Amlodipine Tablets USP

Name of Medicinal Product

Amlodipine 5mg Tablets USP

Pharmaceutical form – Strength and Pack size

Pharmaceutical form: TABLETS

Description: White, Round, Flat beveled, uncoated tablet embossed with a Breakline on one side and Plain on the other.

Strength: Amlodipine Besilate BP equivalent to Amlodipine …. 5mg, per Tablet

Therapeutic Category

Calcium Channel Blocker (Anti-Hypertensive / Anti-Anginal)

Indications

• Amlodipine is used to treat high blood pressure (hypertension) or a certain type of chest pain called angina, a rare form of which is Prinzmetal’s or variant angina.
• In patients with high blood pressure Amlodipine works by relaxing blood vessels, so that blood passes through them more easily. In patients with angina amlodipine works by improving blood supply to the heart muscle which then receives more oxygen and as a result chest pain is prevented. This medicine does not provide immediate relief of chest pain from angina.
• Amlodipine is a calcium channel blocker. It affects the movement of calcium into the cells of the heart and blood vessels. This relaxes the blood vessels and lowers blood pressure. A lower blood pressure will increase the supply of blood and oxygen to the heart.

Contra-indications

Amlodipine is contra-indicated in patients with:

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

Precautions / Warnings

• This medicine may cause angina (chest pain) or a heart attack in certain patients with severe heart or blood vessel disease. Check with doctor, if patient having chest pain or discomfort, fast or irregular heartbeat, nausea or vomiting, pain or discomfort in the arms, jaw, back, or neck, trouble breathing, or sweating.
• Dizziness, lightheadedness, or fainting may also occur, especially when get up suddenly from a lying or sitting position. If patient feel dizzy, lie down so you do not faint. Then sit for a few moments before standing to prevent the dizziness from returning. If patient faint, call doctor right away.
• Dizziness, lightheadedness, or fainting may also occur while exercise or if the weather is hot. Heavy sweating can cause loss of too much water and result in low blood pressure. Use extra care during exercise or hot weather.
• Check with doctor if patient have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.
• If patient using this medicine regularly for several weeks, do not suddenly stop using it. Stopping suddenly may cause chest pain or high blood pressure to come back or get worse. Check with doctor for the best way to reduce gradually the amount taking before stopping completely.
• After taking a dose of this medicine patient may get a headache that lasts for a short time. This should become less noticeable after patient have taken this medicine for a while. If this effect continues, or if the headaches are severe, check with doctor.
• In some patients, tenderness, swelling, or bleeding of the gums may appear soon after treatment with this medicine is started. Brushing and flossing teeth carefully and regularly and massaging your gums may help prevent this. See dentist regularly to have teeth cleaned. Check with doctor or dentist if patient have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums.
• Do not take other medicines unless they have been discussed with doctor. This especially includes prescription or nonprescription (over-the-counter [OTC]) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, and herbal or vitamin supplements.

Pregnancy and Lactation

Pregnancy

• Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy. Accordingly, amlodipine should not be administered during pregnancy or to women of childbearing potential unless effective contraception is used.

Lactation

• Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in lactation. Accordingly, amlodipine should not be administered during lactation.

Side effects / Adverse reactions

• Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
• Check with doctor immediately if any of the following side effects occur:

More common

• Swelling of the ankles or feet

Less common

• Difficult or labored breathing, Dizziness
• Fast, irregular, pounding, or racing heartbeat or pulse
• Feeling of warmth, Redness of the face, neck, arms, and occasionally, upper chest, Tightness in the chest

Rare

• Black, tarry stools, Bleeding gums, blistering, peeling, or loosening of the skin
• Blood in the urine or stools, Blurred vision, Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• Chest pain or discomfort, Chills, Cold and clammy skin, Cold sweats, Confusion, Cough
• Dark yellow urine, Diarrhea, Dilated neck veins, Dizziness or lightheadedness when getting up from a lying or sitting position
• Extra heartbeats, Extreme fatigue
• Fainting, Fever, Itching of the skin
• Joint or muscle pain
• Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• Numbness and tingling of the face, fingers, or toes
• Pain in the arms, legs, or lower back, especially pain in the calves or heels upon exertion
• Painful or difficult urination, Pale, bluish-colored, or cold hands or feet, Pinpoint red or purple spots on the skin
• Red, irritated eyes, Redness of the face, neck, arms, and occasionally, upper chest, Redness, soreness or itching skin
• Shakiness in the legs, arms, hands, or feet, Slow or irregular heartbeat, Sore throat
• Sores, ulcers, or white spots on the lips or in the mouth, Sores, welting, or blisters, Sudden sweating
• Sweating, Swelling of the face, fingers, feet, or lower legs
• Swollen glands, Trembling or shaking of the hands or feet
• Unsteadiness or awkwardness, Unusual bleeding or bruising
• Unusual tiredness or weakness
• Weak or absent pulses in the legs, Weakness in the arms, hands, legs, or feet
• Weight gain, Yellow eyes or skin

Incidence not known

• Abdominal or stomach pain, Clay-colored stools
• Difficulty with speaking, Drooling, Headache
• Loss of appetite, Loss of balance control
• Muscle trembling, jerking, or stiffness, Nausea, Rash
• Shuffling walk, Twisting movements of the body
• Uncontrolled movements, especially of the face, neck, and back, Unpleasant breath odor, Vomiting of blood
• Yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Acid or sour stomach, Belching, Feeling of warmth
• Heartburn, Indigestion
• Lack or loss of strength, Muscle cramps
• Redness of the face, neck, arms, and occasionally, upper chest, Sleepiness or unusual drowsiness
• Stomach discomfort, upset, or pain

Rare

• Abnormal dreams, Anxiety
• Back pain, Bad unusual or unpleasant (after) taste, Bleeding gums, Blistering, crusting, irritation, itching, or reddening of the skin, Bloating, Bloody nose, Burning feeling in the chest or stomach, Burning while urinating, Burning, dry, or itching eyes
• Change in color of the treated skin, Change in sense of smell, Change in taste, Changes in vision, Constipation, Continuing ringing or buzzing or other unexplained noise in the ears, Cracked, dry, or scaly skin
• Decreased sexual performance or desire, Depression, Difficulty with moving, Difficulty with swallowing, Discharge, excessive tearing, Double vision, Dry mouth, Dryness of the skin
• Excess air or gas in the stomach or intestines, Excessive muscle tone, Eye pain
• Feeling of constant movement of self or surroundings, Feeling of unreality, Feeling unusually cold, Flushed, dry skin, Fruit-like breath odor, Full feeling
• General feeling of discomfort or illness
• Hair loss or thinning of the hair, Headache, severe and throbbing, Hearing loss
• Increased appetite, Increased hunger, Increased sweating, Increased thirst, Increased urge to urinate during the night, Increased urination, Irritability, Irritation in the mouth
• Lack of feeling or emotion, Loose stools, Loss of memory
• Muscle pains or stiffness, Muscle tension or tightness, Muscle weakness, Nervousness
• Pain, Pains in the stomach, side, or abdomen, possibly radiating to the back, Passing gas, Problems with memory
• Redness and swelling of the gums, Redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid, Restlessness, Runny nose
• Seeing double, Sensation of spinning, Sense of detachment from self or body, Shakiness and unsteady walk, Shivering, Sneezing, Stuffy nose, Sweating, Swollen joints
• Tenderness in the stomach area, Thirst, Trouble in holding or releasing urine, Trouble sleeping, Twitching
• Uncaring, Unexplained weight loss, Unsteadiness, trembling, or other problems with muscle control or coordination
• Waking to urinate at night, Weight loss

Drug Interactions

• Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycaemic drugs.
• In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indomethacin.
• Caution should be exercised in combination of amlodipine and CYP3A4 inhibitors and CYP3A4 inducers.
• Special Studies: Effect of other agents on amlodipine
• Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, doctor may want to change the dose, or other precautions may be necessary. When patients are taking this medicine, it is especially important that doctor know if you are taking any of the medicines listed below.

• The following interactions have been selected on the basis of their potential significance and are not necessarily all inclusive.
• Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, doctor may change the dose or how often you use one or both of the medicines.

1. Atazanavir
2. Ceritinib
3. Clarithromycin
4. Clopidogrel
5. Conivaptan
6. Cyclosporine
7. Dantrolene
8. Digoxin
9. Domperidone
10. Droperidol
11. Epirubicin
12. Fosnetupitant
13. Lacosamide
14. Netupitant
15. Piperaquine
16. Rifampin
17. Ritonavir
18. Simvastatin
19. Tacrolimus
20. Tegafur
21. Telaprevir
22. Indinavir
23. Rifapentine

Other Interactions

• Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

• The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

1. Angina (chest pain) or
2. Heart attack, acute or
3. Heart or blood vessel disease (eg, coronary artery disease) or
4. Hypotension (low blood pressure)—Use with caution. May make these conditions worse.
5. Aortic stenosis (heart valve problem), severe or
6. Heart or blood vessel disease—Use with caution. May cause side effects to become worse.
7. Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Dosage & Administration

• The dose of this medicine will be different for different patients. Follow doctor's orders. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless doctor tells you to do so.
• The amount of medicine that take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage forms:

A. For angina (chest pain):

• Adults: 5 to 10 mg once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 10 mg per day.
• Children: Use and dose must be determined by your doctor.

B. For high blood pressure:

• Adults: At first, 5 mg once a day. Some patients may be started on 2.5 mg once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 10 mg per day.
• Children 6 to 17 years of age: 2.5 to 5 mg once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 5 mg per day.
• Children younger than 6 years of age: Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses. Do not take this medicine if it has been more than 12 hours since you missed your last dose.

Overdosage

• In humans, experience with intentional overdose is limited. Gastric lavage may be worthwhile in some cases. Available data suggest that gross overdosage (> 100 mg) could result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension due to amlodipine overdosage 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 channel blockade. In healthy volunteers, the use of charcoal up to 2h after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Effects on ability to drive and use machines

• Clinical experience with amlodipine indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.
• In patients suffering from dizziness, headache, fatigue or nausea the ability to react may be impaired.

Shelf life

24 months from the date of manufacturing

Special precautions for storage

Store in a cool and dry place. Protect from light, heat and moisture.

Mechanism of Action

• The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:

1. Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) 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 also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilation increases myocardial oxygen delivery in patients with coronary 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 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet 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.

Pharmacokinetic Properties

Absorption, distribution, plasma protein binding

• After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 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 is not affected by food intake.

Biotransformation / Elimination

• The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in 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 tends to be decreased with resulting increases in “area under the curve” (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 patient age group studied.

Use in children

• A population PK study has been conducted in 74 hypertensive children aged from 1to 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 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

In patients with renal failure

• Amlodipine is extensively metabolised to inactive metabolites. 10% of the parent compound is excreted unchanged in urine. Changes in amlodipine concentration are not correlated with degree of renal impairment. Therefore the normal dosage is recommended. Amlodipine is not dialysable.