Active ingredients: Ranolazine
Ranexa 375 mg prolonged-release tablets
Ranexa 500 mg prolonged-release tablets
Ranexa 750 mg prolonged-release tablets
Why is Ranexa used? What is it for?
Ranexa is a medicine used in combination with other medicines for the treatment of angina pectoris, a disorder that occurs with pain or discomfort in the chest located anywhere in the upper part of the trunk between the neck and the upper abdomen, often triggered by exercise. physical or excessive "activity.
Talk to your doctor if you don't feel better or if you feel worse.
Contraindications When Ranexa should not be used
Do not take Ranexa
- if you are allergic to ranolazine or any of the other ingredients of this medicine
- 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, voriconazole, posaconazole), HIV infection (protease inhibitors), depression (nefazodone) or disorders heart rhythm (e.g. quinidine, dofetilide or sotalol).
Precautions for use What you need to know before taking Ranexa
Talk 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.
- if you weigh little (60 kg or less).
- if you have heart failure. In these cases, your doctor may decide to give you a lower dose or to take other precautions.
Interactions Which drugs or foods may change the effect of Ranexa
Do not use the following medicines if you are taking Ranexa:
- certain medicines to treat bacterial infections (clarithromycin, telithromycin), fungal infections (itraconazole, ketoconazole, voriconazole, posaconazole), HIV infection (protease inhibitors), depression (nefazodone) or rhythm disturbances cardiac (e.g. quinidine, dofetilide or sotalol).
Tell your doctor or pharmacist before taking 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 (cyclosporine), or if you are taking heart tablets such as diltiazem or verapamil . These medicines may increase the number of side effects, such as dizziness, nausea or vomiting, which are possible side effects of Ranexa. Your doctor may decide to prescribe a reduced dose.
- medicines to treat epilepsy or another neurological disorder (eg phenytoin, carbamazepine or phenobarbital); if you are taking rifampicin for an "infection (eg tuberculosis) or the herbal product" St. John's wort ", as these medicines may reduce the effectiveness of Ranexa.
- heart medicines containing digoxin or metoprolol, as your doctor may decide to change the dose of these medicines while you are taking Ranexa.
- certain medicines for the treatment of allergies (eg terfenadine, astemizole, mizolastine), heart rhythm disorders (eg disopyramide, procainamide) and depression (eg "imipramine, doxepin or" amitriptyline), as these medicines may alter the ECG.
- certain medicines to treat depression (bupropion), psychosis, HIV infection (efavirenz) or cancer (cyclophosphamide).
- certain medicines to treat high blood cholesterol levels (e.g. simvastatin, lovastatin, atorvastatin). These medicines can cause pain and muscle damage. Your doctor may decide to change the dose of these medicines while you are taking Ranexa.
- certain medicines used to prevent organ transplant rejection (e.g. tacrolimus, cyclosporine, sirolimus, everolimus), as your doctor may decide to change the dose of these medicines while you are taking Ranexa.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Ranexa with food and drink
Ranexa can be taken with or without food. You should not drink grapefruit juice while being treated with Ranexa.
Warnings It is important to know that:
Pregnancy
Do not take Ranexa if you are pregnant unless advised to by your doctor.
Feeding time
Do not take Ranexa if you are breastfeeding. Ask your doctor for advice if you are breastfeeding. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this 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 on driving and using machines.
Ranexa may cause side effects such as dizziness (common), blurred vision (uncommon), confusion (uncommon), hallucinations (uncommon), double vision (uncommon), abnormal coordination (rare), which could affect your ability to drive or operate machinery. If you get these symptoms, do not drive or use machines until they have completely resolved.
Ranexa 750 mg prolonged-release tablets contain the azo coloring substance E102. This coloring substance could induce allergic reactions.
Ranexa 750 mg prolonged-release tablets contain lactose monohydrate. If you have been told by your doctor that you have an "intolerance to some type of sugar, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Ranexa: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The tablets should always be swallowed whole with water. You should not crush, suck or chew the tablets or break them in half, as this may affect the way the medicine is released from the tablet into your body.
The starting dosage in adults is one 375 mg tablet twice a day. After 2-4 weeks the doctor may increase the dosage to achieve the desired effect. The maximum dosage of Ranexa is 750 mg twice a day.
It is important that you tell your doctor if you experience side effects such as dizziness, nausea or vomiting. Your doctor may reduce your dose or, if this is not enough, stop your Ranexa treatment.
Use in children and adolescents
Children and adolescents under 18 years of age should not take Ranexa.
Overdose What to do if you have taken too much 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 them straight away. If you cannot contact your doctor, go to the nearest emergency room. Take any remaining tablets with you, including the container and box so that hospital staff can easily understand what you are taking.
If you forget to take Ranexa
If you forget to take a dose, take it as soon as you remember unless it is almost time for your next dose (if there is less than 6 hours to go). Do not take a double dose to make up for a forgotten dose.
Side Effects What are the side effects of Ranexa
Like all medicines, this medicine can cause side effects, although not everybody gets them.
You should stop taking Ranexa and see your doctor immediately if you experience the following symptoms of angioneurotic edema, which is a rare but sometimes serious condition:
- swelling of the face, tongue or throat
- difficulty swallowing
- hives or difficulty in breathing.
Tell your doctor if you experience common side effects such as dizziness, nausea or vomiting. Your doctor may reduce your dose or stop treatment with Ranexa.
Other side effects you may experience include:
Common side effects (affects 1 to 10 users in 100):
constipation
dizziness
headache
nausea,
He retched
feeling of weakness.
Uncommon side effects (affects 1 to 10 users in 1000):
impaired sensitivity
anxiety, difficulty sleeping, confusion, hallucinations
blurred vision, visual disturbances, changes in the senses (of touch or taste), tremor, feeling tired or sluggish, numbness or sleepiness, feeling faint or faint, dizziness when standing up
dark urine, blood in the urine, difficulty urinating
dehydration
difficulty in breathing, cough, nosebleed
double vision
excessive sweating, itching
feeling of swelling or fullness
hot flashes, low blood pressure
increases in a substance called creatinine or increases in blood urea, increases in the number of platelets or white blood cells, changes in the cardiac ECG trace
joint swelling, pain in extremities
loss of appetite and / or weight loss
muscle cramps
sensation of ringing in the ears and / or dizziness
stomach pain or discomfort, indigestion, dry mouth or intestinal air.
Rare side effects (affects 1 to 10 users in 10,000):
difficulty urinating normally
altered laboratory values for the liver
acute renal failure
altered sense of smell, numbness of the mouth or lips, impaired hearing
cold sweats, rash
problems in coordination
drop in blood pressure when standing up, decrease or loss of consciousness
disorientation
feeling of cold in the hands and legs, hives, allergic skin reaction
impotence
difficulty walking due to lack of balance
inflammation of the pancreas or intestines
memory loss
tightness in the throat.
The following side effect has also been reported: Muscle weakness
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on each blister of tablets and on the outside of the carton and bottle after "EXP".
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Ranexa contains
The active ingredient in Ranexa is ranolazine. Each tablet contains 375 mg, 500 mg or 750 mg of ranolazine.
The other ingredients are: hypromellose, magnesium stearate, copolymer of ethyl acrylate and methacrylic acid, microcrystalline cellulose, sodium hydroxide, titanium dioxide and carnauba wax.
Depending on the strength of the tablet, the coating also contains:
375 mg tablet: macrogol, polysorbate 80, blue No. 2 / E132 indigo carmine aluminum lake
500 mg tablet: macrogol, talc, partially hydrolyzed polyvinyl alcohol, yellow iron oxide (E172), red iron oxide (E172)
750 mg tablet: glycerol triacetate, lactose monohydrate, blue No. 1 / E133 bright blue FCF aluminum lacquer and yellow no. 5 / E102 tartrazine aluminum lake
What Ranexa looks like and contents of the pack
Ranexa extended-release tablets are oval tablets.
The 375 mg tablets are light blue with 375 engraved on one side.
The 500 mg tablets are light orange and debossed with 500 on one side.
The 750 mg tablets are light green and debossed with 750 on one side.
Ranexa is supplied in boxes of 30, 60, or 100 tablets contained in blisters or 60 tablets in a bottle. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
RANEXA 375 MG EXTENDED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 375 mg of ranolazine.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablet
Light blue oval tablet debossed with CVT375 or 375 on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Ranexa is indicated in adults as adjunctive therapy in the symptomatic treatment of patients with stable angina pectoris who are not adequately controlled with, or do not tolerate, first-line antianginal therapies, such as beta-blockers and / or calcium channel blockers.
04.2 Posology and method of administration
Patients should be given the Ranexa package leaflet and the Patient Safety Card, with the warning to present the latter to the healthcare professional along with the list of medicines at each visit.
Dosage
Ranexa is available in 375 mg, 500 mg and 750 mg prolonged-release tablets.
Adults
The recommended starting dose of Ranexa is 375 mg twice a day. After 2-4 weeks the dose should be increased to 500 mg twice daily and, based on patient response, further increased to the maximum recommended dose of 750 mg twice daily (see section 5.1).
If the patient experiences treatment-related adverse events, such as dizziness, nausea or vomiting, the dose of Ranexa may need to be reduced to 500 mg or 375 mg twice daily. If symptoms do not resolve after reducing the dosage, treatment should be discontinued.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors
Careful dose adjustment is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or with P-gp inhibitors (e.g. verapamil, cyclosporine) (see sections 4.4 and 4.5).
Co-administration of strong CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).
Kidney failure
Careful dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance of 30-80 ml / min) (see sections 4.4, 4.8 and 5.2). Ranexa is contraindicated in patients with severe renal insufficiency (creatinine clearance
Hepatic insufficiency
Careful dose adjustment 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).
Senior citizens
Caution should be exercised in dose adjustment in elderly patients (see section 4.4). Exposure to ranolazine may increase in the elderly 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).
Underweight patients
The incidence of adverse events was higher in underweight patients (≤ 60 kg). Caution should be exercised in dose adjustment in underweight patients (see sections 4.4, 4.8 and 5.2).
Congestive Heart Failure (SCC)
Caution should be exercised in dose adjustment in patients with moderate or severe SCC (NYHA class III-IV) (see sections 4.4 and 5.2).
Pediatric population
The safety and efficacy of Ranexa in children below 18 years of age have not been established.
No data are available.
Method of administration
Ranexa tablets should be swallowed whole, without crushing, breaking or chewing them. They can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe renal insufficiency (creatinine clearance
Moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Concomitant administration of strong CYP3A4 inhibitors (eg itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see sections 4.2 and 4.5).
Concomitant administration of class Ia (eg quinidine) or class III antiarrhythmics (eg dofetilide, sotalol) other than amiodarone.
04.4 Special warnings and appropriate precautions for use
Caution should be exercised when prescribing or increasing the dosage of ranolazine in patients in whom "higher exposure is anticipated:"
• 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 insufficiency (see sections 4.2 and 5.2)
• mild or moderate renal insufficiency (creatinine clearance of 30-80 ml / min) (see sections 4.2, 4.8 and 5.2).
• elderly patients (see sections 4.2, 4.8 and 5.2)
• underweight patients (≤ 60 kg) (see sections 4.2, 4.8 and 5.2).
• patients with moderate or severe SCC (NYHA class III-IV) (see sections 4.2 and 5.2).
Further increases in exposure are expected in patients with more than one of the above factors. Dose dependent side effects are likely to occur. Frequent event monitoring is required if Ranexa is used in patients who have a combination of several of the above factors. adverse effects, reduce the dosage and, if necessary, discontinue treatment.
The risk of increased exposure leading to adverse events in these various subgroups is higher in patients with poor CYP2D6 activity (poor metabolisers, ML) than in subjects with good CYP2D6 metabolisers (extensive metabolisers, MR). (See section 5.2). The above precautions are based on the risk reported to a CYP2D6 ML patient, and are required when CYP2D6 status is unknown. In patients with CYP2D6 MR conditions these precautions are less necessary. CYP2D6 patient has been determined, for example by genotyping, or is already known as MR, Ranexa can be used with caution in patients with a combination of several of the above risk factors.
QT prolongation
A "population analysis of pooled data from patients and healthy volunteers showed that the curve estimate of the ratio of plasma concentration to QTc was 2.4 msec per 1000 ng / mL, roughly equal to an increase of 2. -7 msec for the plasma concentration range corresponding to 500-1000 mg ranolazine twice daily. Therefore, caution should be exercised in treating patients with a personal or family history of congenital long QT syndrome, patients with acquired QT interval prolongation and patients treated with drugs that affect the QTc interval (see also section 4.5).
Drug interactions
Poor efficacy is expected when co-administered with CYP3A4 inducers. 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).
Kidney failure
Renal function declines with age and it is therefore important to monitor renal function at regular intervals during treatment with ranolazine (see sections 4.2, 4.3, 4.8 and 5.2).
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other medicinal products on ranolazine
CYP3A4 or P-gp inhibitors
Ranolazine is a substrate of cytochrome CYP3A4. CYP3A4 inhibitors increase the plasma concentrations of ranolazine. As plasma concentrations increase, the risk of dose-related adverse events (eg nausea, dizziness) may also increase. Concomitant treatment with ketoconazole 200 mg twice daily increased ranolazine AUC by 3.0- 3.9 times during treatment. The combination of ranolazine with strong CYP3A4 inhibitors (eg itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a strong inhibitor of CYP3A4.
Diltiazem, a medium potency CYP3A4 inhibitor, at doses ranging from 180 to 360 mg once daily causes dose-dependent increases in mean steady-state ranolazine concentrations of 1.5 to 2.4 times. In patients treated with diltiazem and other medium potency CYP3A4 inhibitors, such as erythromycin or fluconazole, careful adjustment of Ranexa dosage is recommended. The dose of Ranexa may need to be reduced (see sections 4.2 and 4.4).
Ranolazine is a substrate for P-gp. P-gp inhibitors such as cyclosporine or verapamil increase the plasma levels of ranolazine. Verapamil, at a dose of 120 mg three times daily, increases steady-state ranolazine concentrations by 2.2-fold. Careful dose adjustment of Ranexa is recommended in patients treated with P-gp inhibitors. The dose of Ranexa may need to be reduced (see sections 4.2 and 4.4).
CYP3A4 inducers
Rifampicin at a dose of 600 mg once daily reduces steady-state ranolazine concentrations by approximately 95%. Treatment with Ranexa should be avoided during administration of CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) (see section 4.4).
CYP2D6 inhibitors
Ranolazine is partially metabolised by CYP2D6 so inhibitors of this enzyme may increase the plasma concentrations of the drug. Paroxetine, a strong inhibitor of CYP2D6, at a dose of 20 mg once daily increased the steady-state plasma concentrations of ranolazine at a dose of 1000 mg twice daily on average 1.2-fold. No dosage adjustments are necessary. At the 500 mg twice daily dose level, concomitant administration of a strong CYP2D6 inhibitor could result in an increase in ranolazine AUC of approximately 62%.
Effects of ranolazine on other medicinal products
Ranolazine is a moderate / strong inhibitor of P-gp and a mild inhibitor of CYP3A4 and may increase plasma concentrations of P-gp or CYP3A4 substrates. The tissue distribution of drugs carried by P-gp could be increased.
Dose adjustment of CYP3A4 sensitive substrates (e.g. simvasastatin, lovastatin) and CYP3A4 sensitive substrates with a narrow therapeutic index (e.g. cyclosporine, tacrolimus, sirolimus, everolimus) may be required as RANEXA may increase the plasma concentration of these drugs.
Based on the available data, ranolazine appears to be a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily increases plasma concentrations of metoprolol by 1.8-fold. Therefore, exposure to metoprolol or other CYP2D6 substrates (eg propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during concomitant administration with Ranexa and lower doses of these medicinal products may be required.
The inhibitory capacity of CYP2B6 has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin
An average 1.5-fold increase in plasma digoxin concentrations has been reported following concomitant administration of Ranexa and digoxin. Consequently, monitoring of digoxin levels is required after initiation and termination of Ranexa therapy.
Simvastatin
The metabolism and clearance of simvastatin are highly dependent on CYP3A4. Ranexa 1000 mg twice daily increased the plasma concentrations of simvastatin as lactone and as acid by approximately 2-fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa and simvastatin in post-marketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking Ranexa at any dose.
Atorvastatin
Ranexa 1000 mg twice daily increased the Cmax and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3-fold, respectively, and changed the Cmax and AUC of the atorvastatin metabolites by less than 35%. In case of concomitant administration of Ranexa it is recommended to limit the dose of atorvastatin and to perform appropriate clinical monitoring.
In case of concomitant administration of Ranexa it is recommended to limit the dose of other statins metabolised by CYP3A4 (e.g. lovastatin).
Tacrolimus, cyclosporine, sirolimus, everolimus
Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients following administration of ranolazine. It is recommended that blood levels of tacrolimus are monitored during co-administration of Ranexa and tacrolimus and that the tacrolimus dose is adjusted accordingly. This is also recommended in the case of other CYP3A4 substrates with a narrow therapeutic index (e.g. cyclosporine, sirolimus, everolimus).
Drugs transported by OCT2 (organic cation transporter-2): Plasma exposure of metformin (1000 mg twice daily) increased 1.4-fold and 1.8-fold in subjects with type 2 diabetes mellitus in the case of concomitant administration of RANEXA 500 mg and 1000 mg twice daily, respectively. Exposure of other OCT2 substrates - eg pindolol and varenicline - can be affected to a similar extent.
There is a theoretical risk that concomitant treatment with ranolazine and other drugs that prolong the QTc interval will induce a pharmacodynamic interaction, increasing the risk of possible ventricular arrhythmias. These drugs include some antihistamines, such as terfenadine, astemizole or mizolastine, some antiarrhythmics, such as quinidine, disopyramide or procainamide, erythromycin and tricyclic antidepressants, such as imipramine, doxepin or amitriptyline.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data from the use of ranolazine in pregnant women. Animal studies are insufficient to show effects on pregnancy and embryonal / fetal development (see section 5.3). The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary.
Feeding time
It is not known whether ranolazine is excreted in human milk. The excretion of ranolazine in milk has not been studied in animals. Ranexa should not be used during lactation.
Fertility
In animals, reproduction studies did not indicate any adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is not known.
04.7 Effects on ability to drive and use machines
No studies on the effects of Ranexa on the ability to drive and use machines have been performed. Ranexa may cause dizziness, blurred vision, diplopia, confusional state, abnormal coordination and hallucinations (see section 4.8) which may affect the ability to driving vehicles and using machines.
04.8 Undesirable effects
Side effects in patients taking Ranexa are usually mild or moderate and often develop within the first two weeks of treatment. They were reported in the Phase III clinical development program, involving a total of 1030 patients with chronic angina treated with Ranexa.
Below is a list of adverse events considered at least possibly related to treatment, classified by system, organ and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100,
Metabolism and nutrition disorders
Uncommon: anorexia, decreased appetite, dehydration.
Psychiatric disorders
Uncommon: anxiety, insomnia, confusion, hallucinations.
Rare: disorientation.
Nervous system disorders
Common: dizziness, headache.
Uncommon: lethargy, syncope, hypoesthesia, somnolence, tremor, postural dizziness, paraesthesia.
Rare: amnesia, lowered level of consciousness, loss of consciousness, abnormal coordination, abnormal gait, parosmia.
Eye disorders
Uncommon: blurred vision, visual disturbance, diplopia.
Ear and labyrinth disorders
Uncommon: vertigo, tinnitus.
Rare: hearing impairment.
Vascular pathologies
Uncommon: hot flush, hypotension.
Rare: cold in the extremities, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea, cough, epistaxis.
Rare: tightness in the throat.
Gastrointestinal disorders
Common: constipation, vomiting, nausea.
Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
Rare: pancreatitis, erosive duodenitis, oral hypoesthesia.
Skin and subcutaneous tissue disorders
Uncommon: itching, hyperhidrosis.
Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders
Uncommon: pain in extremities, muscle cramp, joint swelling.
Renal and urinary disorders
Uncommon: dysuria, hematuria, chromaturia.
Rare: acute renal failure, urinary retention.
Diseases of the reproductive system and breast
Rare: erectile dysfunction.
General disorders and administration site conditions
Common: asthenia.
Uncommon: fatigue, peripheral edema.
Diagnostic tests
Uncommon: increased blood creatinine, increased blood urea, prolonged corrected QT interval, increased platelet or white blood cell count, weight loss.
Rare: elevation of liver enzymes.
The adverse event profile was generally similar in the MERLIN-TIMI 36 study. Acute renal failure was also reported in this long-term study, with an incidence of less than 1% in both ranolazine and patients treated with placebo. Evaluations of patients who might be considered most at risk of adverse events during treatment with other antianginal medicinal products, such as diabetic patients, those with class I and II heart failure, or with obstructive airway disease confirmed that these conditions are not associated with clinically significant increases in the incidence of adverse events.
Elderly patients, with renal insufficiency or underweight
In general, adverse events occurred more frequently among elderly patients and among patients with renal insufficiency; however, the type of events in these subgroups was similar to that observed in the general population. Among the most commonly reported events, the following occurred with Ranexa (corrected frequencies versus placebo), more often in elderly patients (≥ 75 years) than in younger patients (
In patients with mild or moderate renal impairment (creatinine clearance ≥ 30-80 mL / min) compared to patients with normal renal function (creatinine clearance> 80 mL / min), the most commonly reported events, frequencies corrected compared to placebo , include: constipation (8% vs 4%), dizziness (7% vs 5%) and nausea (4% vs 2%).
In general, the type and frequency of adverse events reported by patients with low body weight (≤ 60 kg) were similar to those of patients with higher body weight (> 60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low-weight patients than in heavier-weight patients: nausea (14% vs 2%), vomiting (6% vs 1%), and hypotension (4% vs 2%).
Laboratory results
Small reversible elevations in serum creatinine levels of no clinical relevance have been observed in healthy subjects and in patients treated with Ranexa, with no associated renal toxicity. A study on renal function in healthy volunteers demonstrated a reduction in creatinine clearance without altering the glomerular filtration rate, compatible with the inhibition of creatinine secretion in the renal tubules.
04.9 Overdose
In a high dose oral tolerability study in patients with angina, the incidence of dizziness, nausea and vomiting increased in a dose-dependent manner. In addition to these adverse events, in a study with intravenous overdose in healthy volunteers. diplopia, lethargy and syncope were observed.In the event of an overdose, the patient should be closely monitored and given symptomatic and supportive treatment.
Approximately 62% of ranolazine is bound to plasma proteins and therefore complete clearance by hemodialysis is unlikely.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other cardiac preparations, ATC code: C01EB18
Mechanism of action
The mechanism of action of ranolazine is largely unknown. Some of the antianginal effects of ranolazine may result from inhibition of late sodium current in heart cells, which would reduce intracellular sodium accumulation and consequently decrease intracellular overload of Calcium By reducing the late sodium current, ranolazine is thought to reduce these intracellular ionic imbalances during ischemia. It is presumed that this reduction in intracellular calcium overload improves myocardial relaxation and therefore leads to less stiffness of the left ventricle in diastole. Clinical evidence of late sodium current inhibition by ranolazine is provided by an open-label study in 5 patients with long QT syndrome (LQT3 with SCN5A δKPQ gene mutation) showing a significant shortening of the QTc interval and a improvement of diastolic relaxation.
These effects are not related to changes in heart rate or blood pressure, or vasodilation.
Pharmacodynamic effects
Hemodynamic effects
Minimal reductions in mean heart rate (beats per minute) and mean systolic blood pressure (
Electrocardiographic effects
Dose and plasma concentration related QTc interval prolongations (approximately 6 msec with 1000 mg twice daily), reductions in T wave amplitude and in some cases notched T waves have been observed in patients treated with Ranexa. believes that these effects of ranolazine on the surface electrocardiogram are consequent to the inhibition of the rapid potassium rectification current, which prolongs the ventricular action potential, and to the inhibition of the late sodium current, which shortens the action potential ventricular. A "population analysis of pooled data from 1308 patients and healthy volunteers showed a mean QTc increase from baseline of 2.4 msec for a plasma ranolazine concentration of 1000 ng / mL. This value is consistent with data from pivotal clinical trials in which mean changes from baseline in QTcF (Fridericia's correction) after doses ranging from 500 to 750 mg twice daily were 1.9 and 4.9 msec respectively.The gradient is more elevated in patients with clinically significant hepatic insufficiency.
In a large outcome study (MERLIN-TIMI 36) of 6,560 patients with ACS UA / NSTEMI, there was no difference between Ranexa and placebo in the risk of all-cause mortality (relative risk ranolazine: placebo 0.99), cardiac death sudden (relative risk ranolazine: placebo 0.87) or in the frequency of documented symptomatic arrhythmias (3.0% vs 3.1%).
In the MERLIN-TIMI 36 study, no proarrhythmic effects were observed in 3162 patients treated with Ranexa based on 7-day Holter monitoring. The incidence of arrhythmias was significantly lower in patients treated with Ranexa (80%) than in those treated with placebo (87%), including ventricular tachycardia ≥ 8 beats (5% vs 8%).
Clinical efficacy and safety
Clinical studies have demonstrated the efficacy and safety of Ranexa in the treatment of patients with chronic angina, either alone or when the benefit obtained with other antianginal medicines was not optimal.
In the pivotal CARISA study, Ranexa was added to treatment with atenolol 50 mg per day, amlodipine 5 mg per day or diltiazem 180 mg per day. Eight hundred and twenty-three patients (23% women) were randomized to either 750 mg twice daily or 1000 mg twice daily Ranexa or placebo for 12 weeks. At both dosages, Ranexa, used as add-on therapy, was more effective than placebo in prolonging the duration of exercise at the trough point to 12 weeks, but there were no differences in exercise duration between the two dosages. (24 seconds versus placebo; p ≤ 0.03).
Ranexa resulted in significant reductions in the number of angina attacks per week and consumption of fast-acting nitroglycerin compared to placebo. No tolerance to ranolazine developed during treatment and no rebound increase in angina attacks was observed following abrupt discontinuation. At the dose level of 1000 mg twice daily the improvement in exercise duration in women was approximately 33% of the improvement in men. However, men and women experienced similar reductions in the frequency of angina attacks and nitroglycerin consumption. Taking into account dose-dependent side effects and similar efficacy with 750 and 1000 mg twice daily, a maximum dose of 750 mg twice daily is recommended.
In a second study, called ERICA, Ranexa was added to treatment with 10 mg per day of amlodipine (the maximum indicated dose). Five hundred and sixty-five patients were randomized to initial treatment with Ranexa at a dose of 500 mg twice daily or with placebo for 1 week, followed by 6 weeks of treatment with Ranexa at a dose of 1000 mg twice daily or with placebo, in addition to to concomitant treatment with 10 mg per day of amlodipine. In addition, 45% of the study population also took long-acting nitrates. Ranexa resulted in significant reductions in the number of angina attacks per week (p = 0.028) and in consumption of fast-acting nitroglycerin (p = 0.014) compared to placebo. The average number of angina attacks and that of nitroglycerin tablets consumed both fell to about one per week.
In the main dose-finding study, called MARISA, ranolazine was used alone. One hundred ninety-one patients were randomized to treatment with Ranexa at a dose of 500 mg twice daily, 1000 mg twice daily, 1500 mg twice daily and the corresponding placebo, for 1 week each, in crossover. Ranexa was significantly superior to placebo in prolonging exercise duration, time to angina, and time to 1 mm ST segment depression at all doses studied; a correlation between dose and response was observed. The improvement in exercise duration was statistically significant compared to placebo for all three dosages of ranolazine, from 24 seconds with 500 mg twice daily to 46 seconds with 1500 mg twice daily, showing a response related to dose. In this study the maximum duration of exercise was reached in the 1500 mg group; however, this led to an excessive increase in undesirable effects, so the dosage of 1500 mg was not examined further.
In a large outcome study (MERLIN-TIMI 36), in 6,560 patients with ACS UA / NSTEMI there was no difference in the risk of all-cause mortality (relative risk ranolazine: placebo 0.99), sudden cardiac death (risk relative ranolazine: placebo 0.87) or in the frequency of documented symptomatic arrhythmias (3.0% vs 3.1%) between Ranexa and placebo, when added to standard medical therapy (beta-blockers, calcium channel blockers, nitrates, antiplatelet agents, lipid-lowering agents and ACE inhibitors). In the MERLIN-TIMI 36 study, approximately half of the patients had a history of angina. Results showed that exercise duration was 31 seconds longer in patients taking ranolazine than in patients taking placebo (p = 0.002). The Seattle Angina Questionnaire demonstrated significant effects on several aspects, including the frequency of angina (p
In controlled clinical trials, non-Caucasians were represented in a limited proportion, so no conclusions can be drawn regarding efficacy and safety in this category of patients.
05.2 Pharmacokinetic properties
After oral administration, peak concentrations of Ranexa (Cmax) are usually observed 2-6 hours apart. Steady state is usually achieved within 3 days with twice daily administration.
Absorption
After oral administration of immediate-release ranolazine tablets the mean absolute bioavailability was between 35 and 50%, with "wide interindividual variability." Ranexa exposure increases more than dose proportionally. By increasing the dose from 500 mg to 1000 mg twice daily, steady-state AUC increased 2.5-3 fold. In a pharmacokinetic study in healthy volunteers, following administration of 500 mg twice daily the Steady-state Cmax averaged 1770 (SD 1040) ng / mL and steady-state AUC0-12 averaged 13,700 (SD 8290) ng xh / mL. Food does not affect the rate and extent of ranolazine absorption.
Distribution
Approximately 62% of ranolazine is bound to plasma proteins, predominantly to alpha-1 acid glycoprotein, and weakly to albumin. The mean steady-state volume of distribution (Vss) is approximately 180 liters.
Elimination
Ranolazine is eliminated predominantly by metabolism. Less than 5% of the dose is excreted unchanged in the urine and faeces. After oral administration of a single 500 mg [14C] -ranolazine dose to healthy volunteers, 73% of the radioactivity was recovered in the urine and 25% in the faeces.
The clearance of ranolazine is dose-dependent and decreases as it "increases". The elimination half-life after intravenous administration is approximately 2-3 hours. The terminal half-life at steady state after oral administration of ranolazine is approximately 7 hours, since elimination is limited by the rate of absorption.
Biotransformation
Ranolazine is rapidly and extensively metabolised. In healthy young adults, ranolazine accounts for approximately 13% of the radioactivity in plasma after a single oral administration of 500 mg [14C] -ranolazine. In humans, several metabolites have been identified in plasma, urine (more than 100) and faeces. 14 main pathways have been identified, of which the most important are O-demethylation and N-dealkylation. In vitro Studies in human liver microsomes indicate that ranolazine is metabolised primarily by CYP3A4, but also by CYP2D6. At a dose of 500 mg twice daily, subjects with poor CYP2D6 activity (poor metabolisers, ML) reported a 62% higher AUC than subjects with good CYP2D6 metabolisers (extensive metabolisers, MR). corresponding difference at the 1000 mg twice daily dose was 25%.
Particular patient populations
The influence of several factors on ranolazine pharmacokinetics was investigated in a population pharmacokinetic evaluation in 928 patients with angina and healthy subjects.
Type: gender showed no clinically relevant effects on pharmacokinetic parameters.
Elderly patients: Age per se did not show clinically relevant effects on pharmacokinetic parameters. However, ranolazine exposure may increase in the elderly due to age-related reduction in renal function.
Body weight: Compared to subjects with a body weight of 70 kg, exposure was estimated to be approximately 1.4 times higher in subjects with a body weight of 40 kg.
SCC: in NYHA class III and IV SCC, plasma concentrations were estimated to be approximately 1.3 times higher.
Kidney failure: In a study evaluating the influence of renal function on ranolazine pharmacokinetics, the AUC of ranolazine was on average 1.7-2 times higher in subjects with mild, moderate and severe renal impairment than in subjects with normal kidney function. A "large interindividual variability" in AUC was observed in subjects with renal insufficiency. The AUC of metabolites increased as renal function decreased. The AUC of a pharmacologically active metabolite of ranolazine was increased 5-fold 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 of 40 ml / min). In subjects with severe renal insufficiency (creatinine clearance of 10-30 ml / min) a 1.3 to 1.8-fold increase in ranolazine exposure has been estimated.
The influence of dialysis on ranolazine pharmacokinetics has not been evaluated.
Hepatic insufficiency: The pharmacokinetics of ranolazine were evaluated in patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment. The AUC of ranolazine was unchanged in patients with mild hepatic impairment but increased 1.8-fold in patients with moderate impairment. QT prolongation was more pronounced in these patients.
Pediatric population: The pharmacokinetic parameters of ranolazine have not been studied in the pediatric population (
05.3 Preclinical safety data
Adverse reactions not observed in clinical studies but found in animals at levels similar to those of clinical exposure are as follows: in rats and dogs, ranolazine was associated with convulsions and increased mortality at approximately 3-fold plasma concentrations. higher than the maximum proposed clinical dose.
Chronic toxicity studies in rats indicated that the treatment is associated with adrenal changes, for exposures slightly higher than those observed in patients. This effect is associated with an increase in plasma cholesterol concentrations. In man no similar alterations or effects on the adrenocortical axis have been identified.
In long-term carcinogenicity studies with ranolazine doses up to 50 mg / kg / day (150 mg / m2 / day) in mice and up to 150 mg / kg / day (900 mg / m2 / day) in rats are not Significant increases in the incidence of cancers of any type have been observed. In terms of mg / m2 these doses are respectively 0.1 and 0.8 times the maximum recommended human dose of 2 grams and represent the maximum tolerated doses in humans. these species.
Signs of embryonic and maternal toxicity, but not of teratogenicity, were observed with ranolazine doses up to 400 mg / kg / day (2400 mg / m2 / day) in rats and up to 150 mg / kg / day (1800 mg / day). m2 / day) in the rabbit. These doses correspond to 2.7 and 2 times the maximum recommended human dose, respectively.
Animal studies do not indicate direct or indirect harmful effects of ranolazine on male or female fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Excipients for all prolonged-release ranolazine tablets:
carnauba wax
hypromellose
magnesium stearate
copolymer of ethyl acrylate and methacrylic acid (1: 1)
microcrystalline cellulose
sodium hydroxide
titanium dioxide
Additional excipients for the 375 mg tablet:
macrogol
polysorbate 80
blue n. 2 / E132 indigo carmine aluminum lake
06.2 Incompatibility
Not relevant.
06.3 Period of validity
Blister packaging: 5 years.
Bottle: 4 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC / PVDC / aluminum blister of 10 tablets per blister. Each carton contains 3, 6, or 10 blisters (30, 60, or 100 tablets) or an HDPE bottle with 60 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg
Luxembourg
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/462/001 60 tablets in blister pack - AIC: 038917011
EU / 1/08/462/002 60 tablets in bottle - AIC: 038917023
EU / 1/08/462/007 30 tablets in blister pack - AIC: 038917074
EU / 1/08/462/008 100 tablets in blister pack - AIC: 038917086
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 09 July 2008
Date of last renewal: 06 March 2013
10.0 DATE OF REVISION OF THE TEXT
April 2013
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