A Pharmaceutical Evaluation Of The Drug Norvasc Biology Essay


Norvasc® is a quality drug, invented and sold by Pfizer Inc. New York, NY, USA. [1]. Amlodipine besylate is the active ingredient in Norvasc, and categorized as a dihydropyridine calcium channel blocker, Amlodipine. [2] Norvasc has become a blockbuster medicine for its effective treatment for hypertension and angina. [3]


In this essay, I have attempted to report the pharmaceutical assessment of Norvasc.

Abbreviations: PREVENT - Prospective randomized evaluation of the vascular effects of Norvasc trial. CAMELOT - Comparison of Amlodipine versus Enalapril to limit occurrences of thrombosis.


Norvasc contains the active ingredient amlodipine besylate, a calcium channel blocker (CCB) of the 1, 4-dihydropyridine type. [1] Norvasc has a long plasma half-life enabling once daily dosing, [1, 4] and the presence of chlorine in the aromatic compound enhances photostability. [5] Norvasc (amlodipine besylate) is hepatically metabolised. [1, 6] Thus, Norvasc is a drug for patients with hypertension, and coronary artery diseases (CAD). [1, 5] Norvasc is a prescription only medicine, [5] and is widely distributed across United States of America, and around the world.

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Clinical name: Amlodipine besylate. [1] Generic name: Amlodipine. [1]

Chemical name: (RS) -3Ethyl-5methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)- 1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate benzenesulphonate [1, 7]

Appearance: white to off-white crystalline powder. [1]

Melting point: 195- 204ÌŠ C [1]

Molecular weight: 567.1g/mole [1]

Solubility: Partially soluble in water and isopropyl alcohol; slightly soluble in

dehydrated alcohol; and soluble in methyl alcohol. [8, 9]

Stability: stable in ordinary conditions. The condition for instability is excess heat. [1, 9]

Dosage forms&strengths: Tablets equivalent to "2.5, 5 and 10 mg" of amlodipine. [1]

Chemical structure: The structure has been confirmed by IR, UV, NMR and

MS. [5] (Fig 1)

C20H25ClN2O5 C6H6O3S [6, 8]

Figure : Structural formula of amlodipine besylate



Synthesis of Norvasc (amlodipine besylate) is as simple as the chemical reaction between an acid and a base to form a salt. [10]

As described in patents, [10, 11, 12] In this case of the Synthesis of Amlodipine besylate, amlodipine base (a nitrogen organic base), is reacted with benzene sulphonic acid or ammonium benzenesulphonate in the presence of a preferred inert solvent, for e.g. methanol at the room temperature of 5ËšC. (See fig 2)


Figure : Synthetic route for making amlodipine besylate (Norvasc) from

benzenesulphonic acid and amlodipine base

Amlodipine base is synthesized from the deprotection of synthesized amino - protected dihydropyridines intermediates.(see fig 3b & 3c) [13,14,15]

Fig 3a below describes the formula- (I) of the 1,4 dihydropyridine derivatives.

[13, 14, 15]

Figure 3a: Formula (I) - primary and secondary amines, for e.g. amlodipine base


"Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3) - or -CH2C(CH3)2-;

R is selected from;

a phenyl group optionally substituted by one or two substituents, each selected from nitro, halo, C1 - C4 alkyl ,C1 - C4 alkoxy, hydroxyl, trifluoromethyl, and cyano;

a 1- or 2-naphthyl group; and

benzofuranyl; benzothienyl; pyridyl optionally monosubstituted by methyl or cyano; quinolyl; benzoxazolyl; 2,1,3- benzoxadiazol - 4-yl; benzothiadazol- 4- yl; or thienyl optionally monosubstitued by halo or C1 - C4 alkyl;

R1 and R2 are each independently C1 - C4 alkyl or 2- methoxyethyl;

R3 is hydrogen, C1 - C4 alkyl, 2-(C1 - C4 alkoxy) ethyl, cyclopropyl methyl, benzenyl or - CH2)m COR4; "m" is 1, 2, or 3 ;

R4 is hydroxyl, C1 - C4 alkoxy or NR5R6

(both R5R6 are each hydrogen or C1 - C4 alkyl)" [13,14,15]

removal of protecting group Compound I Fig 3b: Formula (II) -

Organic acid addition salt;

(E.g. oxalate or acetic acid)

Where; Q is an amino group

R, R1, R2, R3 and Y are as defined in Formula (I) [13, 14, 15]


removal of protecting group Compound I

Figure 3c: Formula (II) -

Where; R, R1, R2 and Y are as defined in Formula (I) [13, 14, 15]

Synthesis of benzyl-, azido-, phthalimido- protected dihydropyridine intermediate starting materials.

(Note that a dibenzylamino-protected dihydropyridine intermediate (that is R3 and Q are benzyl groups) is not discussed here, but its many synthesis is described and claimed in EP 0060674 [16]

Synthetic route for Benzylamino-protected precursor

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Hantzch Synthesis;

+ + (III) (IV)

(II) [13, 14, 15]

Alternative route;

+ (VI)


(II) [13, 14, 15]

As described in the said patent [13, 14, 15], removal of benzylamino-protecting group is carried out to yield Formula (I), with R3=H


Synthetic route for Phthalimido-protected precursor

Hantzch Synthesis (under conditions similar to route A above);

1st Step


[13, 14, 15]

2nd Step


(II) [13, 14, 15]

As described in the said patent [13, 14, 15], removal of phthalimido-protecting group is carried out to yield Formula (I), with R3=H

Synthetic route for Azido-protected precursor

Hantzch Synthesis (under conditions similar to those described above);

+ RCHO +

Azido-containing acetoacetates

(II) [13, 14, 15]

As described in the said patent [13, 14, 15], removal of azido-protecting group is carried out to yield Formula (I), with R3=H

Conclusion: A likely problem encountered in these methods is that, associated with yield and/or purity inefficiencies due to tendency of starting materials to react, leading to formation of side products. [14]


According to patent US 5438145 [17], Route B above (Hantzch's synthesis) is the best route. This is based on a few modifications to eradicate the step of having to prepare and isolate amlodipine in the form of base. This way, amlodipine besylate is prepared in a "simple and feasible" way which produces a high yield and high purity compound. [17]

As described in the patent, [17] this Hantzch synthesis, is the condensing of ethyl 4[2-N-tritylamino)ethoxyacetotate, methyl-(E)-3-aminocrotonate and 2-chlorobenzyaldehyde in a preferred solvent (for e.g. methanol) at reflux temperature of the mixture to form a tritylamino-protected group compound, of which, in the process, this protective trityl group splits off (at about -10ËšC, with continuous stirring), from the obtained amlodipine precursor, without being isolated from the crude reaction mixture and at once reacts with benzenesulphonic acid. Thus, direct isolation of amlodipine besylate takes place at temperature range between 20ËšC and reflux temperature.


"The besylate salt of amlodipine shows a unique combination of good solubility, good stability, non-hygroscopicity and good processability" [10, 11, 12]; than the previously preferred amlodipine maleate (has tabletting and stability problems). [18]

Amlodipine besylate is most suitable for the preparation of pharmaceutical formulations (tablet, capsule and sterile aqueous solution) of amlodipine. [11, 12, 19] Apparently, Clinical studies in the NDA show the two salt forms as being bioequivalent. [17]

Thus, NORVASC is a tablet formulation of amlodipine besylate. [1]


2.2.1 PATENT REFERENCE - US 4879303 [11, 12]

Batch Process 1

According to the said patent, [11, 12] Amlodipine base (65.6g, 0.161mols) is slurried in industrial methylated spirit (326.4ml) and cooled to 5ËšC. Benzene sulphonic acid (26.2g, 0.1688 mols) is dissolved in industrial methylated spirit (65.6ml) at 5ËšC and added to the slurried-base. The slurry is granulated, filtered and washed with industrial methylated spirit (65.6ml), to extract some crystals. The damp solid crystals is slurried at 5ËšC for 1hour in industrial methylated spirit (327.6ml), filtered, washed with industrial methylated spirit (65.6ml) and dried under vacuum at 55ËšC for 24hours. A yield of 6.5g (83.6%) is obtained; of the melting point: 201.0ËšC. [11, 12]

2.2.2 PATENT REFERENCE - US 5438145 [18]

Batch-Process 2

According to said patent, [18] "2-chlorobenzaldehyde (95%, 50.2 g, 0.35 moles), methyl (E)-3-aminocrotonate (97%, 41.5 g, 0.35 moles) and ethyl-4-[2-(N-tritylamino)ethoxy] acetoacetate (96%, 160.5 g, 0.35 moles)", are obtained as described in Example 3 of this same patent) are dissolved in methanol (350 ml). The reaction mixture is heated for 10 hours (reflux temp.) and then cooled to room temp. A crude mixture of "3-ethyl 5-methyl (±) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1, 4-dihydro-6-methyl -3, 5-pyridine dicarboxylate", is obtained and benzenesulphonic acid (aq.) (105 g, 0.53 moles, 80%) is added. This mixture is reheated for 3 hours (reflux temp.), then cooled at -10˚C, for 10 hours (with continuous stirring). The separated precipitate is filtered off. The filtrate is concentrated in vacuo to form a viscous resin. This warm resin is poured into a 2-litre continuous extractor for extraction (with lower-specific-density solvent). To the resin, hot water (1500 ml) and toluene (1500 ml), in a distillate receiver. Non-polar impurities are continuously extracted for 24 hours from the three-phase system resin-water-toluene. The oil, which is formed from the resin (neither soluble in water nor toluene), is separated from water and toluene and dissolved in chloroform (1500 ml). The chloroform solution is poured into a 2-litre continuous extractor for extraction (with lower-specific-density-solvent and water) (1500 ml), and into the distillate receiver. Polar impurities are continuously removed (with water), the chloroform layer is separated and the solvent is evaporated in vacuo. Thus, a brown foam (37.2 g) is obtained, which solidifies to an amorphous solid, to which ethyl acetate (90 ml) is added and the obtained mixture is stirred for 1 hour (at 0˚C). At this point, crystals of crude amlodipine besylate are formed, filtered off and dried in vacuo at 60˚C. Purification is done by recrystallization of dried crude salt crystals (24.1g) from methanol (50 ml). A wet product obtained, is digested for 2 hours (at 0˚C), in methanol (25 ml), filtered off and dried in vacuo at 60˚C. Thus, 13.8 g of white crystals of amlodipine besylate of high purity (over 99% purity, as assessed by HPLC method), melting point, 201.0˚C, are obtained. [18]

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Batch-Process 3

According to said patent, [18 ] "Ethyl-4-[(2(N-tritylamino)ethoxy)]acetoacetate (87.5%, 2.520 kg, 5.12 moles)"obtained as described in Example 4 of this same patent, methyl(E)-3-aminocrotonate (97%, 0.608 kg, 5.12 moles) and 2-chlorobenzaldehyde (98%, 0.734 kg, 5.12 moles) are dissolved in methanol (6.40 l). The mixture is heated for 15 hours (reflux temp.) and cooled to room tempera. To this cooled crude solution of "3-ethyl 5-methyl (±) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6- methyl-3,5-pyridine dicarboxylate" in methanol; benzenesulphonic acid (0.980 kg, 92%) in methanol (1.95 l) is slowly added with stirring. The mixture is reheated for 3 hours (at reflux temperature with stirring) and slowly cooled to 0˚C, for 5 hours (with continuous stirring). The precipitate of triphenylmethyl methylether, separates out, and is filtered off. The filtrate is concentrated in vacuo, first at 40˚C, and gradually to 70˚ C. Thus, a brown viscous resin is obtained. This resin, with water (4.2 l) is poured into a continuous extractor for extraction with a solvent of lower specific density. Non-polar impurities are continuously extracted for 48 hours [with a mixture of toluene (1.38 l) and n-heptane (1:1 v/v)], and then transferred to a separatory funnel. The residues of the reactor, gathered at his point, are dissolved in chloroform (0.47 l) and into the separatory funnel. The oil which forms from the resin is separated conventionally, to yield an amorphous solid, to which ethyl acetate (0.75 l) is added at 0˚C (with stirring). The crystalline crude amlodipine besylate is formed. The crystals are filtered off and dried in vacuo at 70˚C. Purification is done by recrystallization of dried crude salt crystals (0.640 kg) from methanol (1.15 l) and the wet product is digested for 1 hour (at 0˚C) in methanol (0.290 l), then filtered off and dried in vacuo (at temp. not exceeding 70˚C). Thus, 0.300 kg of white crystals of amlodipine besylate of high purity (over 98% as assessed by HPLC method) is obtained; melting point, 201.0˚C. [18]



Formulation = Active ingredients + pharmaceutical excipients

According to the Example 2 in patent [11, 12], "amlodipine besylate is blended with sodium starch glycollate (disintegrant) and anhydrous dibasic calcium phosphate (additive) for 5minutes". This mixture is sieved and then blended with microcrystalline cellulose (compression aid). This mixture is sieved again and blended for about 10 minutes. Finally, magnesium stearate (lubricant) is added and final blending is done for 5 minutes and then pressed into tablets using conventional rotary tablet press machinery. [11, 12, 20]


Labella Gus, in his reports, [20] has showed that amlodipine besylate (Norvasc) can be processed by wet granulation, dry granulation and direct compression processes. Each process produced tablets with excellent tablet hardness, friability, disintegration times, ejection forces, and weight variations. However, wet granulated tablets had largest geometric mean particle size and the fastest flow rate, while dry granulated tablets had highest tablet hardness [20]


Analysis on used excipients is done to ensure compliance with their respective monographs in the Pharmacopeia(s) and also on active ingredient, in accordance with Country's Pharmacopeia. [5] Excipients used in Norvasc formulation, do not contain animal or human origin. [5]

During manufacture of amlodipine besylate (Norvasc), engineering controls require the use of process enclosures and ventilation [9, 20], and in-process control of used bulk substances. [21]

Safety measures for personal protection, include, the use of safety glasses, protective clothing (for e.g. lab coat), dust respirator (approved and certified), boots, and gloves. For an extreme case of large spill; a specialist may be consulted before handling the product. As with most organic solids, flammability or fire is possible at high temperature. [9] Therefore, for small fire, use of dry chemical powder is advised and for large fire, use water spray, fog or foam (water jet unacceptable). Products of combustion of amlodipine besylate are toxic compounds in the form of carbon oxides (CO, CO2); nitrogen oxides (NO, NO2, etc) or halogenated compounds. [9] High performance liquid chromatography is most common validation method employed for cleaning procedures in equipments with drug residues. [22, 23, 24]

Waste disposal is done in according to federal, state and local environmental control regulations. A small or large spill during manufacture is collected by the use of tools or shovel. [20]

For storage, product is kept away from heat and any source of ignition. Stored in tight, light-resistant containers (bottles) and kept in a cool, well ventilated area of a controlled room temperature (15-30ËšC). [1, 5, 20]

With the required quality control analysis on the drug, to ensure consistency from batch to batch, Norvasc specification is satisfactory. [1, 5, 8]


"2.5 mg tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are white, diamond, flat-faced, inclined edged" with "NORVASC" inscription on one side and "2.5" on the other side. Supply details:

NDC 0069-1520-68 Bottle of 90 [1]

"5 mg tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, inclined edged" with "NORVASC" and "5" on one side and the other side left plain. Supply details:

NDC 0069-1530-68 Bottle of 90

NDC 0069-1530-41 Unit Dose package of 100

NDC 0069-1530-72 Bottle of 300 [1]

10 mg Tablets

"10 mg tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, inclined edged" with both "NORVASC" and "10" on one side and the other side left plain. Supply details:

NDC 0069-1540-68 Bottle of 90

NDC 0069-1540-41 Unit Dose package of 100 [1]



Norvasc is orally administered, and absorption takes place at peak plasma concentrations between 6 and12 hours. [1, 25] Bioavailability is estimated as 64%-90%. [1] The bioavailability of Norvasc is not altered by the presence of food [1, 2] The Liver is the major source of Norvasc- amlodipine's pharmacokinetic interactions, by extensively converting amlodipine to inactive metabolites with the parent compound (10%) and the metabolites(60%) eliminated via urine. [1] Ex vivo studies have shown how the circulating drug is bound to plasma proteins in hypertensive patients. [1, 26, 27] Elimination from the plasma is in two distinct phases, with a terminal elimination half-life of about 30-58 hours. [28, 29] Steady-state plasma levels of the drug are reached within 7 to 8 days of consistent daily dosing medication. [1] See 3.4.1 for dosage administration.


Hemodynamics: A therapeutic dose of Norvasc, given to patients with hypertension, produces vasodilation resulting in a reduction of blood pressures. [1] These decreases in blood pressure, even with chronic dosing, did not have a significant change in heart rate or plasma "catecholamine" level. [1] But hemodynamic studies of patients with chronic stable angina treated with acute intravenous administration of amlodipine shows blood pressure reduction and increase in heart rate. [1, 2] Antihypertensive effectiveness of the drug can be stable for 24 hours. Plasma concentrations have same effect in both young and elderly patients. [1] The extent of effectiveness Norvasc is also dependent on with the level of pre-treatment condition. "Individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg)". [1, 28, 30] "Non-hypertensive patients experienced no significant change in blood pressures (+1/-2 mmHg)". [1] In hypertensive patients with good renal function, therapeutic doses of Norvasc resulted in a decrease in renal vascular resistance, increase in rate of glomerular filtration rate and effective renal plasma flowwith no alterations of filtration fraction. [1] No negative inotropic effect reported so far, for therapeutic dose range of Norvasc, even in combination with beta-blockers. [1]

Electrophysiologic effects: Norvasc does not change atrioventricular conduction in intact animals or man. [1] The same effect is observed in patients with chronic stable angina, treated with intravenous administration of 10 mg. [1] In clinical studies, based on electrocardiographic parameters, combination of Norvasc, with beta-blockers, to patients with either hypertension or angina, no adverse effect was observed. [1]


Drug-drug interaction

Amlodipine has been safely administered with "diazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroid anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs". [5]

In Vitro Data

In vitro data show that Norvasc has "no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin". [1]

Norvasc with other agents

Cimetidine: no effect on the pharmacokinetics of Norvasc. [1, 5, 31]

Magnesium and aluminium hydroxide antacid: no significant effect on the pharmacokinetics of Norvasc. [1]

Sildenafil: no effect on the pharmacokinetics of Norvasc. Norvasc and sildenafil both exerted their own blood pressure lowering effect. [1]

Atorvastatin: no significant change in the steady-state pharmacokinetics of atorvastatin. [1]

Digoxin: no change in serum digoxin levels or digoxin renal clearance in normal volunteers. [1, 31]

Warfarin: no change in the warfarin prothrombin response time. [1, 31]

Ethanol (alcohol): no significant effect on the pharmacokinetics of ethanol. [1]

Grapefruit Juice

Administration of Norvasc with grapefruit or juice has no significant interaction [31] but Pfizer advises against such use, since bioavailability may be increased in certain patients, resulting in increased blood pressure lowering effects. [1]

CYP3A4 Inhibitors

When used with erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine increased by 22% and 50 % respectively. [1, 31]

"Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir)" may increase the plasma concentrations of amlodipine to a greater extent. [1, 31] Low but not zero probability of an interaction is usually anticipated. [31]

CYP3A4 Inducers

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. Therefore, amlodipine besylate together with CY3A4 inducers should still be used with caution. [1]




For antihypertensive therapy, Norvasc is given as an oral dose of 5 mg once daily with a maximum of 10 mg once daily. [1] Dosage can be adjusted according to each patient's need, for instance; elderly and hepatic impaired patients may be started on 2.5 mg once daily and also, when combining Norvasc to other antihypertensive drugs. [1] The recommended dose for chronic stable angina and coronary artery disease (CAD) is 5-10 mg, but most patients will require 10 mg for resuscitating effect on treatment of a chronic stable angina, and then lower doses still suggested for patients with hepatic insufficiency and the elderly. [1]


However, the effective dose in hypertensive pediatric patients' (6-17 years) is 2.5 mg to 5 mg once daily. 5mg doses in paediatric have not been studied or published. [1]

Specific class of patients / contraindications

Pregnant women: There is insufficient information on clinical studies in pregnant women; but testing on animals (rats and rabbits) with the maximum doses, 10mg before and during gestation indicated intrauterine deaths and longer gestation and labour periods. However, Norvasc is administered, if only there is no potential risk on the fetus. [1]

Nursing mothers: Since there is no information yet, on whether amlodipine is excreted in human milk, it is advised that nursing be discontinued while Norvasc

administered. [1]

Children < 6years: Effect of Norvasc on blood pressure in these fragile patients is not known. [1]

Patients with aortic stenosis: Norvasc should not be given as symptomatic hypotension might arise. [1]

Patients with severe CAD: Norvasc should not be given as worsening angina and myocardial infarction can develop. [1]

Patients with hepatic failure: Since amlodipine has a long half-life, even in patients with hepatic disorder, Norvasc can be administered, with caution and close monitoring. [1]

Allergic or hypersensitive patients: Norvasc is contraindicated in patient with sensitivity to amlodipine or any excipient in the tablet. [1] NORVASC, AS A COMBINATION PRODUCT

Nowadays, Norvasc is available, in combinations of other active compounds or additives for the treatment of severe cases. Such examples include;

Pfizer's Caduet tablets: a combination of amlodipine besylate and atorvastatin calcium.

Lotrel capsules: a combination of amlodipine besylate and benazepril hydrochloride.

Azor tablets: a combination of amlodipine besylate and olmesartan medoxomil.


As with many drugs, [32] Norvasc (amlodipine) is a chiral drug, in a racemic mixture of (R)- and (S)-enantiomers (1:1 ratio). [7, 31] It has been reported that the (S)- enantiomer has a more positive pharmacologic effect than the (R)- enantiomer, therefore the effect of (S)- enantiomer is said to be responsible for lowering blood pressure (BP). [7, 45] And the (R)- enantiomer is reported to form nitric oxide (NO), which is likened to the drug's adverse events, for e.g. peripheral edema and flushing. [7, 45] However, Kim et al, 2000 [7] in a comparative study of their newly developed (S)- enantiomer amlodipine (amlodipine gentisate) and amlodipine racemate (amlodipine besylate) reported no significant difference in both (in terms of effect on BP, heart rate).

As a calcium channel blocker, Norvasc (amlodipine) inhibits calcium influx across cell membrane into vascular smooth muscle and cardiac muscle; although, experimental data suggest that it does this selectively, with a greater effect on the vascular muscle. [1] Norvasc's pharmacokinetic interactions, is characterized by a gradual rate of association and dissociation with the receptor binding site, and then a gradual onset of effect. [1]

Norvasc acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure; therefore, reducing end organ damage too. [1, 33, 34, 35]

The mechanisms by which amlodipine (Norvasc) relieves angina is thought to be by a total peripheral resistance against which the heart works, therefore reducing the rate pressure product, and "myocardial oxygen demand" irrespective of length of exercise. [1, 35, 36, 37] Then for Prinzmetal's or variant angina, in vitro data show that Norvasc causes vasolidation, to restore blood flow in coronary arteries. [1, 5, 35, 36, 37]


Most side effects during therapy with Norvasc are mild or moderate. The most common side effects are usually headache and edema. [1, 28, 29] Others include: fatigue, dizziness, flushing, heart palpitations, arrhythmia, stomach pain, nausea and extreme sleepiness. [1, 28, 29] These may or may not occur in individuals. [1]


So far, amlodipine besylate is not reported in the literature, for any adverse event of overdose, including pediatric overdose [38], or as any cause of death [1, 28, 29]


The risk benefit of Norvasc is considered to be positive from over a thousand clinical experiences. [1, 5]


Pre-clinical studies

Informing the regulatory body of beginning of clinical studies

Patent application

Animal testing




Clinical studies

Phase 1

Phase 4

Phase 3


Phase 2

Figure 3: Overview of drug development process

[39, 40]


Pre-clinical assessment of Norvasc, claims similarity to amlodipine maleate. Rats and mice treated for up to two years, with dose similar to maximum recommended in human dose of 10mg/day, and no drug issues in carcinogenesis, mutagenesis and fertility were observed. [1]



Adult Patients

Efficacy of Norvasc in treatment of hypertension in adults, has been confirmed in a total of "15 double-blind, placebo-controlled, randomized studies involving 800 patients on the drug and 538 on placebo". [1, 41] Adverse effects are mild to moderate. [1] The effect on systolic pressure was greater in older patients; could be greater baseline systolic pressure. [1, 34] Effects were similar in patients of different races. [1]

Pediatric Patients

Efficacy of Norvasc in treatment of hypertension in children aged 6 to 17 years, has been demonstrated in a total of double-blind, placebo-controlled, randomized studies involving 268 patients on the drug and placebo" for a couple of weeks. [1] The actual dose effect is difficult to estimate, but probably not more than 5mm/Hg systolic. [1] Adverse effect is similar to those experienced in adults. [1]


Efficacy of Norvasc medication, in exercise-induced angina and chronic stable angina has been demonstrated in "8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 Norvasc, 354 placebo. [1] 10 mg of Norvasc effectively decreases angina attack rate. [1] The consistent effectiveness of Norvasc in angina patients has been demonstrated over long-term dosing. [1]


"In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, Norvasc therapy produced positive results compared to the placebo. [1]


"In PREVENT 825 patients with coronary artery diseases were randomized to Norvasc, (5-10 mg once daily) or placebo for up to 3 years. [1] although the study did not show significant change in coronary luminal diameter as assessed angiographically, the data showed improvement on condition, with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD". [1, 4, 27, 42, 43, 44]

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. [1] Patients of different races, with a history of angina, were randomized to double-blind treatment for up to 19 months, with either Norvasc (5-10 mg once daily) or placebo, and in use of other drugs apart from other calcium CCBs. [1] There was no significant difference between amlodipine and placebo on the change of atheroma volume in the coronary artery (by intravascular ultrasound). [1, 4, 43]


Norvasc is fully licensed. The Patents under which it was protected include:

EP 0244944 (Europe); [12] granted 11, November 1987 and valid until 31 March 2007; but for a few countries, for e.g., France and Italy, it got extended by months due to SPC granted. [10] The United States equivalent is US 4879303 [11]; granted 7, November 1989 and valid until 25 March 2007.

In some countries, where Pfizer could not patent the product, Pfizer succeeded by obtaining a "patent for the production process of an amlodipine besylate sal"t. [10] for e.g. In Argentina, patency was obtained under patent number, AR 242562 [10] granted on 30, April 1993. Pfizer's Norvasc entry into the market was launched in1990. [45]

NDA approval for Norvasc (amlodipine besylate) tablets was granted to Pfizer Pharmaceuticals Inc., on 15 April 1999. [46] Pfizer, herein, declared its manufacturing facility located in Parsippany, New Jersey as a packaging site for Norvasc. [46]


Norvasc has been used safely and effectively used in patients with chronic obstructive pulmonary disease, fair congestive heart failure, CAD, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. [1]


Pfizer's Norvasc is a highly successful pharmaceutical. [47] It is the world's leading "branded medicine" for hypertension and CAD with sales recording up to $1.97 billion in 2009. [48] According to a sales review report on blockbuster medicines 2002-2004, Norvasc was ranked fifth position, although the author cautions that commercial reports which exaggerate a bit, can differ with company data [3] Med Ad News, 2005 [49] also published similar reports of Norvasc as fourth-ranked in 2004 amongst other top-selling prescription drugs. However, patent expiration and also FDA issues pose big threats to Norvasc. [48] By the end of patent protection on Norvasc, Apotex Inc., (Canadian Pharmaceutical with a subsidiary in US; Apotex Corp.) released a generic Norvasc (identical in composition to original Norvasc, into the market by May, 2007. [48] As well, many other generics, or competitor-cardiovascular diseases drugs, for e.g. Diovan (produced by Norvatis for lowering blood pressure); etc have flooded the CCB crowded market. [45, 50] Norvasc is facing a tight generic competition, which has caused a significant decline in US sales of 12% by 2009. [48] In the United Kingdom, where drug sales are re-structured by the National Health Service, the fate of this drug amidst generic competitors is obvious decline in profits. [51] In some other countries, issues of importation, direct price control by Government and pirating (in developing countries) are factors that affect the sales of Norvasc, as with other drugs. [51] And, recently, Pfizer has announced "plans to shift from further research and development (R&D) on heart diseases drugs to cancer and biotechnology drugs which it says are more profitable in comparison to large developments costs in R&D". [48]