NIKP-Manidipine

NIKP-Manidipine tablet 10 mg: Pale yellowish uncoated tablet with a scored line on each side and engraved with n731 on one side and 10 on the other side.
Each tablet contains 10 mg of manidipine hydrochloride.
NIKP-Manidipine tablet 20 mg: Pale yellowish uncoated tablet with a scored line on each side and engraved with n732 on one side and 20 on the other side.
Each tablet contains 20 mg of manidipine hydrochloride. (See Table 1.)

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Excipients/Inactive Ingredients: Lactose, corn starch, hydroxypropylcellulose, talc, magnesium stearate and riboflavin.

Pharmacology: Pharmacodynamics: Molecular mechanism: Long-acting hypertensive effect by dilating blood vessels, mainly by calcium channel blockade.
Pharmacokinetics: Absorption: Bioavailability is 36 to 60%. Time to peak concentration: 2-4 hours for oral single dose, and Tmax was 6 hours after repeated oral administration (20 mg once a day for 8 days). Onset: Single dose, initial response in 15-45 minutes and duration is 24 hour.
Food increases bioavailability. The mean maximum concentration of manidipine was 4.65 and 7.65 ng/mL following administration of a 20 mg dose before and after breakfast respectively, in 6 healthy Asian volunteers. AUC values were 25.57 and 36.75 ng/h/mL before and after the meal. These result suggest a better bioavailability in non-fasting conditions.
In healthy Caucasian volunteers, the extent of absorption increased by about 50% when manidipine was administered after a standard breakfast, while Cmax and Tmax were not significantly altered. Therefore, administration after a standard breakfast increase the bioavailability of the drug without modifying the rate of absorption.
Distribution: Protein binding 99%.
Metabolism: Manidipine is extensively metabolized in the liver.
Excretion: Excretion via renal 31.4% and mainly excrete in the faeces (63.3%) within 24 hour. The elimination half-life is about 5-8 hours.
Bioequivalence Study in Japan: When a single oral dose of two tablets of NIKP-Manidipine tablet 10 mg or two tablets of the reference product (both tablets contain 20 mg of manidipine hydrochloride) was administered to healthy male adults during fasting with a cross-over method, the plasma concentrations of manidipine hydrochloride were measured. In a statistical analysis for the obtained pharmacokinetic parameters (AUC and Cmax), calculation results of 90% confidence intervals for the parameters were within a range between log (0.8) and log (1.25), demonstrating the bioequivalence of the two formulations.
Similarly, one tablet of NIKP-Manidipine tablet 20 mg or one tablet of the reference product (both tablets contain 20 mg of manidipine hydrochloride) showed bioequivalence between the two formulations. (See Tables 2, 3 and Figures 1, 2.)

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Plasma concentration and pharmacokinetic parameters such as AUC and Cmax may vary depending on study conditions including selection of subjects, body fluid sampling frequency/sampling time, etc.
Bioequivalence Study in Thailand: See Tables 4, 5 and Figures 3, 4.

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Conclusion: The test product of Manidipine Hydrochloride Tablets (10 mg) manufactured by Nichi-Iko Pharmaceutical Co., Ltd. Toyama plant 1, Japan and imported by Nichi-Iko (Thailand) Co., Ltd. was bioequivalence to the reference product of Madiplot 10 mg.

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Conclusion: The test product of Manidipine Hydrochloride Tablets (20 mg) manufactured by Nichi-Iko Pharmaceutical Co., Ltd. Toyama plant 1, Japan and imported by Nichi-Iko (Thailand) Co., Ltd. was bioequivalence to the reference product of Madiplot 20 mg.

Mild or moderate Hypertension.
Hypertension with renal impairment.
Severe Hypertension.

The usual adult dosage and administration for each preparation are as follows.
NIKP-Manidipine tablet 10 mg: 1-2 tablets orally once a day with food in morning or 30 minutes after breakfast.
NIKP-Manidipine tablet 20 mg: ½-1 tablet orally once a day with food in morning or 30 minutes after breakfast.
Remark: Administration should be started at a dose of 5 mg daily and titrated up as needed.
Elderly: Since it is generally acknowledged that excessive reduction in blood pressure should be avoided in elderly patients. (Cerebral infarction may occur.). Thus when NIKP-Manidipine tablet is given in elderly, it is advisable to start with a low dose, treat with attention and under close observation.
Children: The safety of NIKP-Manidipine tablets in children has not been established. (No clinical experience.) Thus, it should not be administered in children.
Mode of Administration: Since concomitant food intake enhances significantly (about 50%) the extent of absorption, but impacts slightly the rate of absorption. Therefore, Manidipine is suggested to be taken with food in morning or 30 minutes after breakfast.
NIKP-Manidipine tablet 10 mg and NIKP-Manidipine tablet 20 mg can be divided. Due to it is not controlled release dosage form.

Atropine may be tried if hemodynamically significant bradycardia occurs; however, infranodal heart block is usually resistant to atropine in CCB toxicity.
Empiric use of glucagon (adults: 5-15 mg IV) may be warranted for patients with an unknown overdose who present with bradycardia or hypotension.
Treat hypotension with fluid boluses of normal saline if no evidence of decompensated congestive heart (CHF) exists. Administer IV calcium gluconate (up to 4 g) or IV calcium chloride (1 g) and/or glucagon (5-10 mg) if hypotension persists.
If the patient deteriorates to cardiac arrest from a CCB overdose, perform prolonged cardiopulmonary resuscitation (CPR) in the field. Patients with CCB overdose have survived neurologically intact after 1 hour of CPR.
Avoid ipecac syrup. Administer activated charcoal (AC) if the patient's airway is protected. Activated charcoal has been demonstrated to significantly absorb immediate-release medications within 1 hour of ingestion and extended-release medications as long as 4 hours after ingestion. If the ingested dose is known, a 10:1 charcoal-to-drug weight ratio can be used to calculate the optimal dose of activated charcoal to completely bind the ingested drug. Otherwise, a 1-g/kg initial dose is recommended.

NIKP-Manidipine tablets are contraindicated in pregnant women or women suspected of being pregnant. [Prolongation of the gestation period and delayed delivery have been reported in animal experiments (in rats)].

NIKP-Manidipine tablets should be administered with care in the following patients: Patients with serious hepatic disorder [The metabolism and excretion of NIKP-Manidipine tablets may be delayed.]
Elderly patients (see Elderly under Dosage & Administration).
Important Precautions: Abrupt withdrawal of calcium antagonists has been reported to aggravate symptoms in some patients. If NIKP-Manidipine tablets are withdrawn, the dosage should be gradually reduced under close observation. In addition, the patient must be instructed not to discontinue taking NIKP-Manidipine tablets without direction by a physician.
An excessive decrease in blood pressure may occur rarely which results in symptoms such as transient loss of consciousness or cerebral infarction. If such symptoms are observed, appropriate therapeutic measures such as reducing the dose or withdrawing the drug should be taken. (See Clinically Significant Adverse Reactions under Adverse Reactions.)
Since NIKP-Manidipine tablets may induce dizziness, etc. due to its hypotensive effects, patients should be instructed to use caution when operating hazardous machinery such as working at heights or driving a car.
Other precaution: It has been reported that dialysis effluent of patients on CAPD (continuous ambulatory peritoneal dialysis) may become cloudy and lipid (e.g. triglyceride) levels in dialysis effluent increased. Pay attention to making the distinction from peritonitis, etc.

NIKP-Manidipine tablets should not be administered to pregnant women or women suspected of being pregnant. [Prolongation of the gestation period and delayed delivery have been reported in animal experiments (in rats).]
It is desirable to avoid the administration of NIKP-Manidipine tablets to nursing mothers. However, if the administration is indispensable, nursing should be discontinued. [Excretion in breast milk has been reported in animal experiments (in rats).]

Clinically significant adverse reactions (Frequency unknown): An excessive decrease in blood pressure: Transient loss of consciousness and cerebral infarction due to an excessive decrease in blood pressure may occur. (See Elderly under Dosage & Administration.)
Agranulocytosis and thrombocytopenia: Since agranulocytosis or thrombocytopenia may occur, patients should be carefully monitored. If any abnormality is observed, appropriate therapeutic measures such as discontinuing administration should be taken.
Ventricular extrasystole and supraventricular extrasystole: Since ventricular extrasystole and supraventricular extrasystole may occur, patients should be carefully monitored. If such symptoms are observed, administration should be discontinued and appropriate therapeutic measures taken.
Erythroderma: Since erythroderma may occur, patients should be carefully monitored. If such symptoms are observed, administration should be discontinued and appropriate therapeutic measures taken.
Other Adverse Reactions: See Table 6.

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Precautions for coadministration NIKP-Manidipine tablets with the following drugs. (See Table 7.)

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Store below 30°C in a tight container and light-resistant.

Calcium Antagonists

C08CA11 - manidipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.

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