoretical risk that concomitant treatment of ranolazine with other drugs known to prolong
the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of
ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine,
astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide),
erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).
4.6
Pregnancy: There are no adequate data from the use of ranolazine in pregnant women. Animal studies
are insufficient with respect to effects on pregnancy and embryofoetal development (see section 5.3).
The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly
necessary.
Lactation: It is unknown whether ranolazine is excreted in human breast milk. The excretion of
ranolazine in milk has not been studied in animals. Ranexa should not be used during breast-feeding.
4.7
No studies on the effects of Ranexa on the ability to drive and use machines have been performed.
Ranexa may cause dizziness and blurred vision (see section 4.8), which may affect the ability to drive
and use machines.
4.8
Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and often
develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical
development programme, which included a total of 1,030 chronic angina patients treated with Ranexa.
The adverse events, considered to be at least possibly related to treatment, are listed below by body
system, organ class, and absolute frequency. Frequencies are defined as very common (
³
1/10),
common (
³
1/100 to
<
1/10), uncommon (
³
1/1,000 to < 1/100), rare (
³
1/10,000 to < 1/1,000), and
very rare (< 1/10,000).
Metabolism and nutrition disorders
27
Uncommon:
anorexia, decreased appetite, dehydration.
Psychiatric disorders
Uncommon:
anxiety, insomnia.
Rare:
disorientation.
Nervous system disorders
Common:
dizziness, headache.
Uncommon:
lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness.
Rare:
amnesia, depressed level of consciousness, loss of consciousness, parosmia.
Eye disorders
Uncommon:
blurred vision, visual disturbance.
Ear and labyrinth disorders
Uncommon:
vertigo, tinnitus.
Rare:
impaired hearing.
Vascular disorders
Uncommon:
hot flush, hypotension.
Rare:
peripheral coldness, orthostatic hypotension.
Respiratory, thoracic, and mediastinal disorders
Uncommon:
dyspnoea, cough, epistaxis.
Rare:
throat tightness.
Gastrointestinal disorders
Common:
constipation, vomiting, nausea.
Uncommon:
abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
Rare:
pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders
Uncommon:
pruritus, hyperhydrosis.
Rare:
allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders
Uncommon:
pain in extremity, muscle cramp, joint swelling.
Renal and urinary disorders
Uncommon:
dysuria, haematuria, chromaturia.
Reproductive system and breast disorders
Rare:
erectile dysfunction.
General disorders and administration site conditions
Common:
asthenia.
Uncommon:
fatigue, peripheral oedema.
Investigations
Uncommon:
increased blood creatinine, increased blood urea, prolonged QT corrected interval,
increased platelet or white blood cell count, decreased weight.
Rare:
elevated levels of hepatic enzyme.
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. Evaluations in patients who may be considered at higher risk of adverse events when treated
with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or
28
obstructive airway disease, confirmed that these conditions were not associated with clinically
meaningful increases in the incidence of adverse events.
Elderly, renal impairment, and low weight: In general, adverse events occurred more frequently
among elderly patients and patients with renal impairment; however, the types of events in these
subgroups were similar to those observed in the general population. Of the most commonly reported,
the following events occurred more often with Ranexa (placebo-corrected frequencies) in elderly
(
30–80 ml/min) compared
to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported
events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7%
versus 5%), and nausea (4% versus 2%).
³
60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-
corrected frequencies of the following common adverse events were higher in low body weight than
heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus
2%).
Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels
have been observed in healthy subjects and patients treated with Ranexa. There was no renal toxicity
related to these findings. A renal function study in healthy volunteers demonstrated a reduction in
creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal
tubular secretion of creatinine.
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).
4.9
In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, and
vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia,
lethargy, and syncope were observed in an intravenous overdose study in healthy volunteers. In the
event of overdose, the patient should be closely monitored and the treatment should be symptomatic
and supportive.
Approximately 62% of ranolazine is bound to plasma proteins, and therefore, complete clearance by
haemodialysis is unlikely.
5.
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other cardiac preparations, ATC code: C01EB18
Mechanism of action: The mechanism of action of ranolazine is largely unknown. Ranolazine may
have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces
intracellular sodium accumulation and consequently decreases intracellular calcium overload.
Ranolazine, via its action to decrease the late sodium current, is considered to reduce these
intracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload is
expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness.
Clinical evidence of inhibition of the late sodium current by ranolazine is provided by a significant
29
75 years of age) than younger patients (< 75 years of age): constipation (8% versus 5%), nausea
(6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
³
In patients with mild or moderate renal impairment (creatinine clearance
In general, the type and frequency of adverse events reported in patients with low body weight
(
£
shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of
5 patients with a long QT syndrome (LQT3 having the SCN5A ∆KPQ gene mutation).
These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
Pharmacodynamic effects
Haemodynamic effects: Minimal decreases in mean heart rate (< 2 beats per minute) and mean
systolic blood pressure (< 3 mm Hg) were observed in patients treated with ranolazine either alone or
in combination with other antianginal medicinal products in controlled studies.
Electrocardiographic effects: Dose and plasma concentration-related increases in the QTc interval
(about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched
T waves, have been observed in patients treated with Ranexa. These effects of ranolazine on the
surface electrocardiogram are believed to result from inhibition of the fast-rectifying potassium
current, which prolongs the ventricular action potential, and from inhibition of the late sodium current,
which shortens the ventricular action potential. A population analysis of combined data from
1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msec
per 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotal
clinical studies, where mean changes from baseline in QTcF (Fridericia’s correction) after doses of
500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients with
clinically significant hepatic impairment.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference between Ranexa and placebo in the risk of all-cause mortality (relative risk
ranolazine:placebo 0.99), sudden cardiac death (relative risk ranolazine:placebo 0.87), or the
frequency of symptomatic documented arrhythmias (3.0% versus 3.1%).
No proarrhythmic effects were observed in 3,162 patients treated with Ranexa based on 7-day Holter
monitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmias
in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia
³
Clinical efficacy: Clinical studies have demonstrated the efficacy and safety of Ranexa in the
treatment of patients with chronic angina, either alone or when the benefit from other antianginal
medicinal products was sub-optimal.
In the pivotal study, CARISA, Ranexa was added to treatment with atenolol 50 mg once daily,
amlodipine 5 mg once daily, or diltiazem 180 mg once daily. Eight-hundred and twenty-three patients
(23% women) were randomised to receive 12 weeks of treatment with Ranexa 750 mg twice daily,
1000 mg twice daily, or placebo. Ranexa demonstrated greater efficacy than placebo in prolonging
exercise time at trough at 12 weeks for both doses studied when used as an add-on therapy. However,
there was no difference in exercise duration between the two doses (24 seconds compared to placebo;
p
0.03).
Ranexa resulted in significant decreases in the number of angina attacks per week and consumption of
short-acting nitroglycerin compared to placebo. Tolerance to ranolazine did not develop during
treatment and a rebound increase in angina attacks was not observed following abrupt discontinuation.
The improvement in exercise duration in women was about 33% of the improvement in men at the
1000 mg twice-daily dose level. However, men and women had similar reductions in frequency of
angina attacks and nitroglycerin consumption. Given the dose-dependent side effects and similar
efficacy at 750 and 1000 mg twice daily, a maximum dose of 750 mg twice daily is recommended.
In a second study, ERICA, Ranexa was added to treatment with amlodipine 10 mg once daily (the
maximum labelled dose). Five-hundred and sixty-five patients were randomised to receive an initial
dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with
Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg
30
8 beats (5% versus 8%).
£
once daily. Additionally, 45% of the study population also received long-acting nitrates. Ranexa
resulted in significant decreases in the number of angina attacks per week (p = 0.028) and
consumption of short-acting nitroglycerin (p = 0.014) compared to placebo. Both the average number
of angina attacks and nitroglycerin tablets consumed decreased by approximately one per week.
In the main dose-finding study, MARISA, ranolazine was used as monotherapy. One-hundred and
ninety-one patients were randomised to treatment with Ranexa 500 mg twice daily, 1000 mg twice
daily, 1500 mg twice daily, and matching placebo, each for 1 week in a crossover design. Ranexa was
significantly superior to placebo in prolonging exercise time, time to angina, and time to 1 mm ST
segment depression at all doses studied with an observed dose-response relationship. Improvement of
exercise duration was statistically significant compared to placebo for all three doses of ranolazine
from 24 seconds at 500 mg twice daily to 46 seconds at 1500 mg twice daily, showing a dose-related
response. In this study, exercise duration was longest in the 1500 mg group; however, there was a
disproportional increase in side effects, and the 1500 mg dose was not studied further.
In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no
difference in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99), sudden cardiac
death (relative risk ranolazine:placebo 0.87), or the frequency of symptomatic documented
arrhythmias (3.0% versus 3.1%) between Ranexa and placebo when added to standard medical therapy
(including beta-blockers, calcium channel blockers, nitrates, anti-platelet agents, lipid-lowering
medicinal products, and ACE inhibitors). Approximately one-half of the patients in MERLIN-TIMI 36
had a history of angina. The results showed that exercise duration was 31 seconds longer in ranolazine
patients versus placebo patients (p = 0.002). The Seattle Angina Questionnaire showed significant
effects on several dimensions, including angina frequency (p < 0.001), compared to placebo-treated
patients.
A small proportion of non-Caucasians was included in the controlled clinical studies; therefore, no
conclusions can be drawn regarding the effect and safety in non-Caucasians.
5.2
Pharmacokinetic properties
After oral administration of Ranexa, peak plasma concentrations (C
max
) are typically observed between
2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.
Absorption: The mean absolute bioavailability of ranolazine after oral administration of immediate-
release ranolazine tablets ranged from 35−50%, with large inter-individual variability. Ranexa
exposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state
AUC as the dose was increased from 500 mg to 1000 mg twice daily. In a pharmacokinetic study in
healthy volunteers, steady-state C
max
was, on average, approximately 1770 (SD 1040) ng/ml, and
steady-state AUC
0-12
was, on average, 13,700 (SD 8290) ng x h/ml following a dose of 500 mg twice
daily. Food does not affect the rate and extent of absorption of ranolazine.
Distribution: Approximately 62% of ranolazine is bound to plasma proteins, mainly alpha-1 acid
glycoprotein and weakly to albumin. The mean steady-state volume of distribution (V
ss
) is about 180 l.
Elimination: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted
unchanged in the urine and faeces. Following oral administration of a single 500 mg dose of
[
14
C]-ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% in
faeces.
Clearance of ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life is
about 2−3 hours after intravenous administration. The terminal half-life at steady state after oral
administration of ranolazine is about 7 hours, due to the absorption rate-limited elimination.
Biotransformation: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults,
ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral
500 mg dose of [
14
C]-ranolazine. A large number of metabolites has been identified in human plasma
31
(47 metabolites), urine (> 100 metabolites), and faeces (25 metabolites). Fourteen primary pathways
have been identified of which O-demethylation and N-dealkylation are the most important.
In vitro
studies using human liver microsomes indicate that ranolazine is metabolised primarily by CYP3A4,
but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolisers,
PM) had 62% higher AUC than subjects with CYP2D6 metabolising capacity (extensive metabolisers,
EM). The corresponding difference at the 1000 mg twice-daily dose was 25%.
Special populations
The influence of various factors on the pharmacokinetics of ranolazine was assessed in a population
pharmacokinetic evaluation in 928 angina patients and healthy subjects.
Gender effects: Gender had no clinically relevant effect on pharmacokinetic parameters.
Elderly patients: Age alone had no clinically relevant effect on pharmacokinetic parameters.
However, the elderly may have increased ranolazine exposure due to age-related decrease in renal
function.
Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold
higher in subjects weighing 40 kg.
CHF: CHF NYHA Class III and IV were estimated to have about 1.3-fold higher plasma
concentrations.
Renal impairment: In a study evaluating the influence of renal function on ranolazine
pharmacokinetics, ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild,
moderate, and severe renal impairment compared with subjects with normal renal function. There was
a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites
increased with decreased renal function. The AUC of one pharmacologically active ranolazine
metabolite was 5-fold increased in patients with severe renal impairment.
In the population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was estimated
in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal
impairment (creatinine clearance 10–30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure
was estimated.
The influence of dialysis on the pharmacokinetics of ranolazine has not been evaluated.
Hepatic impairment: The pharmacokinetics of ranolazine have been evaluated in patients with mild or
moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in
patients with moderate impairment. QT prolongation was more pronounced in these patients.
Paediatrics
: The pharmacokinetic parameters of ranolazine have not been studied in the paediatric
population (< 18 years).
5.3
Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinical
exposure, were as follows: Ranolazine was associated with convulsions and increased mortality in rats
and dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinical
dose.
Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes at
exposures slightly greater than those seen in clinical patients. This effect is associated with increased
plasma cholesterol concentrations. No similar changes have been identified in humans. No effect on
the adreno-cortical axis was noted in humans.
32
In long-term carcinogenicity studies at doses of ranolazine up to 50 mg/kg/day (150 mg/m
2
/day) in
mice and 150 mg/kg/day (900 mg/m
2
/day) in rats, no relevant increases in the incidence of any tumour
types were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximum
recommended human dose of 2 grams on a mg/m
2
basis, and represent the maximum tolerated doses in
these species.
Signs of embryonal and maternal toxicity, but not teratogenicity, were seen at doses of ranolazine up
to 400 mg/kg/day (2400 mg/m
2
/day) in rats and 150 mg/kg/day (1275 mg/m
2
/day) in rabbits. These
doses represent 2 and 1 times, respectively, the maximum recommended human dose.
6.
6.1
List of excipients
Excipients for all ranolazine prolonged-release tablets:
Carnauba wax
Hypromellose
Magnesium stearate
Methacrylic acid-ethyl acrylate copolymer (1:1)
Microcrystalline cellulose
Sodium hydroxide
Titanium dioxide
Additional excipients for 750 mg tablet:
Glycerol triacetate
Lactose monohydrate
Blue #1/Brilliant Blue FCF Aluminium Lake (E133) and Yellow #5/Tartrazine Aluminium Lake
(E102)
6.2
Incompatibilities
Not applicable
6.3
Shelf life
4 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVDC/Aluminium blisters of 10 tablets per blister card. Each carton contains 3, 6, or 10 blister
cards (30, 60, or 100 tablets) or one HDPE bottle containing 60 tablets.
Not all pack-sizes may be marketed.
6.6
Special precautions for disposal
No special requirements
7.
33
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
8.
EU/1/08/462/005 60 tablets in blister pack
EU/1/08/462/006 60 tablets in bottle
EU/1/08/462/011 30 tablets in blister pack
EU/1/08/462/012 100 tablets in blister pack
9.
Date of first authorisation: 09 July 2008
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
34
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
35
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Brecon Pharmaceuticals Ltd.
Pharos House
Wye Valley Business Park
Hay-on-Wye
Hereford HR3 5PG
United Kingdom
or
Fine Foods N.T.M. SpA
Via dell’Artigianato 8/10
24041 Brembate (BG)
Italy
or
Menarini - Von Heyden GmbH
Leipziger Straβe 7-13
01097 Dresden
Germany
or
Berlin-Chemie AG
Glienicker Weg 125
12489 Berlin
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
·
Medicinal product subject to medical prescription.
·
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH must agree the details of a Patient Alert Card (PAC) with the National Competent
Authorities . The PAC – which is inserted inside the carton box - must include the following key
messages:
Health Care Professional information
The PAC should include the following information for the healthcare professional information
regarding Ranexa:
·
To refer to the Ranexa SPC prior to prescribing any medications to the patient, as there are
potential drug interactions which should be taken into consideration.
36
·
Ranexa is contraindicated in patients taking:
• Potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazol, posaconazol, HIV
protease inhibitors, clarithromycin, telithromycin, nefazodone)
• Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than
amiodarone
·
A dose reduction of Ranexa may be needed in combination with:
• Moderate CYP3A4 inhibitors (e.g. diltiazem, erythromycin, fluconazole)
• P-gp inhibitors (e.g. ciclosporin, verapamil)
·
Caution should be exercised when prescribing Ranexa to patients:
• Taking certain other drugs mentioned in the product information
• With certain other risk factors listed in the product information
·
Inform the patient about the potential for an interaction with other prescribed medicinal products
and to contact his/her doctor in case of dizziness, nausea or vomiting.
Patient information
The PAC should include the following information for the patient:
·
That the card should be shown to any doctor involved in their treatment
·
That prior to Ranexa treatment the patient should tell their doctor if they have any of the
following:
• Kidney problems
• Liver problems
• Have ever had an abnormal electrocardiogram (ECG)
• Is taking medications to treat epilepsy, bacterial or fungal infections, HIV infection,
depression or heart rhythm disorders
• Is taking the herbal remedy St John’s Wort
• Is taking allergy medicines
·
That during treatment with Ranexa the patient should:
• Not drink Grapefruit Juice
• Call their doctor if they feel dizzy or sick, become sick or experience any unexpected
symptoms after starting Ranexa.
·
To refer to the Ranexa package leaflet for more information.
·
To ensure to take a list of all their other medicines with them at any visit to the health care
professional.
·
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 10 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 0006 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
37
In addition, an updated RMP should be submitted
·
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
·
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
·
At the request of the EMEA
38
ANNEX III
LABELLING AND PACKAGE LEAFLET
39
A. LABELLING
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Carton containing blister strips or carton containing HDPE bottle and bottle label.
1.
Ranexa 375 mg prolonged-release tablets
Ranolazine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each prolonged-release tablet contains 375 mg ranolazine.
3.
LIST OF EXCIPIENTS
4.
30 prolonged-release tablets
60 prolonged-release tablets
100 prolonged-release tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Swallow whole. Do not chew.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
41
11.
Menarini International O. L. S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
12.
EU/1/08/462/001 60 tablets in blister pack
EU/1/08/462/002 60 tablets in bottle
EU/1/08/462/007 30 tablets in blister pack
EU/1/08/462/008 100 tablets in blister pack
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
Open Here
16.
INFORMATION IN BRAILLE
Ranexa 375 mg
42
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PVC/PVDC/Aluminium blisters
1.
Ranexa 375 mg prolonged-release tablets
Ranolazine
2.
Menarini International O.L. S.A.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Carton containing blister strips or carton containing HDPE bottle and bottle label.
1.
Ranexa 500 mg prolonged-release tablets
Ranolazine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each prolonged-release tablet contains 500 mg ranolazine.
3.
LIST OF EXCIPIENTS
4.
30 prolonged-release tablets
60 prolonged-release tablets
100 prolonged-release tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Swallow whole. Do not chew.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
44
11.
Menarini International O. L. S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
12.
EU/1/08/462/003 60 tablets in blister pack
EU/1/08/462/004 60 tablets in bottle
EU/1/08/462/009 30 tablets in blister pack
EU/1/08/462/010 100 tablets in blister pack
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
Open Here
16.
INFORMATION IN BRAILLE
Ranexa 500 mg
45
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PVC/PVDC/Aluminium blisters
1.
Ranexa 500 mg prolonged-release tablets
Ranolazine
2.
Menarini International O.L. S.A.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
46
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
Carton containing blister strips or carton containing HDPE bottle and bottle label.
1.
Ranexa 750 mg prolonged-release tablets
Ranolazine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each prolonged-release tablet contains 750 mg ranolazine.
3.
LIST OF EXCIPIENTS
Contains colouring agent E102 and lactose; see package leaflet for further information.
4.
30 prolonged-release tablets
60 prolonged-release tablets
100 prolonged-release tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Swallow whole. Do not chew.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
47
11.
Menarini International O. L. S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
12.
EU/1/08/462/005 60 tablets in blister pack
EU/1/08/462/006 60 tablets in bottle
EU/1/08/462/011 30 tablets in blister pack
EU/1/08/462/012 100 tablets in blister pack
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
Open Here
16.
INFORMATION IN BRAILLE
Ranexa 750 mg
48
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PVC/PVDC/Aluminium blisters
1.
Ranexa 750 mg prolonged-release tablets
Ranolazine
2.
Menarini International O.L. S.A.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
49
PULL OUT
Ranexa
®
Patient Alert Card
During Ranexa treatment
·
(Carry this card with you at all times)
Do not drink Grapefruit Juice whilst
taking Ranexa.
Information to the patient
·
Call your doctor if you feel dizzy or
sick, become sick or experience any
unexpected symptoms after starting
Ranexa.
This card contains important safety
information you should know before you
are given Ranexa and during treatment with
Ranexa.
Dates of Ranexa treatment:
·
Show this card to any doctor involved
in your treatment.
Start………………………
Prior to Ranexa treatment
Before taking Ranexa speak to your doctor if
you:
·
Have problems with your kidneys
·
See the Ranexa package leaflet for
more information.
·
Have liver problems
·
Please make sure you have a list of all
your other medicines with you at any
visit to the health care professional.
·
Have ever had an abnormal
electrocardiogram (ECG)
·
Are taking medications to treat
epilepsy, bacterial or fungal infections,
HIV infection, depression or heart
rhythm disorders
Patient’s name…………………………..
·
Are taking the herbal remedy St John’s
Wort
·
Are taking allergy medicines
Doctor’s name…………………………..
Doctor’s phone………………………….
50
PULL OUT
Ranexa Patient Alert Card
A dose reduction of Ranexa may be needed in
combination with:
·
(Information for Health Care Professionals)
Moderate CYP3A4 inhibitors
(eg, diltiazem, erythromycin,
fluconazole)
The patient carrying this card is treated
with Ranexa for symptomatic angina
pectoris.
·
P-gp inhibitors (eg, ciclosporin,
verapamil)
Please refer to the Ranexa SPC prior to
prescribing any medications to this patient,
as there are potential drug interactions
which should be taken into consideration.
Caution should be exercised when prescribing
Ranexa to patients:
·
Taking certain other drugs mentioned
in the product information
·
With certain other risk factors listed in
the product information
Ranexa is contraindicated in patients taking:
·
Potent CYP3A4 inhibitors (eg,
itraconazole, ketoconazole,
voriconazol, posaconazol, HIV
protease inhibitors, clarithromycin,
telithromycin, nefazodone)
Inform the patient about the potential for an
interaction with other prescribed medicinal
products and to contact his/her doctor in case
of dizziness, nausea or vomiting.
Please refer to the Ranexa SPC for further
recommendations.
·
Class Ia (eg, quinidine) or Class III (eg,
dofetilide, sotalol) antiarrhythmics
other than amiodarone
For Medical Information:
Freephone: xxxx-xxx-xxxx
51
B. PACKAGE LEAFLET
52
PACKAGE LEAFLET: INFORMATION FOR THE USER
Ranexa 375 mg prolonged-release tablets
Ranexa 500 mg prolonged-release tablets
Ranexa 750 mg prolonged-release tablets
Ranolazine
Read all of this leaflet carefully before you start taking this medicine.
In addition to this leaflet, you will be given a Patient Alert Card, which contains important safety
information that you need to know before you are given Ranexa and during treatment with Ranexa.
-
Keep this leaflet and the Patient Alert Card. You may need to read it again.
-
Always show the Patient Alert Card to any doctor involved in your treatment, including physicians
treating conditions other than angina pectoris.
-
Please make sure you have a list of all your other medicines with you at any visit to a health care
professional.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
1. What Ranexa is and what it is used for
2. Before you take Ranexa
3. How to take Ranexa
4. Possible side effects
5.
How to store Ranexa
6. Further information
1.
WHAT RANEXA IS AND WHAT IT IS USED FOR
Ranexa is a medicine used in combination with other medicines to treat angina pectoris, which is a
chest pain or discomfort that you feel anywhere along the upper part of your body between your neck
and upper abdomen, often brought on by exercise or too much activity.
2.
BEFORE YOU TAKE RANEXA
Do not take Ranexa
- if you are allergic (hypersensitive) to ranolazine or any of the other ingredients of Ranexa listed in
section 6 of this leaflet.
- if you have severe kidney problems.
- if you have moderate or severe liver problems.
- if you are using certain medicines to treat bacterial infections (clarithromycin, telithromycin),
fungal infections (itraconazole, ketoconazole, voriconazol, posaconazol), HIV infection (protease
inhibitors), depression (nefazodone) or heart rhythm disorders (e.g. quinidine, dofetilide, or
sotalol).
Take special care with Ranexa
Speak to your doctor before taking Ranexa:
- if you have mild or moderate kidney problems.
- if you have mild liver problems.
- if you have ever had an abnormal electrocardiogram (ECG).
- if you are elderly.
53
- if you have low weight (60 kg or less).
- if you have heart failure.
Your doctor may decide to give you a lower dose or take other precautions if any of these apply to
you.
Using other medicines
Do not use the following medicines if you take Ranexa:
- certain medicines to treat bacterial infections (clarithromycin, telithromycin), fungal infections
(itraconazole, ketoconazole, voriconazole, posaconazole), HIV infection (protease inhibitors),
depression (nefazodone), or heart rhythm disorders (e.g. quinidine, dofetilide, or sotalol).
Tell your doctor or pharmacist before you take Ranexa if you use:
- certain medicines to treat a bacterial infection (erythromycin), or a fungal infection (fluconazole),
a medicine used to prevent rejection of a transplanted organ (ciclosporin), or if you are taking
some heart tablets such as diltiazem or verapamil. These medicines may cause an increase in the
number of side effects, such as dizziness, nausea, or vomiting, which are possible side effects of
Ranexa (see section 4). Your doctor may decide to give you a lower dose.
- medicines to treat epilepsy or another neurologic disorder (e.g. phenytoin, carbamazepine, or
phenobarbital); are taking rifampicin for an infection (e.g. tuberculosis); or are taking the herbal
remedy St. John's Wort, as these medicines may cause Ranexa to be less effective.
- heart medicines containing digoxin or metoprolol, as your doctor may want to change the dose of
this medicine whilst you are taking Ranexa.
- certain medicines to treat allergies (e.g. terfenadine, astemizole, mizolastine), heart rhythm
disorders (e.g. disopyramide, procainamide), and depression (e.g. imipramine, doxepin,
amitriptyline), as these medicines may affect your ECG.
- certain medicines to treat depression (bupropion), psychosis, HIV infection (efavirenz), or cancer
(cyclophosphamide).
Please tell your doctor or pharmacist if you are using or have recently used any other medicines,
including medicines obtained without a prescription.
Taking Ranexa with food and drink
Ranexa can be taken with or without food. While being treated with Ranexa, you should not drink
grapefruit juice.
Pregnancy
You should not take Ranexa if you are pregnant unless your doctor has advised you to do so.
Breast-feeding
You should not take Ranexa if you are breast-feeding. Ask your doctor for advice if you are breast-
feeding.
Ask your doctor for advice before using any medicine.
Driving and using machines
No studies on the effects of Ranexa on the ability to drive and use machines have been performed. Ask
your doctor for advice about driving or using machines.
Ranexa may cause side effects such as dizziness (common) and blurred vision (uncommon) that may
affect your ability to drive or use machinery. If you experience these symptoms, do not drive or
operate machinery until they have resolved completely.
Important information about some of the ingredients of Ranexa
The 750 mg prolonged-release tablets contain the azo colouring agent E102. This colouring agent-
may cause allergic reactions.
54
The 750 mg prolonged-release tablets contain lactose monohydrate. If you have been told by your
doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal
product.
3.
HOW TO TAKE RANEXA
Always take Ranexa exactly as your doctor has told you to. You should check with your doctor or
pharmacist if you are not sure.
Always swallow the tablets whole with water. Do not crush, suck, or chew the tablets or break them in
half, as this might affect the way the medicine is released from the tablets into your body.
The starting dose for adults is one 375 mg tablet twice a day. After 2−4 weeks, your doctor may
increase the dose to get the right effect. The maximum dose of Ranexa is 750 mg twice a day.
It is important that you tell your doctor if you get side effects such as dizziness or feeling or being
sick. Your doctor may lower your dose or, if this is not sufficient, stop treatment with Ranexa.
Children and adolescents under 18 years old should not take Ranexa.
If you take more Ranexa than you should
If you accidentally take too many Ranexa tablets or take a higher dose than recommended by your
doctor, it is important that you tell your doctor at once. If you cannot contact your doctor, go to the
nearest accident and emergency department. Take along any tablets that are left, including the
container and the carton, so that the hospital staff can easily tell what you have taken.
If you forget to take Ranexa
If you forget to take a dose, take it as soon as you remember unless it is nearly time to take your next
dose. Do not take a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Ranexa can cause side effects, although not everybody gets them. These are
usually mild or moderate.
You should stop taking Ranexa and see your doctor immediately if you experience the following
symptoms of angioedema, which is a rare condition but can be severe:
·
swollen face, tongue, or throat
·
difficulty swallowing
·
hives or difficulty breathing
Tell your doctor if you experience common side effects such as dizziness or feeling sick or vomiting.
Your doctor may lower your dose or stop treatment with Ranexa.
Other side effects you may experience include the following:
Common side effects (occur in 1 to 10 users in 100) are:
Constipation
Dizziness
Headache
Feeling sick, vomiting
Feeling weak
55
Uncommon side effects (occur in 1 to 10 users in 1,000) are:
Anxiety, difficulty sleeping
Blurred vision, visual disturbance
Changes in sensation (touch or taste), tremor, feeling tired or sluggish, sleepiness or drowsiness,
faint or fainting, dizziness upon standing
Dark urine, blood in urine, difficulty urinating
Dehydration
Difficulty breathing, cough, nose bleed
Excessive sweating, itching
Feeling swollen or bloated
Hot flushes, low blood pressure
Increases in a substance called creatinine or increases in urea in your blood, increase in blood
platelets or white blood cells, changes in ECG heart tracing
Joint swelling, pain in extremity
Loss of appetite and/or weight loss
Muscle cramp
Ringing in the ears and/or feeling a spinning sensation
Stomach pain or discomfort, indigestion, dry mouth, or wind
Rare side effects (occur in 1 to 10 users in 10,000) are:
Abnormal laboratory values for liver
Change in sense of smell, numbness in mouth or lips, impaired hearing
Cold sweat, rash
Decrease in blood pressure upon standing
Decreased or loss of consciousness
Disorientation
Feeling of coldness in hands and legs
Hives, allergic skin reaction
Impotence
Inflammation of pancreas or intestine
Loss of memory
Throat tightness
In some isolated cases, acute kidney failure has been reported with the use of Ranexa.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE RANEXA
Keep out of the reach and sight of children.
Do not use Ranexa after the expiry date which is stated on each blister strip of tablets and on the
outside of the carton and bottle.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Ranexa contains
The active substance in Ranexa is ranolazine. Each tablet contains 375 mg, 500 mg, or 750 mg
ranolazine.
56
The other ingredients are: hypromellose, magnesium stearate, methacrylic acid-ethyl acrylate
copolymer, microcrystalline cellulose, sodium hydroxide, titanium dioxide and carnauba wax.
Depending on the tablet strength, the tablet coatings also contain:
375 mg tablet: macrogol, polysorbate 80, Blue #2/Indigo Carmine Aluminium Lake (E132)
500 mg tablet: macrogol, talc, polyvinyl alcohol-part hydrolyzed, iron oxide yellow (E172), iron
oxide red (E172)
750 mg tablet: glycerol triacetate, lactose monohydrate, Blue #1/Brilliant Blue FCF Aluminium Lake
(E133) and Yellow #5/Tartrazine Aluminium Lake (E102)
What Ranexa looks like and contents of the pack
Ranexa prolonged-release tablets are oval shaped tablets.
The 375 mg tablets are pale blue and are engraved with CVT375 on one side.
The 500 mg tablets are light orange and are engraved with CVT500 on one side.
The 750 mg tablets are pale green and are engraved with CVT750 on one side.
Ranexa is supplied in cartons containing 30, 60, or 100 tablets in blister strips or 60 tablets in plastic
bottles. Not all pack-sizes may be marketed.
Marketing Authorisation Holder
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg
Manufacturer
Brecon Pharmaceuticals Ltd
Pharos House, Wye Valley Business Park
Hay-on-Wye
Hereford HR3 5PG
United Kingdom
or
Fine Foods N.T.M. SpA
Via dell’Artigianato 8/10
24041 Brembate (BG)
Italy
or
Menarini - Von Heyden GmbH
Leipziger Straβe 7-13
01097 Dresden
Germany
or
Berlin-Chemie AG
Glienicker Weg 125
12489 Berlin
Germany
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
57
België/Belgique/Belgien
Menarini Benelux NV/SA
Tél/Tel: + 32 (0)2 721 4545
Luxembourg/Luxemburg
Menarini Benelux NV/SA
Tél/Tel: + 32 (0)2 721 4545
България
ТП “Берлин-Хеми АГ”
тел.: +359 2 96 00 860
Magyarország
Berlin-Chemie/A. Menarini Kft.
Tel.: +36 23501301
Česká republika
Berlin-Chemie/A.Menarini Ceska republika
s.r.o.
Tel: +420 272 937 381
Malta
Menarini International Operations
Luxembourg S.A.
Tel: +352 264976
Danmark
Berlin-Chemie/A.Menarini Danmark ApS
Tlf: +4548 217 110
Nederland
Menarini Benelux NV/SA
Tel: +32 (0)2 721 4545
Deutschland
Berlin-Chemie AG
Tel: +49 (0) 30 67070
Norge
Menarini International Operations
Luxembourg S.A.
Tlf: +352 264976
Eesti
OÜ Berlin-Chemie Menarini Eesti
Tel: +372 667 5001
Österreich
A. Menarini Pharma GmbH.
Tel: +43 1 879 95 85-0
Ελλάδα
MENARINI HELLAS AE
Τηλ: +30 210 8316111-13
Polska
Berlin-Chemie/Menarini Polska Sp. z o.o.
Tel.: +48 22 566 21 00
España
Laboratorios Menarini S.A.
Tel: +34-93 462 88 00
Portugal
A. Menarini Portugal – Farmacêutica, S.A.
Tel: +351 210 935 500
France
MENARINI France
Tél: +33 (0)1 45 60 77 20
România
Berlin-Chemie Menarini Group
Tel: +40 211 232 34 32
Ireland
A. Menarini Pharmaceuticals Ltd
Tel: +353 1 284 6744
Slovenija
Berlin-Chemie AG, Podružnica Ljubljana
Tel: +386 01 300 2160
Ísland
Menarini International Operations
Luxembourg S.A.
Sími: +352 264976
Slovenská republika
Berlin-Chemie AG - obchodné zastúpenie v
SR
Tel: +421 2 544 30 730
58
Italia
A. Menarini Industrie Farmaceutiche
Riunite s.r.l.
Tel: +39-055 56801
Suomi/Finland
Berlin-Chemie/A.Menarini Suomi OY
Puh/Tel: +358 403 000 760
Κύπρος
MENARINI HELLAS AE
Τηλ: +30 210 8316111-13
Sverige
Menarini International Operations
Luxembourg S.A.
Tel: +352 264976
Latvija
SIA Berlin-Chemie/Menarini Baltic
Tel: +371 67103210
United Kingdom
A. Menarini Pharma U.K. S.R.L.
Tel: +44 (0)1628 856400
Lietuva
UAB “BERLIN-CHEMIE MENARINI
BALTIC”
Tel: +370 52 691 947
This leaflet was last approved in (MM/YYYY)
.
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/.
59
Source: European Medicines Agency
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