Hypertension
Chronic stable angina pectoris
Vasospastic (Prinzmetal’s) angina

Posology
Adults
For both hypertension and the usual initial dose is 5 mg Lodipam once daily which may be increased to a maximum dose of 10 mg depending on the individual patient’s response.
In hypertensive patients Lodipam has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotension converting enzyme inhibitor. For angina, Lodipam may be used as monotherapy or in combination with other antianginal medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of beta blockers.
No dose adjustment of Lodipam is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotension-converting enzyme inhibitors.

Special populations
Elderly
Lodipam 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 (see sections 4.4 and 5.2).

Hepatic impairment
Dosage recommendation have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range (see sections 4.4 and 5.2 the pharmacokinetic of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Renal impairment
Change in Amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialyzable.

Pediatric population
Children and adolescents with hypertension from 6years to 17 years of age The recommended antihypertensive oral dose in pediatric patients age 6-17 years is 2.5 mg once daily as a starting dose, up-titrated to 5mg 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 (see sections 5.1and 5.2)

Doses of Amlodipine 2.5 mg are not possible with this medicinal product.

Children under 6years old
No data are available.

Method of administration
Oral administration.

The safety and efficacy of Amlodipine in hypertensive crisis has not been established.

Patients with cardiac failure
Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in Patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the Amlodipine treated group in the placebo group (see section 5.1).

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

Use in patients with impaired hepatic function
The half life of Amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. 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 doses. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Use in elderly patients
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Use in renal failure
Amlodipine may be used in such patients at normal doses. Changes in Amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.

Effects of other medicinal products on Amlodipine
CYP3A4 inhibitors: Concomitant on Amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in Amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers: there is no data available regarding the effect of CYP3A4 inducers on Amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericcum) may give a lower plasma concentration of Amlodipine. Amlodipine should be use with caution together with CYP3A4 inducers.

Administration of Amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): in animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as Amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of Amlodipine on other medicinal products
The blood pressure lowering effects of Amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

In clinical interaction studies, Amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine.

Pregnancy
The safety of Amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doss (see section 5.3).
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus.

Breast-feeding
It is not known whether Amlodipine is excreted in breast milk. A decision on whether to Continue/discontinue breast-feeding or to continue/discontinue therapy with Amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of Amlodipine therapy to the mother.

Fertility
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effects of Amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking Amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

a) Summary of the safety profile
The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

b) Tabulated list of adverse reactions
The following adverse have been observed and reported during treatment with Amlodipine with the following frequencies: Very common (≥1/10); common (≥1/100to <1/10); uncommon (≥1/1,000 to ≥1/100); rare (≥1/10,000); very rare (≥1/10,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing
seriousness.

*mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

a) Description of selected adverse reactions
Dizziness: is the feeling of being lightheaded, woozy, or unbalanced. It affects the sensory organs, specifically eyes and ears. It can cause fainting. Dizziness is not a disease but a symptom of other disorders.
Headache: a continuous pain in the head
Palpitations: a noticeably rapid, strong, or irregular heartbeat due to agitation, exertion, or illness.
Flushing: become red and hot, typically as the result of illness or strong emotion.
Abdominal pain: Pain in the belly. Abdominal pain can be acute or chronic. It may reflect a major problem with one of the organs in the abdomen.
Nausea: a feeling of sickness with an inclination to vomit.
Oedema: a condition characterized by an excess of watery fluid collecting in the cavities or tissues of the body.
Fatigue: extreme tiredness resulting from mental or physical exertion or illness.

b) Pediatric Population
Safety and efficacy not established in children younger than 6 yr of age.
Above 6 years to 17 years adverse events were similar to those seen in adults.

c) Other special population(s)
The following information addresses dosage of amlodipine in special populations.
Dosage of drugs administerein fixed combination with amlodipine also may require adjustment in certain patient populations; the need for such dosage adjustment must be considered in the context of cautions, precautions and contraindications specific to that population and drug.

Hepatic impairment
Hyper tension
Initially, amlodipine 2.5 mg daily (as initial or add on therapy).

Angina
Initially, amlodipine 5mg daily.

Renal Impairment
Amlodipine dosage modification not necessary.
Preparations containing amlodipine in fixed combination with benazepril are not recommended in patients with CIcr <30 ml / minute or Scr > 3 mg /dL

Geriatric Patients
Hypertension
Initially amlodipine 2.5 mg daily ( as initial or add – on therapy) adjust subsequent dosage based on patient response and tolerance.
Angina
Initially, amlodipine 5mg daily.

To reports any side effect(s) :
- The National Pharmacovigilance and Drug Safety Centre (NPC)

• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

In human experience with intentional overdose is limited.

Symptoms
Available data suggest that gross over dosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment
Clinically significant hypotension due to Amlodipine over dosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the of charcoal up to 2 hours after administration of Amlodipine 2.5mg, 5mg and 10mg has been shown to reduce the absorption rate of Amlodipine.

Since Amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular effects. ATC code: C08CA01.
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blockers or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of Amlodipine is due o a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Amlodipine relives angina has not been fully determined but Amlodipine reduces total ischemic burden by the following two actions:

1) Amlodipine dilates peripheral and thus, reduces the total peripheral resistance (after load) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients’ artery spasm (Prinzmetal’s or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of Amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate table consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.

Use in patients with coronary artery disease (CAD)
The effectiveness of Amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-center, randomized, double- blind, placebo controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 2.5-5-10 mg were treated with enalaprin 2.5-5.10 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in tablet 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.

Abbreviations: CHF , congestive heart failure; CI, confidence interval; MI, myocardial information; TIA, transient ischemic attack.
Us in patients with heart failure
Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that Lodipam did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that Lodipam did not lead to anincrease in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo controlled study (PRAISE-2) of Lodipam in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, diuretics, Lodipam had no effects on total cardiovascular mortality. In this same population Lodipam was associated reports of pulmonary oedema.

Treatment to prevent heart attack trial (ALLHAT)
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack trial (ALLHAT) was performed to compare newer drug therapies: Amlodipine 2.5, 5 and 10mg (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension.”

A total of 33.357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had it least one additional CHD risk factor, including: previous myocardial infarction or stroke (>6 month prior to enrollment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C<35 mg /DL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current smoking (21.9%).

The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no singnificant difference in the primary endpoint between Amlodipine-based therapy and clorthalidone-based therepy: RR 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a component combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs. 7.7%, RR1.38,95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy. RR 0.95% CI [0.89-1.02] p=0.20.

Use in children (aged 6years and older)
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a2.5 mg dose and 5mg dose and 10 mg dose of amlodipine with placebo, showed that both doses reduced systolic Blood pressure significantly more that placebo. The difference between the two doses was not statistically significant.

The long-time effects of amlodipine on growth, puberty and general development have not been studied. The long-time efficacies of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.

Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The bioavailability of amlodipine I not affected by food intake.

Biotransformation/ elimination
The terminal plasma elimination half is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Use in hepatic impairment
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Use in the elderly
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tender to be decreased with resulting increase in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patients age group studied.

Use in children
A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6.to 12 years and in adolescents

Reproductive toxicology
Reproductive studies in rats and mice have shown delayed data of delivery, prolonged duration of lab our and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besylate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatide and Sertoli cells.

Carcinogenesis, mutagenesis
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

*Based on patient weight of 50kg

2.5 mg, 5 mg, and 10 mg tablets
Microcrystalline cellulose,
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Not applicable.

2.5mg, 5 mg, and 10 mg tablets
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2.5 mg tablets
PVC /Aluminum blisters containing 10 tablets
5 mg tablets
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