Amlodipine Besylate and Benazepril Hydrochloride (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.3 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with this combination. However, these studies have been conducted with amlodipine and benazepril alone (see below). No adverse effects on fertility occurred when the benazepril:amlodipine combination was given orally to rats of either sex at doses up to 15:7.5 mg (benazepril:amlodipine)/kg/day, prior to mating and throughout gestation.

Benazepril

No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to 2 years at doses of up to 150 mg/kg/day. When compared on the basis of body surface area, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (MRHD) (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria, in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 to 500 mg/kg/day (6 to 60 times the MRHDon a body surface area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Amlodipine

Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a body surface area basis, similar to the MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a body surface area basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a body surface area basis).

13.4 Reproductive Toxicity

When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area basis, the 2.5 mg/kg/day dose of amlodipine is 3.6 times the amlodipine dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride capsule is given to a 50-kg woman. Similarly, the 5 mg/kg/day dose of benazepril is approximately twice the benazepril dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride capsule is given to a 50 kg woman. No teratogenic effects were seen when benazepril and amlodipine were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the MRHD on a body surface area basis, assuming a 50 kg woman). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the MRHD of amlodipine and benazepril hydrochloride capsules given to a 50 kg woman).

Benazepril

No teratogenic effects of benazepril were seen in studies of pregnant rats, mice, and rabbits. On a body surface area basis, the maximum doses used in these studies were 60 times (in rats), 9 times (in mice), and about equivalent to (in rabbits) the MRHD (assuming a 50 kg woman).

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the MRHD of 10 mg amlodipine on a body surface area basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

14 CLINICAL STUDIES

Over 950 patients received amlodipine and benazepril hydrochloride capsule once daily in 6 double-blind, placebo-controlled studies. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing.

Once-daily doses of benazepril/amlodipine using benazepril doses of 10 to 20 mg and amlodipine doses of 2.5 to10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10 to 25/6 to13 mmHg.

In 2 studies in patients not adequately controlled on either benazepril 40 mg alone (n = 329) or amlodipine 10 mg alone (n = 812) once daily doses of amlodipine and benazepril hydrochloride capsules 10 mg/40 mg further decreased seated blood pressure compared to the respective monotherapy alone.

Combination therapy was effective in blacks and nonblacks. Both components contributed to the antihypertensive efficacy in nonblacks, but virtually all of the antihypertensive effect in blacks could be attributed to the amlodipine component. Among nonblack patients in placebo-controlled trials comparing amlodipine and benazepril hydrochloride capsules to the individual components, the blood pressure lowering effects of the combination were shown to be additive and in some cases synergistic.

During chronic therapy with amlodipine and benazepril hydrochloride capsules, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of amlodipine and benazepril hydrochloride capsules have continued during therapy for at least 1 year. Abrupt withdrawal of amlodipine and benazepril hydrochloride has not been associated with a rapid increase in blood pressure.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 68151-1364

NDC: 68151-1364-0 1 CAPSULE in a PACKAGE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Female patients of childbearing age should be told about the consequences of exposure to amlodipine and benazepril hydrochloride during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. [See WARNINGS and PRECAUTIONS (5.5)]

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

MADE IN INDIA

Revised: July 2015 ID# 241557

Patient Information

AMLODIPINE AND BENAZEPRIL HYDROCHLORIDE CAPSULES USP

(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 the most important information I should know about amlodipine and benazepril hydrochloride capsules?

  • Amlodipine and benazepril hydrochloride capsules can cause harm or death to an unborn baby.
  • Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
  • If you get pregnant while taking amlodipine and benazepril hydrochloride capsules , tell your doctor right away.

What is amlodipine and benazepril hydrochloride capsule?

Amlodipine and benazepril hydrochloride capsule contains 2 prescription medicines that work together to lower blood pressure: amlodipine besylate (the active ingredient found in Norvasc®), a calcium channel blocker, and benazepril hydrochloride (Lotensin®), 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 have 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 may pass into your milk. Don’t breastfeed while you are taking amlodipine and benazepril hydrochloride capsules.
  • 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)
  • you are taking already a diuretic (a medicine to increase the amount of urine you produce)

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 (Eskalith® , Lithobid®)
  • 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 nonsteroidal anti-inflammatory drugs (NSAIDs), 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:

o you have nausea

o you feel more tired or weaker than usual

o you have itching

o your skin or eyes look yellow

o you have pain in your upper right stomach

o 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, non-productive, 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 at www.fda.gov/medwatch.

How do I store amlodipine and benazepril hydrochloride capsules?

  • Store amlodipine and benazepril hydrochloride capsules at room temperature (59 to 86°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, address medical inquiries to www.lupinpharmaceuticals.com or call 1-800-399-2561.

What are the ingredients in amlodipine and benazepril hydrochloride capsules?

Active ingredients: amlodipine besylate (the active ingredient found in Norvasc®), benazepril hydrochloride (Lotensin®)

Inactive ingredients: crospovidone, hydrophobic fumed silica, lactose anhydrous, magnesium stearate, microcrystalline cellulose, povidone, gelatin, titanium dioxide (not present in 10 mg/20 mg strength), black iron oxide, red iron oxide (present in 5 mg/10 mg, 5 mg/20 mg and 10 mg/ 20 mg strength), yellow iron oxide, (present in 5 mg/10 mg strength), D&C Yellow #10 (present in 5 mg/40 mg strength), FD&C Blue #1 (present in 10 mg/40 mg strength), FD&C Blue #2 (present in 10 mg/20 mg strength), FD&C Green #3 (present in 5 mg/40 mg strength),FD&C Red #40 (present in 10 mg/40 mg strength), FD&C Yellow #6 (present in 5 mg/ 40 mg strength), shellac, propylene glycol, potassium hydroxide.

Norvasc® is a registered trademark of Pfizer, Inc. Lotensin® is a registered trademark of Novartis Pharmaceuticals Corporation. Eskalith® and Lithobid® are registered trademarks of Noven Therapeutics, LLC.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

MADE IN INDIA

Revised: July 2015 ID#: 241558

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