INTRODUCTION:
Epidemiological studies have shown that elevated heart rate represents a risk factor for cardiovascular morbidity both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental data suggest that sustained elevations of heart rate may play a role in the pathogenesis of coronary atherosclerosis.3 Chronic stable angina pectoris (CSAP) usually occurs in patients with coronary artery disease (CAD) that affects one or more large epicardial arteries. Stable angina pectoris is common and disabling, affecting 30 000 to 40 000 per 1 million people in Europe and the United States.
Angina results from an imbalance between myocardial perfusion and myocardial metabolic demands. Elevated heart rate (HR) is an important factor in the development of myocardial ischemia and angina pectoris. Heart rate reduction can alter both elements of this imbalance beneficially. 1, 4
Ideally, pharmacological interventions aimed at reducing heart rate selectively should be free of consequences on other cardiovascular parameters; unfortunately, however, conventional drug therapies based on β-blockers and Ca2+ antagonists are often associated with mild to severe decreases in ventricular contractility and modification of vascular tone. However, the use of β-blockers is limited by poor compliance related to contraindications and comorbidities, especially in elderly patients. This explains why the search for specific heart rate-reducing agents has long been, and still is, a major goal of cardiac pharmacologists.2,4
Cardiac pacemaker rate is controlled by the duration of the diastolic depolarization, and the main source of depolarizing current responsible for this phase is the so-called pacemaker or ‘funny’ (If) current. In the past several years, various f-channel inhibitors such as alinidine (ST567), falipamil (AQ-A39), ZD7288 and zatebradine (UL-FS 49) have been developed and shown to reduce heart rate but, because of lack of selectivity and/or presence of undesired side effects, further development aimed at their clinical use has not been pursued. More recently, Ivabradine (Servier), a new molecule selected for higher f-channel selectivity and reduced side effects, has been developed and is now being marketed for pharmacological treatment of chronic stable angina. Ivabradine is a new selective HR-lowering agent that selectively inhibits the pacemaker current If in the sinus atrial node.2
The If current inhibitor Ivabradine was approved for the treatment of CSAP by the European Medicines Agency (EMEA) in 2005.5 In several randomized controlled trials, Ivabradine 5-10 mg twice daily has demonstrated equivalent anti-ischemic and Antianginal activity to β-blockers and CCBs, with a good safety and tolerability profile. 2, 4
The direct electrophysiological consequence of this inhibition is a reduction in the slope of the diastolic depolarisation curve and a decrease in heart rate. Pharmacological inhibition of the If current with Ivabradine has been shown to preserve coronary vasodilatation upon exercise, i.e. myocardial perfusion, with no negative inotropic effects and maintenance of cardiac contractility. Ivabradine protects the myocardium during ischaemia, improves left ventricular function in congestive heart failure, and reduces remodelling subsequent to myocardial infarction. Pure heart rate reduction by specific and selective If inhibition decreases oxygen demand, improves myocardial energetics and improves perfusion of the ischaemic myocardium.6
Clinical Pharmacokinetics of Ivabradine
Under physiological conditions, Ivabradine is rapidly released from tablets and is highly water-soluble (>10 mg/ml). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of Ivabradine has been identified as the main active metabolite in humans.
Absorption and bioavailability
Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hour, and increased plasma exposure by 20 to 30 %. The intake of the tablet during meals is recommended in order to decrease intra-individual variability in exposure.
Distribution
Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-state is close to 100 l in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%). The average plasma concentration is 10 ng/ml (CV=38%) at steady-state.
Biotransformation
Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Inversely, potent inhibitors and inducers may substantially affect Ivabradine plasma concentrations
Elimination
Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about 70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an oral dose is excreted unchanged in urine.
Dosage and Route of Administration
The usual recommended starting dose of Ivabradine is 5 mg twice daily. After three to four weeks of treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response.
Dosage Regimen and Treatment Periods
For the different doses film-coated tablets containing 5 mg and 7.5 mg Ivabradine are available.The usual recommended starting dose of Ivabradine is 5 mg twice daily. After three to four weeks of treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response. If, during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward including the possible dose of 2.5 mg twice daily (one half 5 mg tablet twice daily). Treatment must be discontinued if heart rate below 50 bpm or symptoms of bradycardia persists. Tablets must be taken orally twice daily, i.e. once in the morning and once in the evening during meals.
Indications and Uses
Symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm, who have a contra-indication or intolerance for beta-blockers.7
Study Rationale
The Macleods Pharmaceuticals Ltd. has developed generic alternative to the reference-listed brand of Ivabradine tablets therefore, its bioequivalence to the reference brand must be evaluated. The single dose of test product Ivabradine 7.5mg Tablets (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Macleods Pharmaceuticals Ltd., India was compared with Procoralanâ (Ivabradine) tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Les Laboratories Servier, France in healthy, adult, human subjects under fasting condition.
Justification of Choice of Reference Product
Procoralanâ 7.5 mg tablet is qualified as acceptable reference product.
MATERIALS AND METHODS:
Study Design
An open label, balanced, analyst blind, randomized, two-treatment, two-period, two sequence, single dose, crossover bioequivalence study on 12 + 2 (standby) healthy, adult, human subjects under fasting condition.
Objectives
i) Pharmacokinetic: To evaluate the comparative Bioavalibility of single dose of Ivabradine tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Macleods Pharmaceuticals Ltd. comparing with Procoralanâ (Ivabradine) tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Les Laboratories Servier, France in healthy, adult, human subjects under fasting condition.
ii) Safety: To monitor the safety and tolerability of a single dose of Ivabradine tablet 7.5 mg when administered in healthy adult, human subjects.
Investigational products
Test Formulation (T): Ivabradine tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg), Manufactured by Macleods Pharmaceuticals Ltd., India. Dose-7.5mg (1 tablet), Mode of administration: Administered orally with 240 ml of drinking water.
Reference Formulation (R): Procoralanâ (Ivabradine) tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg), Manufactured by: Les Laboratories Servier, France. Dose-7.5mg (1 tablet), Mode of administration: Administered orally with 240 ml of drinking water.
Number of Subjects (planned and analysed)
A total of 12 + 2 (stand by) subjects were planned and enrolled. Of these 13 subjects completed the study. Subject number 10 was withdrawn due to positive urine drugs of abuse results. The data of first 12 completing subjects with balanced sequence were taken for pharmacokinetic and statistical evaluations
Diagnosis and main criteria for inclusion
Healthy human subjects within the age range of 18 to 45 years with body-mass index (BMI) of ³ 18.70kg/m2 and £ 25.30 kg/m2 having absence of significant disease or clinically significant laboratory values or laboratory evaluation, medical history or physical examination during the screening and complying with inclusion and exclusion criteria were included.
Criteria for Evaluation
Efficacy: The 90 % confidence interval for Cmax, AUC0-t, AUC0-¥ of Ivabradine will form the basis for concluding the equivalence of Ivabradine in product R and T. If the confidence intervals are entirely included in the range of 80 – 125 % for AUC0-t, AUC0-¥, Cmax, log-transformed then the treatments will be claimed to be bioequivalent.
Safety: To monitor the safety and tolerability of single dose of Ivabradine tablet7.5 mg when administered in healthy adult, human subjects.
Statistical methods: The log-transformed pharmacokinetic parameters (Cmax, AUC0-t and AUC0-¥.) are analysed using an ANOVA model. Calculated 90% confidence interval for the ratio of both the products averages (geometric means) of Cmax, AUC0-t and AUC0-¥. Ratios of mean AUC0-t to mean AUC0-¥ for test and reference are expressed in percentage and power test is performed using SAS® version 9.1.3.
Ethical Conduct of the Study
Independent Ethics Committee
This protocol and corresponding informed consent form (ICF) (containing information about the study to be given to the subjects) to be used to obtain written informed consent of study subjects were reviewed by the IEC and subjects were not be enrolled into the study until the IEC approved the protocol and the ICF.
This study was conducted in accordance with the principles of the Declaration of Helsinki, ‘ICH GCP’, National Regulations (ICMR Guidelines), ‘Indian GCP’, and “Schedule Y” of Indian Drugs and Cosmetics Act.
Written Informed Consent
The Principal Investigator or designated study personnel informed the subjects (in English and/or Marathi language understandable by the subject) before initiation of the study through an oral presentation regarding the purpose, procedures to be carried out, investigational products, potential hazards and rights of the study subjects. The subjects were required to understand and sign the ICF prior to check-in for the study in the first period and the signed ICF was filed in the respective study file.
Overall Study Design and Plan – Description
This was an open label, balanced, analyst blind, randomized, two-treatment, two-period, two sequence, single dose, crossover bioequivalence study on 12 + 2 (standby) healthy, adult, human subjects under fasting condition.
Selection of Study Population
The general screening was carried out after obtaining the written consent on IEC approved ‘Informed Consent for Screening’ from the volunteers. The screening procedure included Demographic data including sex, completed age, height and weight, Body Mass Index (BMI), diet, history of tobacco use, intake of abusive/recreational drugs, alcohol intake, history of blood donation and history of participation in a drug research study. Medical history, including relevant past medical / surgical history, family history, history of allergies (food / drug / any other), past medication history in the last 90 days. Medical examination including recording of vital signs (Blood Pressure (BP), Pulse, Temperature and Respiration), general examination, physical and systemic examination. 12-lead ECG for heart rate, rhythm and specific finding (if any). Chest X-ray (PA view); Laboratory parameter investigation including Complete blood count – erythrocyte count, platelet count, haemoglobin, Hematocrit, leucocyte count, ESR and differential leucocyte count (DLC); Blood grouping (if previously not performed by Bioequivalence department of Macleods Pharmaceuticals Ltd.), Biochemistry – blood sugar (fasting), triglycerides and cholesterol, Hepatic profile – SGOT, SGPT, GGT, Alk. Phosphatase and Bilirubin (Total, Direct, Indirect), Renal profile –creatinine, BUN, calcium, electrolytes (sodium, potassium, chlorides) and Infectious diseases – HIV, HbsAg and HCV and routine urine examination.
No clinically significant abnormalities in ECGs, chest X-ray (PA view) were reported in subjects who were included in the study. Additionally, serological tests (HIV, Hepatitis B and C, HCV) were negative. The volunteers with laboratory values within normal limits or with clinically non- significant values were called one day prior to the study for study informed consent form presentation.
Only those volunteers who signed the study informed consent form were checked in for the study on the day of check-in (one day prior to dosing).
All the volunteers were found negative for breath alcohol test and urine test for drugs of abuse test [Cocaine (COC), Amphetamines (AMP), Marijuana (TMC), Morphine (MOP), Barbiturates (BAR), Benzodiazepine (BZO)]. Hence all 14 fit and consenting volunteers fulfilling inclusion/exclusion criteria were enrolled in the study.
Volunteers were given the rank orders based on their reporting time to the facility on pre-study day. Based on their rank orders and depending on the compliance to the requirements of the protocol, subject numbers were allotted serially.
Inclusion Criteria
Subjects had to fulfill all of the following criteria to be considered for inclusion into this study:
1. Healthy volunteers within the age range of 18 to 45 years.
2. Presently non-tobacco users.
3. Willingness to provide written informed consent to participate in the study.
4. Body mass index of ³ 18.70kg/m2 and £ 25.30 kg/m2, with body weight not less than 50 kg (for males).
5. Absence of significant disease or clinically significant laboratory values or laboratory evaluation, medical history or physical examination during the screening.
6. Have a normal 12-lead ECG or one with abnormality considered to be clinically insignificant.
7. Have a normal chest X-ray PA view.
8. Comprehension of the nature and purpose of the study and compliance with the requirement of the distributed ICF.
9. Body mass index of ³ 17.70 kg/m2 and £ 23.92 kg/m2, with body weight not less than 45 kg (for females).
10. Volunteer is regularly menstruating / Volunteer is in postmenopausal phase for at least 1 year / is surgically sterile (for females).
11. Volunteer of child bearing potential practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s) such as condoms, foams, jellies, diaphragm, and intrauterine device (IUD) or abstinence etc. except hormonal contraceptives (for females).
Exclusion Criteria
The subjects were excluded based on the following criteria:
1. Personal history of allergy or hypersensitivity to Ivabradine drug or allied drugs.
2. Any major illness in the past 90 days or any clinically significant ongoing chronic medical illness e.g. Congestive Cardiac Failure (Heart failure), Hepatitis, Hypotensive episodes, Hyperglycemia etc.
3. Presence of any clinically significant abnormal values during screening e.g. significant abnormality of liver function test, renal (kidney) function test etc.
4. Severe cardiac, renal or liver impairment, gastro-intestinal disease or other conditions, any other organ or system impairment.
5. History of seizures, epilepsy or any kind of Neurological disorders.
6. Past history of Anaphylaxis or angioedema.
7. Presence of disease markers of HIV and hepatitis B, C virus.
8. History of consumption of alcohol for more than 2 years or having consumed alcohol within 48 hours prior to dosing.
9. Consumption of Xanthine containing derivatives (coffee, tea, cola – drinks, chocolate) or tobacco products within 48 hours prior to dosing.
10. Use of any recreational drug or a history of drug addiction.
11. Participation in any clinical trial within the past 90 days.
12. History of difficulty with donating blood or difficulty in accessibility of veins in left or right arm.
13. Donation of blood (one unit or 350 mL) within 90 days prior to receiving the first dose of study medication.
14. Receipt of any other prescription drug or over the counter (OTC) drugs within two weeks prior to receiving the first dose of study medication or repeated use of drugs within the last four weeks.
15. An unusual diet for whatever reason e.g. low sodium diet, for two weeks prior to receiving any medication and throughout subject’s participation in the study.
16. Recent history of dehydration from diarrhoea, vomiting or any other reason within a period of 24 hours prior to the study.
17. Known hypersensitivity to heparin.
18. Use of oral contraceptive for at least 90 days (for females).
19. Pregnant / lactating volunteer (for females).
Treatments Administered
An oral dose of Reference product (R) or Test product (T) will be administered at 0.00 hours during each period with 240 mL (about 8 oz) of water at room temperature as per the randomization schedule under the supervision of the Medical Officer where end time of the dosing will be recorded in raw data forms. Subjects will receive the alternate ‘treatment’ in the subsequent periods, in such a way that each subject would have received the two ‘treatments’ test and reference each, at the end of the study.
Method of Assigning Subjects to Treatment Groups
The subjects were assigned to the sequence either test or reference product, according to the randomization schedule.
The order of receiving test or reference product for each subject during the study was determined according to randomization schedule (generated using SAS® version 9.1.3).
Subject number was allocated as per the rank order of the reporting time of the subject to the clinical facility.
Drug Concentration Measurements
Concentration of Ivabradine was measured in plasma samples of the subjects. The blood samples were collected during the study at sampling hours at pre-dose and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.00, 16.00, 24.00 and 48.00 hours post dose. (Time points being relative to the formulation dosing). Samples were collected through an indwelling cannula placed in a forearm vein. The pre-dose samples were collected within one hour prior to drug dosing. The post-dose samples upto 24 hours in house stay were collected within 2 minutes of the scheduled time where the end time of collection to the nearest minute was recorded.
Intravenous indwelling cannula was kept in place as long as required by injecting not more than 0.5 mL of 5 IU/mL of heparin in normal saline solution during the collection of multiple samples. In such a case, the blood sample was collected after discarding the first 0.5 mL of heparinised blood from the tubing. Blood was also withdrawn from vein by using disposable syringe and needle if the cannula was blocked or the cannula is removed for other reasons.
Each blood sample was collected in 5 ml graduated polypropylene tube containing 50 µL of 5% EDTA solution as anticoagulant during each period. The samples collected at each time point were centrifuged at 4°C and 4000 rpm for 15 minutes to separate plasma, after receiving the blood samples from all the subjects. Plasma samples were centrifuged within 30 minutes after collection of samples; if there was any delay in centrifugation then sample was kept cool in refrigerator. The separated plasma was aliquoted in single aliquot in prelabelled polypropylene tubes during each period. These tubes were labelled with Study Number, Period Number, Subject Number, Sample Number, Time Point (hrs), and Aliquot Number. These tubes were then transferred to a deep freezer maintained at –20°C for temporary storage and finally to a deep freezer maintained below –50°C or colder for storage at the end of the day or as and when required.
485 samples (Aliquot I) of Period-I and Period-II were transferred to Bio analytical section at 1115 hrs. The investigational products were administered in fasting conditions and no food was served till four hours post dose. No fluid, except 240 mL drinking water administered with the investigational products was allowed from 1 hour pre-dose and 2 hours post dose. The investigational products were administered to the subjects while in sitting posture. Subjects were instructed to remain seated or be ambulatory (avoiding any strenuous activity) for first two hours following the drug administration (except during recording of vitals). During this interval, under supervision, subjects were permitted to leave the bed for brief periods, e.g. to use the washroom facilities. Thereafter the subjects were allowed to engage only in normal activities while avoiding severe physical exertion.
Restrictions
All subjects were instructed to abstain from alcohol and xanthine containing food and beverages (chocolates, tea, coffee or cola drinks), cigarettes and tobacco products, for at least 48 hours, prior to dosing and during their participation in the study. Subjects were also instructed to abstain from an unusual diet for whatever reason e.g. low sodium diet, for two weeks prior to receiving any medication and throughout their participation in the study.
Prior and Concomitant Therapy
Receipt of any other prescription drug or over the counter (OTC) drugs within two weeks prior to receiving the first dose of study medication or repeated use of drugs within the last four weeks was an exclusion criterion. Further, the subjects were not supposed to consume any medication during the conduct of the study. Fourteen four subjects, who checked-in study, confirmed that they did not consume any medication within the 2 weeks of the start of first period or during the study.
Bioanalytics and data processing
Validated LC-MS/MS method was employed for the estimation of Ivabradine in plasma. During estimation of Ivabradine in plasma quality control samples were distributed throughout each batch of study samples.
Whenever possible, samples from each subject was analyzed on the same standard curve. Samples with drug concentration greater than upper limit of the validated range of the analysis would be diluted with the appropriate drug free biological matrix and reanalyzed as per the method validation report.
The analysts concerned were blinded with respect to the randomization code, and as a result to the order of administration of the study medication.
Appropriateness of Measurements
The plasma samples of subjects were analyzed by a validated LC-MS/MS method. The limit of quantification of 25.02 ng/mL for Ivabradine was enough to quantify the analyte from the plasma samples collected up to 24.00 hours after drug administration. The linearity range of 25.02 ng/mL to 4009.92 ng/mL for Ivabradine was enough to quantify the expected concentration range of Ivabradine from subject plasma with the proposed dose of 7.5 mg of Ivabradine.
Insurance policy
Macleods Pharmaceuticals. Ltd. had an insurance policy to cover the risks to the subjects and/or any other eventualities pertaining to the study.
Confidentiality of data
The data identifying each subject by name was kept confidential and was accessible only to the study personnel and if necessary, to the QA auditors, IEC, Sponsor representative and Regulatory agency.
Statistical and Analytical Plans
Following were the plans for statistical analysis:
Use SAS® system version 9.1.3 for estimation of pharmacokinetic parameters and its Statistical analysis for Stavudine at from their plasma concentration data.
Report the summary statistics for all pharmacokinetic parameters for both the test and reference products. The reported parameters are the minimum, maximum, arithmetic means, standard deviation and the coefficient of variation for untransformed data and relevant pharmacokinetic parameters are the arithmetic means and the standard deviation for the log-transformed (natural) data.
Analyze the log-transformed pharmacokinetic parameters (Cmax, AUC0-t, AUC0-) using an ANOVA model with main effects of sequence, subject nested within sequence, period, and treatment.
Use a separate ANOVA model to analyze each of the parameters. Use a 5% level of significance to test significance of all effects.
Include calculation of mean square error, coefficient of variance and the associated degree of freedom for each analysis of variance.
Use SAS procedure ‘PROC GLM’ to perform analysis of variance.
Calculate and report ratio of geometric means using the LSM for log transformed Cmax, AUC0-t and AUC0-.
Report the geometric means of the test and reference product. And express ratios of mean AUC0-t to mean AUC0- for test and reference in percentage.
Calculate the power of the ANOVA model to detect the ratio of the two products averages (geometric means) being equal to 125% (or 80%) at the 5 % significance level for analyses using the log-transformed data.
Calculate the coefficient of
variation using 
with help of SAS version 9.1.3. Where MSE
is mean squared error obtained from Analysis of Variance model.
Calculate a 90% confidence interval for the ratio of both the products averages (geometric means) by first calculating the 90% confidence interval for the differences in the averages (least square means) of the log-transformed data and then taking the antilogarithms of the obtained confidence limits.
The confidence intervals are entirely included in the range of 80% – 125 % for AUC0-t, AUC0– and Cmax log-transformed then the treatments were claimed to be bioequivalence.
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RESULTS:
Demographic and Other Baseline Characteristics
The mean weight, height, age and BMI ± SD values for normal healthy human subjects recruited in the study and those analyzed were 59.26 ± 7.707 kg and 61.48 ± 5.603 kg, 1.659 ± 0.0543 meters and 1.673 ± 0.0349 meters, 26.6 ± 3.89 years and 27.1 ± 6.10 years, 21.482 ± 2.1385 kg/m2 and 22.001 ± 2.1746 kg/m2 respectively. The demographic data is summarized in table-1.
Analysis of Efficacy
The various un-transformed mean pharmacokinetic parameters estimated for both the reference and test formulations of Ivabradine under fasting conditions are mentioned in Table-2. The comparative linear plot of Ivabradine Mean concentration (ng/ml) of Test and reference product Vs Time (hours (hrs)) shown in Figure-1.
Ratio And 90% Confidence Interval:
For Ivabradine: The ratio of geometric mean and 90% confidence interval for the ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-¥ were found to be respectively 101.84% and 88.40% – 117.32%; 96.66% and 85.13% – 109.74% and 96.15% and 85.44% – 108.19%.
Power and Intra Subject Variability:
For Ivabradine: The power and intra subject variability for ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-¥ was found to be respectively 72.86% and 19.30%; 81.95% and 17.29% and 87.08% and 16.05%.
Efficacy Conclusions
The 90% confidence intervals for the means of the primary efficacy variables Cmax, AUC0-t and AUC0–¥ lie between the acceptance ranges of 80-125% for all the parameters.
Thus it is concluded that the test formulation of Ivabradine tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Macleods Pharmaceuticals Ltd. Is bioequivalent to Procoralanâ (Ivabradine) tablet 7.5 mg (each film-coated tablet contains Ivabradine hydrochloride equivalent to Ivabradine 7.5 mg) manufactured by Les Laboratories Servier, France in healthy, adult, human subjects under fasting condition.
Safety Conclusions
There were no adverse events during the study.
There was an out of normal range laboratory value obtained at the post-study assessment, which was clinically significant. The clinically significant out of reference range values for the post study examination of the subject’s laboratory investigations is tabulated below:
The relationship of the drug to the clinically significant out of reference range laboratory value obtained during post study evaluation was unlikely, shown in table-4