ANNEX I
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL
PRODUCT, ROUTE OF ADMINISTRATION, APPLICANTS / MARKETING AUTHORISATION
HOLDERS IN THE MEMBER STATES
1
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Lisonorm and associated names, INN-lisinopril + amlodipine, Exams of Marketing
Lisonorm is a new fixed-dose combination containing 10mg lisinopril (an ACE inhibitor) and 5mg amlodipine (a calcium antagonist), indicated for patients ...
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2021/2022
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ANNEX I
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL
PRODUCT, ROUTE OF ADMINISTRATION, APPLICANTS / MARKETING AUTHORISATION
HOLDERS IN THE MEMBER STATES
Member State
Marketing Authorisation Holder
Applicant
(Invented) Name
Strength
Pharmaceutical Form
Route of administration
Bulgaria
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary
Dironorm
10 mg/5 mg
tablets
oral use
Czech Republic
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary
Lisonorm*
1
10 mg/5 mg
tablets
oral use
Estonia
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary.
Dironorm
10 mg/5 mg
tablets
oral use
Hungary
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary.
Lisonorm
10 mg/5 mg
tablets
oral use
Latvia
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary.
Dironorm
10 mg/5 mg
tablets
oral use
Lithuania
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary.
Dironorm
10 mg/5 mg
tablets
oral use
Poland
Gedeon Richter Plc. 1103 Budapest, Gyömr
ői út 19-21.
Hungary.
Dironorm
10 mg/5 mg
tablets
oral use
1 Name approval pending
2
ANNEX II
SCIENTIFIC CONCLUSIONS AND GROUNDS PRESENTED BY THE EMEA
SCIENTIFIC CONCLUSIONS
OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF LISONORM AND
ASSOCIATED NAMES (SEE ANNEX I)
Lisonorm is a new fixed-dose combination containing 10mg lisinopril (an ACE inhibitor) and 5mg amlodipine (a calcium antagonist), indicated for patients with blood pressure adequately controlled with lisinopril and amlodipine given concurrently at the same dose level. The applicant, Gideon Richter, sought a Marketing Authorisation in several member states (CZ, EE, LT, LV, PL, RO, and SK,) through the Mutual Recognition Procedure with Hungary acting as the reference member state. An Article 29 referral procedure was initiated due to concerns raised by the CZ and LV on the potential serious risk to public health regarding insufficient proof of bioequivalence since the Applicant did not use the originator´s products (Aulin Gel) as reference treatments but used monocomponent-containing generics in the originally submitted bioequivalence study.
In line with the regulatory requirements (CHMP/EWP/191583/2005), a formal proof of bioequivalence, evidence of a wide therapeutic experience, and an adequately established benefit/risk ratio should be demonstrated for new fixed dose combination products claiming substitution indication. For Lisonorm (new lisinopril 10mg/ amlodipine 5mg combination), a positive benefit/risk ratio had not been established given that the initial bioequivalence study submitted was not conducted with the appropriate control, and that preliminary results of a new bioequivalence study (No.67289) did not allow a full assessment of the benefit risk ratio.
Therefore, the Applicant acknowledged the limitations arising from the product selection in the initial pivotal BE study and performed a study (Protocol No 67289) to investigate bioequivalence of LISONORM FORTE (fixed-combination of amlodipine 10 mg and lisinopril 20 mg), co-administration of NORVASC 10 mg (containing amlodipine 10 mg) and PRINIVIL 20 mg (containing lisinopril 20 mg), and LISONORM (fixed-combination of amlodipine 5 mg and lisinopril 10 mg) under fasting conditions.
Pharmacokinetic parameters were calculated for amlodipine and lisinopril by the means of Bioequiv 3. software using a model independent approach. The Applicant provided these pharmacokinetic results for amlodipine and lisinopril along with semi-logarithmic mean plasma concentration-time curves. The geometric mean ratios, 90% confidence intervals and corresponding intra-individual CVs for Cmax , AUC0-t and AUC0-∞ for amlodipine and lisinopril were also presented.
Overall, the CHMP considered that the applicant had responded adequately by providing the results of an additional study, BES No.67289, and had demonstrated formal proof of bioequivalence. The overall design of the study was adequately pre-specified in the protocol and was considered acceptable. Subjects were selected by appropriate inclusion criteria and the regimen was standardized, excluding factors influencing pharmacokinetic interactions. The sampling interval and wash-out period were considered long enough and the statistical evaluation was also appropriate. LC-MS/MS methods were validated for analysis of both compounds, and the stability of the samples was documented over the period of sample storage.
Based on the data provided, bioequivalence for both amlodipine 10 mg and lisinopril 20 mg after administration of single oral doses of LISONORM FORTE, co-administration of NORVASC 10 mg and PRINIVIL 20 mg, or administration of LISONORM (fixed-combination of amlodipine 5 mg and lisinopril 10 mg) could be concluded. The 90% confidence intervals calculated for AUC(0-t), AUC(0-inf) and Cmax were within the range of 0.8-1.25 for both components (lisinopril and amlodipine).
With regards to safety, there were 3 drop-out subjects. A total of 96 post-dose adverse events were reported by 35 of the 48 subjects who received at least one dose of the study medication. As expected in this type of
ANNEX III
SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
ANNEX III
SUMMARY OF PRODUCT CHARACTERISTICS,
LABELLING AND PACKAGE LEAFLET
1. NAME OF THE MEDICINAL PRODUCT
Lisonorm and associated names (see Annex I) 10/5 mg tablets [See Annex I - To be completed nationally]
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10 mg lisinopril (as dihydrate) and 5 mg amlodipine (as besilate).
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet.
White or off-white, round, flat, bevel-edged tablet with a score line on one side and with an engraving „A+L” on the reverse side. Diameter: about 8 mm. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of essential hypertension.
Lisonorm is indicated as substitution therapy of patients with blood pressure adequately controlled with lisinopril and amlodipine given concurrently at the same dose level.
4.2 Posology and method of administration
The recommended dose is one tablet daily. The maximum daily dose is one tablet. Since food does not affect absorption, Lisonorm may be taken irrespective of meals.
Patients with renal impairment To find the optimal starting dose and maintenance dose of patients with renal impairment, the patients should be individually titrated using the individual components of lisinopril and amlodipine. Lisonorm is indicated only for patients in whom the optimal maintenance dose of lisinopril and amlodipine has been titrated to 10 mg and 5 mg, respectively. Renal function, serum potassium and sodium levels should be monitored during therapy with Lisonorm. In the case of renal function deterioration, the use of Lisonorm should be discontinued and replaced by the individual components adequately adjusted.
Patients with hepatic impairment The elimination of amlodipine may be prolonged in patients with impaired liver function. No precise dosage recommendations have been established for such cases and, therefore, this medicinal product should be administered with caution to patients with hepatic impairment.
Children and adolescents Lisonorm is not recommended for use in children below age 18 due to a lack of data on safety and efficacy.
Elderly (> 65 years)
In clinical studies, there was no age-related change in the efficacy or safety profile of amlodipine or lisinopril. To find the optimal maintenance dose for elderly patients they should be individually titrated using the free combination of lisinopril and amlodipine. Lisonorm is indicated only for patients in whom the optimal maintenance dose of lisinopril and amlodipine has been titrated to 10 mg and 5 mg, respectively (see section 4.4).
4.3 Contraindications
- Hypersensitivity to lisinopril or to any other angiotensin converting enzyme (ACE) inhibitor.
- Hypersensitivity to amlodipine or to any other dihydropyridine derivatives.
- Hypersensitivity to any of the excipients.
- Severe hypotension.
- A history of angioedema relating to previous ACE inhibitor therapy.
- Hereditary or idiopathic angioedema (see section 4.4).
- Haemodynamically significant obstruction in the outflow tract of the left ventricle (aortic stenosis, hypertrophic cardiomyopathy), mitral stenosis or cardiogenic shock.
- Heart failure after acute myocardial infarction (during the first 28 days).
- Unstable angina pectoris (excluding Prinzmetal’s angina).
- Pregnancy and lactation (see section 4.6).
4.4 Special warnings and precautions for use
Symptomatic hypotension Substantial decrease in blood pressure and hence symptomatic hypotension can occur in patients with volume and/or sodium depletion resulting from diuretic therapy, fluid loss of other origin such as excessive diaphoresis, prolonged vomiting and/or diarrhoea (see section 4.2). If hypotension occurs, the patient should be placed in a supine position and intravenous fluid replacement (intravenous infusion of physiologic saline) should be administered if necessary. Preferably, sodium and/or volume depletion should be corrected before treatment with Lisonorm is started. The magnitude of antihypertensive effect should be closely monitored after administering the initial dose.
Aortic and mitral stenosis, obstructive hypertrophic cardiomyopathy As with all vasodilators, Lisonorm should be administered with caution to patients with obstruction in the outflow tract of the left ventricle and with stenosis of mitral valve.
Renal function impairment Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when angiotensin converting enzyme inhibitors has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. In some patients with bilateral renal artery stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. To find the optimal maintenance dose of patients with renal impairment, the patients should individually be titrated using the individual components of lisinopril and amlodipine, with close monitoring of renal function. Lisonorm is indicated only for patients with titrated optimal maintenance dose of lisinopril and amlodipine of 10 mg and 5 mg, respectively.
In the case of renal function deterioration, Lisonorm should be withdrawn and replaced by the therapy with individual components adequately adjusted. Dose reduction and/or discontinuation of the diuretic may also be required.
Angioedema
factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisonorm should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Lisonorm is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
Cough Commonly, cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non- productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/general anaesthesia In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs, probably as a consequence of this mechanism, it can be corrected by volume expansion
Elderly When advanced age is associated with decrease in renal function Lisonorm dose adjustments for patients with renal impairment apply (see section 4.2).
Hyperkalaemia Elevations in potassium serum levels have been observed in some patients treated with ACE inhibitors. Patients at risk for the development of hyperkalaemia include those with renal impairment, diabetes mellitus, acute cardiac decompensation, dehydration, metabolic acidosis, or concomitant use of potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or any medicinal products associated with increases in potassium serum levels (e.g. heparin). If concomitant use of the abovementioned substances is needed, regular monitoring of potassium serum levels is recommended (see section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Interactions related to lisinopril Substances affecting potassium levels: Potassium-sparing diuretics (e.g. spironolactone, amiloride, and triamterene), potassium supplements, or potassium-containing salt substitutes and other substances that may increase potassium levels (e.g. heparin) can lead to hyperkalaemia in combination with ACE inhibitors, particularly in patients with renal impairment and other pre-existing conditions (see section 4.4). If a medicinal product that affects potassium levels is to be prescribed in combination with lisinopril, monitoring of potassium serum levels is advised. Therefore, concomitant administration should be carefully considered and only undertaken with increased caution and regular monitoring of both serum potassium levels and renal function.
Diuretics: When a diuretic is added to the therapy of a patient receiving Lisonorm the antihypertensive effect is usually additive (see section 4.4). Lisinopril mitigates the kaliuretic effect of diuretics.
Other antihypertensives: Concomitant use of these agents may increase the hypotensive effects of Lisonorm. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.
Tricyclic antidepressants/antipsychotics/anaesthetics/narcotics: Concomitant use with ACE inhibitors may result in further reduction of blood pressure (see section 4.4).
Alcohol enhances the hypotensive effect.
Allopurinol , procainamide, cytostatics or immunosuppressive agents (systemic corticosteroids) may lead to an increased risk of leukopenia when administered concomitantly with ACE inhibitors.
Antacids decrease the bioavailability of the concomitant use of ACE inhibitors.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Non-steroidal anti-inflammatory drugs (NSAIDs): Chronic administration of NSAIDs, including high-dosed acetylsalicylic acid ≥ 3 g/day, may reduce the antihypertensive effect of an ACE inhibitor.
NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.
Lithium: Lithium elimination may be reduced during concomitant use of ACE inhibitor and therefore, serum lithium levels should be monitored.
Interactions related to amlodipine CYP3A4 inhibitors : A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded. Caution is required with concomitant use.
CYP3A4 inducers: Co-administration with anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, herbal preparations containing St. John’s wort/ Hypericum perforatum ) may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal. Caution is required with concomitant use.
Others: In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, anti- acid medicines (aluminium hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-steroidal anti- inflammatory medicines, antibiotics and oral hypoglycaemic medicines.
4.6 Pregnancy and lactation
Pregnancy The use of ACE inhibitors is not recommended during the first trimester of pregnancy and they are contra- indicated in the second and third trimester.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. ACE inhibitors therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
System Organ Class Frequency ADRs with lisinopril ADRs with amlodipine
Blood and lymphatic system disorders
Very rare Bone marrow depression, Agranulocytosis, Leucopenia, Neutropenia, Thrombocytopenia, Haemolytic anaemia Anaemia, Lymphadenopathies
Thrombocytopenia
Immune system disorders Very rare Autoimmune disorders Hypersensitivity
Metabolism and nutrition disorders
Very rare Hypoglycaemia Hyperglycaemia
Psychiatric disorders Uncommon Mood altered, Sleep disturbances
Insomnia, Mood altered
Rare Mental disorders
Nervous system disorders Common Dizziness, Headache Somnolence, Dizziness, Headache
Uncommon Vertigo, Paraesthesia, Taste disturbance
Syncope, Tremor, Taste perversion, Hypoaesthesia, Paraesthesia
Very rare Peripheral neuropathy
Eye disorders Uncommon Visual disturbances
Ear and labyrinth disorders Uncommon Tinnitus
Cardiac disorders Common Palpitations
Uncommon Myocardial infarction (see section 4.4), Tachycardia, Palpitations, Very rare Myocardial infarction, Ventricular tachycardia, Atrial fibrillation, Arrhythmia Vascular disorders Common Orthostatic hypotension Flushing
Uncommon Cerebrovascular accident (see section 4.4), Raynaud’s phenomenon
Hypotension
Very rare Vasculitis
Respiratory, thoracic and mediastinal disorders
Common Cough
Uncommon Rhinitis Dyspnoea, Rhinitis
System Organ Class Frequency ADRs with lisinopril ADRs with amlodipine Very rare Bronchospasm, Allergic alveolitis/Eosinophilic pneumonia, Sinusitis
Cough
Gastrointestinal disorders Common Diarrhoea, Vomiting Abdominal pain, Nausea
Uncommon Abdominal pain, Nausea, Indigestion
Vomiting, Dyspepsia, Altered bowel habits, Dry mouth Rare Dry mouth
Very rare Pancreatitis, Intestinal angioedema
Pancreatitis, Gastritis, Gingival hyperplasia
Hepatobiliary disorders Very rare Hepatic failure, Hepatitis, Cholestatic jaundice, (see section 4.4)
Hepatitis, Jaundice, Cholestasis
Skin and subcutaneous tissue disorders
Uncommon Hypersensitivity/angioedem a of the face, extremities, lips, tongue, glottis and/or larynx (see section 4.4), Rash, Pruritus
Alopecia, Rash, Purpura, Skin discolouration, Diaphoresis, Pruritus
Rare Psoriasis, Urticaria, Alopecia
Very rare Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Erythema multiforme. Pemphigus, Diaphoresis. A syndrome has been reported that may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive ANA, elevated ESR value, eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations.
Erythema multiforme, Angioedema, Urticaria
Musculoskeletal and connective tissue disorders
Uncommon Arthralgia, Myalgia, Muscle cramps, Back pain
Renal and urinary disorders Common Renal dysfunction
Uncommon Micturition disorder, Nocturia, Increased urinary frequency Rare Acute renal failure, Uraemia
Lisinopril
Lisinopril is an angiotensin converting enzyme (ACE) inhibitor, which results in reduction of plasma angiotensin II and consequently aldosterone levels and elevates those of vasodilatory bradykinin. It reduces peripheral vascular resistance and systemic blood pressure. These changes may be accompanied by an increase in cardiac output at unchanged heart frequency, as well as an increase in renal blood flow. In hyperglycaemic patients, lisinopril contributes to the restoration of impaired endothelial function.
The antihypertensive effect of lisinopril usually ensues 1 hour after administration and peaks after 6 hours. Its duration of action is 24 hours – also depending on dose. The antihypertensive efficacy of lisinopril is also maintained on the long term. Abrupt discontinuation of lisinopril treatment is not associated with any substantial rebound effect (blood pressure elevation).
Although its primary effect is mediated by the renin-angiotensin-aldosterone system, lisinopril is also effective in hypertensive patients with low plasma renin activity. In addition to its direct blood pressure lowering effect, lisinopril mitigates albuminuria by modifying the haemodynamic conditions and tissue structure in the renal glomeruli. In controlled clinical trials conducted in diabetic patients, no changes of blood glucose level and no increase in the incidence of hypoglycaemia were ascertained.
Amlodipine Amlodipine is a dihydropyridine-type calcium channel blocker. It inhibits the influx of calcium into myocardial and vascular smooth muscle cells through the inhibition of slow calcium ion channels of the cell membranes. Amlodipine reduces the tone of smooth muscle in arterioles and hence the peripheral vascular resistance which lowers systemic blood pressure. Amlodipine exerts antianginal effect through the dilation of peripheral arterioles as well as through reduction of cardiac afterload, without resulting in reflex tachycardia, and accordingly, energy consumption and oxygen demand of cardiac muscle decrease. Amlodipine may dilate coronary vessels (arteries and arterioles); it improves oxygen supply to the myocardium both in intact and in ischaemic regions.
Once daily dosing of amlodipine reduces the blood pressure of hypertensive patients both in the supine and standing position throughout the 24-hour interval. Due to the slow onset of action, acute hypotension does not occur.
Calcium channel blocking activity, for example elicits direct arterial dilation accompanied by sodium and water retention. Compensatory activation of the renin-angiotensin-aldosterone system (RAAS) should be expected and therefore, counter-regulatory mechanisms activated by ACE inhibitors may contribute to the restoration of physiological responses to increased salt intake.
5.2 Pharmacokinetic properties
Lisinopril Following oral administration, peak plasma concentrations occur after approximately 6 hours; its bioavailability is 29 %. Lisinopril does not bind to plasma proteins other than ACE; it is not metabolized in the organism and is excreted unchanged in the urine. The effective half-life of lisinopril is 12.6 hours. The major elimination of non protein-bound fraction is accompanied by that of ACE-bound lisinopril at a slower rate, and this can result in prolonged antihypertensive action.
The elimination of lisinopril is prolonged in renal impairment and therefore, dose reduction may be necessary (see section 4.2).
Lisinopril can be removed from the plasma by dialysis.
Amlodipine
Amlodipine is slowly and almost completely absorbed from the gastrointestinal tract following oral administration. Its absorption is unaffected by the consumption of food. Peak plasma concentration (Cmax ) occurs 6 to 10 hours after dosing. The bioavailability of amlodipine is 64 to 80 %; its volume of distribution is approximately 20 l/kg. In the systemic circulation 95 to 98 % of amlodipine is bound to plasma protein. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10 % of the unchanged parent compound and 60 % of metabolites are excreted in the urine. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels are reached after 7 to 8 days of consecutive daily dosing. Amlodipine is transformed into inactive metabolites in the liver primarily, with 10 % of the unchanged parent compound excreted in the urine. Amlodipine cannot be removed from the plasma by dialysis.
The time to reach peak plasma concentrations (t (^) max ) of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be lower with resulting increase in AUC and elimination half-life in the elderly. Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated and therefore, normal dose is recommended for older people.
The half-life of amlodipine is prolonged in patients with hepatic impairment.
In patients with renal impairment, changes in amlodipine plasma concentrations are not correlated with degree of renal impairment.
Fixed dose combination No pharmacokinetic interactions have been described between the active substances of Lisonorm. Pharmacokinetic parameters (AUC, Cmax , t (^) max , half-life) were not different from those observed after administration of the individual components separately.
The gastrointestinal absorption of Lisonorm is not influenced by food.
5.3 Preclinical safety data
Lisinopril Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Fertility was not affected in female and male rats in doses up to 300 mg/kg (33 times the maximum recommended human daily dose when compared on a body surface area). No teratogenic effects of lisinopril were seen in mice, rats and rabbits given doses that were 55 times, 33 times and 0.15 times, respectively, the maximum recommended human daily dose.
Amlodipine Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Teratogenic or other embrio/fetotoxic effects were not found in rats and rabbits given up to 10 mg/kg amlodipine (8 times and 23 times, respectively, the maximum recommended human daily dose of 10 mg on a mg/m^2 basis) during gestation. Amlodipine at this dose level prolonged both the gestation and labour duration.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cellulose, microcrystalline Sodium starch glycolate (Type A) Magnesium stearate