WARNING: FETAL TOXICITY

10 OVERDOSAGE

Only a few cases of human overdose with amlodipine have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of amlodipine with an unknown large quantity of a benzodiazepine, developed refractory shock and died.

Human overdoses with any combination of amlodipine and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death.

Treatment: Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate.

In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage and/or activated charcoal to remove the drug from the gastrointestinal tract (only if presented within 1 hour after ingestion of amlodipine and benazepril hydrochloride).

Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple- drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

The most likely effect of overdose with amlodipine and benazepril hydrochloride is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication.

Analyses of bodily fluids for concentrations of amlodipine, benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis.

No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of amlodipine, benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of amlodipine by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value.

Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril and amlodipine for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [seeWarnings and Precautions**** (5.8)]

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of amlodipine and benazepril hydrochloride remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

12.2 Pharmacodynamics

Benazepril

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10 mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%.

Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted [seeWarnings and Precautions**** (5.4)].

The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

With chronic once-daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta blockers to humans.

Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

12.3 Pharmacokinetics

The rate and extent of absorption of benazepril and amlodipine from amlodipine and benazepril hydrochloride are the same as when administered as individual tablets. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from amlodipine and benazepril hydrochloride have not been studied.

Absorption:Following oral administration of amlodipine and benazepril hydrochloride, peak plasma concentrations of amlodipine are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of amlodipine and benazepril hydrochloride, the peak plasma concentrations of benazepril are reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril is at least 37%. Amlodipine and benazepril exhibit dose proportional pharmacokinetics between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg, respectively.

Distribution:The apparent volume of distribution of amlodipine is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. The apparent volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat’s degree of protein binding should be unaffected by age, by hepatic dysfunction, or—over the therapeutic concentration range—by concentration.

Metabolism: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolized. Benazepril is extensively metabolised to form benazeprilat as the main metabolite, which occurs by enzymatic hydrolysis, mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat.

Elimination:Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. Ten percent of unchanged drug and 60% of amlodipine metabolites are excreted in urine. Effective elimination half-life of amlodipine is 2 days. Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. In the urine, benazepril accounts for less than 1% and benazeprilat for about 20% of an oral dose. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. Benazeprilat’s effective elimination half-life is 10 to 11 hours, while that of amlodipine is about 2 days, so steady-state levels of the 2 components are achieved after about a week of once-daily dosing.

Specific Populations

Geriatric Patients:No specific clinical studies were performed to understand the impact of age on the pharmacokinetics of amlodipine and benazepril as fixed dose combination. As individual component amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve [seeUse in Specific Populations (8.5)].

Hepatic Impairment:Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment [seeUse in Specific Populations (8.6)].

Renal Impairment: The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (CrCl greater than 30 mL/min) is similar to that in patients with normal renal function. In patients with CrCl less than or equal to 30 mL/min, peak benazeprilat levels and the effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics of amlodipine is not significantly influenced by renal impairment [see Dosage and Administration (2.2), Use in Specific Populations (8.7) and Warnings and Precautions (5.7)].****

Drug Interactions

Amlodipine

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Maalox® (antacid): Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.****

Atorvastatin: Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

CYP3A Inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.

Benazepril

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications.

Patient Information

Amlodipine and Benazepril Hydrochloride Capsules, USP

2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg and 10 mg/40 mg

(am loe' di peen and ben az' e pril hye" droe klor' ide)

Read this Patient Information leaflet before you start taking amlodipine and benazepril hydrochloride capsules and each time you get a refill. There may be new information. This leaflet does not replace talking with your doctor. If you have any questions, ask your doctor or pharmacist.

What is amlodipine and benazepril hydrochloride capsules?

Amlodipine and benazepril hydrochloride capsules contains 2 prescription medicines that work together to lower blood pressure: amlodipine besylate, a calcium channel blocker, and benazepril hydrochloride, an ACE inhibitor. Your doctor will prescribe amlodipine and benazepril hydrochloride capsules only after other medicines haven’t worked.

High Blood Pressure (hypertension). Blood pressure is the force of blood in your blood vessels. You have high blood pressure when the force is too much. Amlodipine and benazepril hydrochloride capsules can help your blood vessels relax so your blood pressure is lower.

Amlodipine and benazepril hydrochloride capsules has not been studied in children.

Who should not take amlodipine and benazepril hydrochloride capsules?

Don’t take amlodipine and benazepril hydrochloride capsules if you are allergic to any of the ingredients. There is a complete list at the end of this leaflet.

What should I tell my Doctor before taking amlodipine and benazepril hydrochloride capsules?

Tell your doctor about all your medical conditions, including if:

•you are pregnant or plan to become pregnant. See**“What is the most important information I should know about amlodipine and benazepril hydrochloride capsules?”**

•you are breastfeeding. Amlodipine and benazepril hydrochloride is present in human milk. It is not known whether amlodipine and benazepril hydrochloride affects your breastfed baby or milk production.

• you have a heart condition

• you have liver problems

• you have kidney problems

• you are about to have an operation (including dental surgery) or emergency treatment

• you are suffering from several episodes of vomiting or diarrhea

• you are treated for hyperkalemia (too much potassium in the blood)

Keep a list of your medicines with you, including vitamins and natural or herbal remedies, to show your doctor or pharmacist. Some of your other medicines and amlodipine and benazepril hydrochloride capsules could affect each other, causing serious side effects. Tell your doctor about all your medicines, especially:

• Simvastatin (a medicine used to control elevated cholesterol)

• medicines for high blood pressure or heart failure

• water pills, extra potassium or a salt substitute

• Lithium

• potassium-containing medicines, potassium supplements or salt substitutes containing potassium

• cyclosporine, an immunosuppressant medicine used in transplanted patients to reduce the risk of organ rejection

• indomethacin and other non-steroidal anti-inflammatory agents, medicines used to relieve pain and inflammation

• insulin or oral antidiabetics, medicines that help a person with diabetes to control their level of glucose (sugar) in the blood

• gold for the treatment of rheumatoid arthritis

• probenecid, a medicine used to treat gout and hyperuricemia

• medicines used to prevent and treat fungal skin infections (e.g., ketoconazole, itraconazole)

• medicines used to treat AIDS or HIV infections (e.g., ritonavir, indinavir)

• medicines used to treat bacterial infections (e.g., clarithromycin)

• medicines used in organ transplant recipients or for treating some cancers (e.g. temsirolimus, sirolimus, everolimus)

Avoid alcohol until you have discussed the matter with your doctor. Alcohol may make blood pressure fall more and/or increase the possibility of dizziness or fainting.

How do I take amlodipine and benazepril hydrochloride capsules?

• Take amlodipine and benazepril hydrochloride capsules exactly as your doctor tells you.

• Take amlodipine and benazepril hydrochloride capsules at the same time each day, with or without food.

• If you miss a dose, take it as soon as you remember. If it is more than 12 hours, just take your next dose at the regular time.

• Your doctor may test for kidney problems or check your blood potassium level.

• If you take too much amlodipine and benazepril hydrochloride capsules, call your doctor or Poison Control Center, or go to the emergency room.

• Tell all your doctors or dentist you are taking amlodipine and benazepril hydrochloride capsules if you:

- are going to have surgery

- are getting allergy shots for bee stings

- go for kidney dialysis

What are the possible side effects of amlodipine and benazepril hydrochloride capsules?

Amlodipine and benazepril hydrochloride capsules can cause serious side effects including:

•serious allergic reactions that can be life threatening.

Stop amlodipine and benazepril hydrochloride capsules and get emergency help right away if you get:

- swelling of your face, eyelids, lips, tongue or throat

- have trouble swallowing

- asthma (wheezing) or other breathing problems

These allergic reactions are rare but happen more times in people who are African-American.

•low blood pressure (hypotension). Low blood pressure is most likely to happen if you also take water pills, are on a low salt diet, get dialysis treatments, have heart problems or get sick with vomiting or diarrhea. Lie down if you feel faint or dizzy.

•liver problems. Call your doctor if:

• you have nausea

• you feel more tired or weaker than usual

• you have itching

• your skin or eyes look yellow

• you have pain in your upper right stomach

• you have flu-like symptoms

•kidney problems. Some people will have changes on blood tests for kidney function and need a lower dose of amlodipine and benazepril hydrochloride capsules. Call your doctor if you get swelling in your feet, ankles, or hands or unexplained weight gain.

•more chest pain and heart attacks in people that already have severe heart problems. Get emergency help if you get worse chest pain or chest pain that does not go away.

The more common side effects of amlodipine and benazepril hydrochloride capsules are:

• dizziness, fainting on standing up

• cough (dry, nonproductive, mainly at night, continuing)

• swelling of the feet, ankles, and hands

If any of these affects you severely, tell your doctor.

These are not all the side effects of amlodipine and benazepril hydrochloride capsules. For a complete list, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA 1088 or by visiting www.fda.gov/medwatch.

How do I store amlodipine and benazepril hydrochloride capsules?

• Store amlodipine and benazepril hydrochloride capsules at 20°-25°C (68°-77°F)

• Keep amlodipine and benazepril hydrochloride capsules in a closed container in a dry place.

• Keep amlodipine and benazepril hydrochloride capsules and all medicines out of the reach of children.

General Information about amlodipine and benazepril hydrochloride capsules

Doctors can also use medicine for a condition that is not in the patient information leaflet. Take amlodipine and benazepril hydrochloride capsules the way your doctor tells you. Do not share it with other people. It may harm them.

For more information, ask your doctor or pharmacist, or call 1-888-375-3784.

What are the ingredients in amlodipine and benazepril hydrochloride capsules?

Active ingredients: amlodipine besylate, benazepril hydrochloride.

Inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated castor oil, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and talc. Each hard- gelatin capsule contains gelatin, sodium lauryl sulfate, titanium dioxide, D&C yellow # 10 and D&C red # 28, (5 mg/20 mg, 10 mg/40 mg), FD&C blue # 1 and FD&C red # 40 (5 mg/20 mg, 5 mg/40 mg), FD & C Yellow 6 (5 mg/40 mg), FD&C green # 3 (2.5 mg/10 mg), iron oxide black (10 mg/20 mg) and iron oxide red (5 mg/20 mg and 10 mg/20 mg ) as coloring agents.

RX Only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Bachupally - 500 090 INDIA

Revised: 0220

Dispense with Patient Information Sheet available at:

www.drreddys.com/pi/amloandbenazeprilcaps.pdf