Moxovas A

Uses

Patients with mild to moderate hypertension (alone or in combination with other antihypertensives).

The treatment of chronic stable and vasospastic angina.

Raynaud\'s disease.

Moxonidine belongs to a group of drugs called anti-hypertensives that lower blood pressure. Moxonidine is used to treat high blood pressure.

Moxovas A is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Events, Chronic Stable Angina Pectoris, Coronary Artery Disease (CAD), High Blood Pressure (Hypertension), Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Mixed Dyslipidemias, Primary Hypercholesterolemia, Vasospastic AnginaHigh Blood Pressure (Hypertension)

How Moxovas A works

Mechanism of action on blood pressure

Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells . Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure .

Mechanism of action in angina

The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold:

Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements .

Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking .

Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines . Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure.

Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors .

Dosage

Moxovas A dosage

For treatment of both hypertension and angina pectoris, the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks, the dose may be increased to a maximum dose of 10 mg once daily. Amlodipine 10 mg once daily provides symptomatic improvement in patients with Raynaud's disease.

Use in children: Use of Amlodipine in children (under 12 years of age) is not recommended.

Adults (including the elderly): Your treatment will normally start with one 200 microgram tablet, taken in the morning. After three weeks, your doctor may increase this dose to 400 micrograms daily, given in a single dose in the morning, or in divided doses in the morning and evening. After another three weeks, your doctor may need to increase this dose to 600 micrograms daily, given in divided doses (morning and evening). You should not take more than 400 micrograms as a single dose, or more than 600 micrograms in any one day.

If you forget to take a dose, take one as soon as you remember, unless it is nearly time to take the next one. Do not take a double dose to make up for a forgotten dose.

If you forget to take a dose, take one as soon as you remember, unless it is nearly time to take the next one. Do not take a double dose to make up for a forgotten dose.

Side Effects

Amlodipine is generally well tolerated. The most commonly observed side effects are headache, peripheral oedema, palpitations, flushing, dizziness, nausea, abdominal pain.

The following side effects have been reported at the approximate frequencies shown:

• Very common: dry mouth, drowsiness
• Common: headache, dizziness (vertigo), flushing (vasodilation), weakness or loss of strength, confusion, sleep disturbances, nausea (feeling sick), being sick (vomiting), stomach upsets (dyspepsia), diarrhoea, rash or itching (pruritus), back pain

Toxicity

Acute oral toxicity (LD50): 37 mg/kg (mouse) .

Overdose

An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported .

Carcinogenesis, mutagenesis, impairment of fertility

Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose .

Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects .

There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose) .

Use in pregnancy

The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug . Use amlodipine only if the potential benefit justifies the potential risk .

Use in nursing

Discontinue when administering amlodipine .

• Contraindicated due to known hypersensitivity to an ingredient (Physiotens tablets contain lactose), heart failure, severe renal impairment, < 16 years old, >75 years old, bradycardia, severe bradyarrhythmia, sick sinus syndrome, second or third degree atrioventricular block, malignant arrhythmias.
• Used with caution in patients with history of severe coronary artery disease (CAD), unstable angina, angioneurotic edema.
• Pregnancy Category B3:Avoid use during pregnancy (inadequate data in pregnant woman) and lactation (maternal blood stream transfer to breast milk shown) unless benefit clearly justifies risk.
• Lack of specific therapeutic experience in cases of intermittent claudication, Raynaud's disease, Parkinson's disease, epileptic disorders, gluacoma, and depression suggest moxonidine should not be used in such instances .
• Carcinogenicity and genotoxicity does not appear significant.
• Concurrent administration of other hypotensives or sedative and hypnotics can enhance the hypotensive effect and intensify sedation respectively.
• Avoid concurrent Tricyclic Antidepressant (TCA) use to avoid reduction of monoxidine efficacy.
• Generally well tolerated with dry mouth and headache the most common adverse effects
• Symptoms of overdose correlate with pharmacodynamic properties:hypotension, sedation, orthostatic dysregulation, bradycardia, dry mouth with no specific counter-treatment known.

Precaution

Hypotension: Since the vasodilUse in renal failure

Although Amlodipine is excreted primarily via kidney, mild renal impairment does not appear to have an effect on the plasma concentrations. Severe renal impairment may however require a dosage reduction. Amlodipine is not dialyzable.

Use in patients with impaired hepatic function

Amlodipine half-life is prolonged in patient with impaired hepatic function. Amlodipine should therefore be administered at lower (5mg) initial dose in these patients.

Use in heart failure

An increased number of pulmonary oedema has been reported.atation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering the drug with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Cardiac failure: Patients with heart failure should be treated with caution. Calcium channel blockers, including Amlodipine, should be usedwith caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Beta blocker withdrawal: Amlodipine gives no protection against the danger of abrupt beta blocker withdrawal; any such withdrawal should be gradualreduction of the dose of beta blocker.

Hepatic failure: The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Tell your doctor before you start to take this medicine if you:

• have a heart problem called "1st-degree AV-block"
• have a severe coronary heart disease, or have angina (chest pain at rest)
• have poor circulation
• have kidney disease
• have been told you have cerebrovascular insufficiency (poor blood supply to the brain which means you are at a greater risk of stroke)
• are below 16 years of age
• have a rare hereditary problem of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption as you should not take this medicine

Patients who are intolerant to lactose should note that Moxonidine tablets contain a small amount of lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Interaction

Use of Amlodipine together with thiazide diuretics or angiotensin-converting-enzyme inhibitors in the treatment of hypertension is additive. There are no hazardous interaction of Amlodipine with Digoxin, Cimetidine, Warfarin and food.

Talk to your doctor if you are taking any of the following:

• beta-blockers, such as propranolol or atenolol, used to treat heart problems
• other medicines used to reduce blood pressure such as furosemide a diuretic, or captopril an angiotensin-converting enzyme inhibitor
• antidepressants such as amitriptyline
• sleeping tablets such as zopiclone, tranquilizers such as nitrazepam, lorazepam or phenobarbital
• Moxonidine is removed from body by kidneys through the process called "tubular excretion". Other medicines removed from the kidneys in the same way could affect how moxonidine works.

Do not drink alcohol whilst taking Moxonidine.

Volume of Distribution

21 L/kg , .

1.8±0.4L/kg.

Elimination Route

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food .

90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%.

Half Life

The terminal elimination half-life of about 30–50 hours .

Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment .

Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours.

Clearance

Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers , .

Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required .

Administered twice daily due to short half life .

However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %.

Elimination Route

Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing . Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure , .

Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces.

Pregnancy & Breastfeeding use

Pregnancy: Safety in pregnancy has not been established.

Lactation: It is not known whether Amlodipine is excreted in breast milk. It is advised to stop breastfeeding during treatment with Amlodipine.

Moxonidine is not recommended if you are pregnant, planning on becoming pregnant or are breastfeeding. Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breastfeeding.

Contraindication

Amlodipine is contraindicated in patients with-

• Hypersensitivity to amlodipine, dihydropyridine derivatives or any of the excipients
• Shock (including cardiogenic shock)
• Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)
• Unstable angina
• Hemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days)
• Severe hypotension

Do NOT take Moxonidine if you:

• Are allergic (hypersensitive) to moxonidine or any of the other ingredients of this medicine
• Have a slow heart rate or suffer from an abnormal heart rhythm or a change in the rate of the heart beat (called “sick sinus syndrome” or “2nd or 3rd degree AV-block”
• Have, or have had, heart failure or other heart problems

Special Warning

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old: The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Patients with kidney problems: If you have moderate problems with your kidneys, you should not take more than one 200 microgram tablet as a single dose or more than 400 micrograms in total, a day.

Children under 16 years of age: Moxonidine is not recommended for use in children.

Acute Overdose

There is no well documented experience with Amlodipine overdosage. In case of clinically significant hypotension due to Amlodipine over dosage, calls for active cardiovascular support including monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. Since Amlodipine is highly protein-bound, dialysis is unlikely to be of benefit.

If you (or someone else) swallow a lot of the tablets all together, or if you think a child has swallowed any of the tablets, contact your nearest hospital casualty department or your doctor immediately. An overdose is likely to cause headache, sleepiness, dry mouth, loss of balance, dizziness, low blood pressure, slowing of the pulse, vomiting, feeling tired, weakness and pain in your stomach. Please take this leaflet, any remaining tablets and the container with you to the hospital or doctor so that they know which tablets were consumed.

Storage Condition

Keep out of the reach of children. Store below 30° C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

Do not store above 30° C. Keep blister in the outer carton in order to protect from light

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