Amlodipine and Benazepril Hydrochloride (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 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 MRHD on 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).

13.3 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 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 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 maximum recommended dose of amlodipine and benazepril hydrochloride 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 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 and amlodipine using benazepril doses of 10 to 20 mg and amlodipine doses of 2.5 to 10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10 to 25/6 to 13 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 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 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, 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 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

Amlodipine and benazepril hydrochloride is available as capsules containing amlodipine besylate equivalent to 5 mg/20 mg They are available as follows:
Amlodipine and Benazepril Hydrochloride Capsules USP, 5 mg/20 mg are white to pale yellow colored powder filled in empty hard gelatin capsule shells, size “0” of pink cap and pink body imprinted with ‘I’ on pink cap and ‘98’ on pink body with black edible ink.
Bottles of 30 NDC 71205-122-30
Bottles of 60 NDC 71205-122-60
Bottles of 90 NDC 71205-122-90


Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in tight container (USP).

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)].
Distributed by:
Rising Health, LLC
Saddle Brook, NJ 07663
Made in India
Code: TS/DRUGS/22/2009
Revised: 10/2017

Repackaged By:
Proficient Rx LP
Thousand Oaks, CA 91320

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 are amlodipine and benazepril hydrochloride capsules?
Amlodipine and benazepril hydrochloride capsules contain 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 already taking 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
o
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.
o
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.
How do I store amlodipine and benazepril hydrochloride capsules?

Store amlodipine and benazepril hydrochloride capsules at room temperature 20° to 25°C (68° to 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. They may harm them.
For more information, ask your doctor or pharmacist, or call Rising Health, LLC at 1-833-395-6928.
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: colloidal silicon dioxide, crospovidone, gelatin, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and titanium dioxide. In addition, the hard gelatin capsule shells of 5 mg/10 mg contains iron oxide black, iron oxide red, and iron oxide yellow, 5 mg/20 mg contains iron oxide red, 5 mg/40 mg and 10 mg/40 mg contains FD&C Blue 1, FD&C Red 3, and 10 mg/20 mg contains D&C Red 28, FD&C Blue 1, FD&C Red 40, and FD&C Yellow 5. The capsules are printed with edible ink containing black iron oxide and shellac.
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.
Distributed by:
Rising Health, LLC
Saddle Brook, NJ 07663
Made in India
Code: TS/DRUGS/22/2009
Revised: 10/2017

Repackaged By:
Proficient Rx LP
Thousand Oaks, CA 91320

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