Ranexa (previously Latixa) · 4.3 Contraindications · 1

HOS-094798 · has-adverse-reaction-information · PDF-Seite 6

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 (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Metabolism and nutrition disorders Uncommon: anorexia, decreased appetite, dehydration. Rare: hyponatremia Psychiatric disorders Uncommon: anxiety, insomnia, confusional state, hallucination. Rare: disorientation. Nervous system disorders Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia. Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia. Not known: myoclonus. Eye disorders Uncommon: blurred vision, visual disturbance, diplopia. 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. 6 Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash. Musculoskeletal and connective tissue disorders Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness. Renal and urinary disorders Uncommon: dysuria, haematuria, chromaturia. Rare: acute renal failure, urinary retention. 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

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HOS-094810 · has-adverse-reaction-information · PDF-Seite 30

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 (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Metabolism and nutrition disorders Uncommon: anorexia, decreased appetite, dehydration. Rare: hyponatremia Psychiatric disorders Uncommon: anxiety, insomnia, confusional state, hallucination. Rare: disorientation. Nervous system disorders Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia. Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia. Not known: myoclonus. Eye disorders Uncommon: blurred vision, visual disturbance, diplopia. Ear and labyrinth disorders Uncommon: vertigo, tinnitus. Rare: impaired hearing. Vascular disorders Uncommon: hot flush, hypotension. Rare: peripheral coldness, orthostatic hypotension. 30 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: angioedema, allergic dermatitis, urticaria, cold sweat, rash. Musculoskeletal and connective tissue disorders Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness. Renal and urinary disorders Uncommon: dysuria, haematuria, chromaturia. Rare: acute renal failure, urinary retention. 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

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094804 · has-adverse-reaction-information · PDF-Seite 18

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 (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Metabolism and nutrition disorders Uncommon: anorexia, decreased appetite, dehydration. Rare: hyponatremia Psychiatric disorders Uncommon: anxiety, insomnia, confusional state, hallucination. Rare: disorientation. Nervous system disorders Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia. Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia. Not known: myoclonus. Eye disorders Uncommon: blurred vision, visual disturbance, diplpopia. 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. 18 Skin and subcutaneous tissue disorders Uncommon: pruritus, hyperhydrosis. Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash. Musculoskeletal and connective tissue disorders Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness. Renal and urinary disorders Uncommon: dysuria, haematuria, chromaturia. Rare: acute renal failure, urinary retention. 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

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HOS-094794 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in 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, voriconazole, posaconazole, 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.

HOS-094806 · has-contraindication-information · PDF-Seite 27

Hypersensitivity to the active substance or to any of the excipients listed in 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, voriconazole, posaconazole, 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.

HOS-094800 · has-contraindication-information · PDF-Seite 15

Hypersensitivity to the active substance or to any of the excipients listed in 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, voriconazole, posaconazole, 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.

HOS-094805 · has-indication-information · PDF-Seite 26

Ranexa is indicated in adults 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).

HOS-094799 · has-indication-information · PDF-Seite 14

Ranexa is indicated in adults 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).

HOS-094793 · has-indication-information · PDF-Seite 2

Ranexa is indicated in adults 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).

HOS-094796 · has-interaction-information · PDF-Seite 4

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

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HOS-094808 · has-interaction-information · PDF-Seite 28

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%. 28 Effects of ranolazine on other medicinal products Ranolazine is a moderate to potent inhibitor o

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HOS-094802 · has-interaction-information · PDF-Seite 16

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

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HOS-094809 · has-pregnancy-information · PDF-Seite 30

Pregnancy: There are limited amount of data from the use of ranolazine in pregnant women. Studies in animals showed embryo toxicity (see Section 5.3). The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary. Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. Available pharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk (for details see Section 5.3). A risk to the suckling child cannot be excluded. Ranexa should not be used during breast-feeding. Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is unknown.

HOS-094803 · has-pregnancy-information · PDF-Seite 17

Pregnancy: There are limited amount of data from the use of ranolazine in pregnant women Studies in animals showed embryo toxicity (see Section 5.3). The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary. Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. Available pharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk (for details 17 see Section 5.3). A risk to the suckling child cannot be excluded. Ranexa should not be used during breast-feeding. Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is unknown.

HOS-094797 · has-pregnancy-information · PDF-Seite 5

Pregnancy: There are limited amount of data from the use of ranolazine in pregnant women. Studies in animals showed embryo toxicity (see Section 5.3). The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary. Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. Available pharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk (for details see Section 5.3). A risk to the suckling child cannot be excluded. Ranexa should not be used during breast-feeding. 5 Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is unknown.

HOS-094795 · has-warning-information · PDF-Seite 3

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: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. 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 when treating patients with a history of congenital or a family history of long QT syndrome, in patients with known acquired 3 QT interval prolongation, and in patients treated with drugs affecting the QTc interval (see section 4.5 also). Drug-drug interactions: Co-administration with CYP3

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HOS-094807 · has-warning-information · PDF-Seite 27

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: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. 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, 27 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 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 CYP3

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HOS-094801 · has-warning-information · PDF-Seite 15

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: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. 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 15 ranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed 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 CYP3

Auszug; vollständigen Abschnitt im Original lesen.