Tribenzor: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

The rationale for no or limited new toxicity from the triple combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide has already been established on the basis of the safety profile of the individual compounds or the dual combinations. To clarify the toxicological profile for Tribenzor, a 3-month repeated dose toxicity study was conducted in rats, and the results demonstrated that the combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide neither augment any existing toxicities of the individual agents nor induce any new toxicities and there were no toxicologically synergistic effects observed in the study.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. However, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone.

Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m 2 basis, about 480 times the MRHD of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (on a mg/m 2 basis, about 120 times the MRHD of 40 mg/day), revealed no evidence of a carcinogenic effect of olmesartan.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD of 40 mg/day on a mg/m 2 basis) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. (Calculations based on a 60 kg patient.)

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 amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m 2 basis, similar to the MRHD of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m 2 basis, about two 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 amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m 2 basis).

Hydrochlorothiazide. Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). These doses in mice and rats are about 117 and 39 times, respectively, the MRHD of 25 mg/day on a mg/m 2 basis. (Calculations based on a 60 kg patient.) The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, or in Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and the Asp ergillus nidulans nondisjunction assay.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses in mice and rats are about 19 and 1.5 times, respectively, the MRHD of 25 mg/day on a mg/m 2 basis. (Calculations based on a 60 kg patient.)

14 CLINICAL STUDIES

14.1 Tribenzor

The antihypertensive efficacy of Tribenzor was studied in a double-blind, active-controlled study in hypertensive patients. A total of 2492 patients with hypertension (mean baseline blood pressure 169/101 mmHg) received olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg (627 patients), olmesartan medoxomil/amlodipine 40/10 mg (628 patients), olmesartan medoxomil/hydrochlorothiazide 40/25 mg (637 patients), or amlodipine/hydrochlorothiazide 10/25 mg (600 patients). Each subject was randomized to one of the three dual therapy combinations for two to four weeks. Patients were then randomized to continue on the dual therapy they were receiving or to receive triple therapy. A total of 53% of patients were male, 19% were 65 years or older, 67% were white, 30% were black, and 15% were diabetic.

After 8 weeks of treatment, the triple combination therapy produced greater reductions in both systolic and diastolic blood pressures (p< 0.0001) compared to each of the 3 dual combination therapies. The full blood pressure lowering effects were attained within 2 weeks after a change in dose.

The seated blood pressure reductions attributable to the addition of a single high-dose drug to each high-dose dual drug combination are shown in Table 2.

Table 2 Additional blood pressure reductions on high-dose Tribenzor compared to high doses of dual combination drugs
Start on Adding BP reduction*
Olmesartan medoxomil 40 / amlodipine 10 mg HCTZ 25 mg8.4/4.5 mmHg
Olmesartan medoxomil 40 / HCTZ 25 mg Amlodipine 10 mg7.6/5.4 mmHg
Amlodipine 10 / HCTZ 25 mg Olmesartan medoxomil 40 mg8.1/5.4 mmHg

*all highly statistically significant.

There were no apparent differences in terms of seated diastolic blood pressure (SeDBP) or seated systolic blood pressure (SeSBP) reductions in black and non-black patients treated with Tribenzor [s ee Use in Specific Populations ( 8.8)].

There were no apparent differences in terms of SeDBP or SeSBP reductions in diabetic and non-diabetic patients treated with Tribenzor.

A total of 440 patients participated in the ambulatory blood pressure monitoring portion of the study. Over the 24-hour period, there was a greater reduction in diastolic and systolic ambulatory blood pressure for olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg compared to each of the dual combination therapies (see Figure 1 and Figure 2).

Figure 1 : Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour

Figure 1:	Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour
(click image for full-size original)

Figure 2 : Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour

Figure 2:	Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour
(click image for full-size original)

The blood pressure lowering effects of lower dose strengths of Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 20/5/12.5 mg, 40/5/12.5 mg, 40/10/12.5 mg, and 40/5/25 mg) have not been studied.

All of the dose strengths of the triple combination are expected to provide superior blood pressure lowering effects compared to their respective mono and dual combination components. The order of the blood pressure lowering effects among the different dose strengths of Tribenzor (olmesartan medoxomil /amlodipine /hydrochlorothiazide) is expected to be 20/5/12.5 mg < 40/5/12.5 mg < (40/10/12.5 mg ≈ 40/5/25 mg) < 40/10/25 mg.

There are no trials of Tribenzor demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tribenzor tablets contain olmesartan medoxomil, amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine, and hydrochlorothiazide in the strengths described below.

Tribenzor tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Tribenzor tablets are supplied for oral administration in the following strength and package configurations:

Tablet Strength (OM/AML equivalent/HCTZ) Package Configuration NDC# Product Code Tablet Color
20 /5 /12.5 mg Bottle of 30 Bottle of 90 10 blisters of 10 0713-0874-30 Not available Not available C51 Orange white
40 /5 /12.5 mg Bottle of 30 Bottle of 90 10 blisters of 10 0713-0875-30 Not available Not available C53 Light yellow
40 /5 /25 mg Bottle of 30 Bottle of 90 10 blisters of 10 0713-0876-30 Not available Not available C54 Light yellow
40 /10 /12.5 mg Bottle of 30 Bottle of 90 10 blisters of 10 0713-0877-30 Not available Not available C55 Grayish red
40 /10 /25 mg Bottle of 30 Bottle of 90 10 blisters of 10 0713-0878-30 Not available Not available C57 Grayish red

Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Pregnancy: Tell female patients of childbearing age about the consequences of exposure to Tribenzor during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] .

Lactation: Advise nursing women not to breastfeed during treatment with Tribenzor [see Use in Specific Populations (8.2)] .

Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, Tribenzor should be discontinued until the physician has been consulted. Tell patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope .

Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

Acute myopia and secondary angle-closure glaucoma: Advise patients to discontinue Tribenzor and seek immediate medical attention if they experience symptoms of acute myopia or secondary angle-closure glaucoma [see Warnings and Precautions (5.9)].

Marketed by Cosette Pharmaceuticals, Inc., South Plainfield, NJ 07080

8-TRIBCP1 Iss. 02/2022

PRINCIPAL DISPLAY PANEL

NDC 0713-0874-30

TRIBENZOR

(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets

20 mg/5 mg*/12.5 mg

30 Tablets

PRINCIPAL DISPLAY PANEL NDC 0713-0874-30 TRIBENZOR (olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets 20 mg/5 mg*/12.5 mg 30 Tablets Rx only
(click image for full-size original)

PRINCIPAL DISPLAY PANEL

NDC 0713-0875-30

TRIBENZOR

(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets

40 mg/5 mg*/12.5 mg

30 Tablets

PRINCIPAL DISPLAY PANEL NDC 0713-0875-30 TRIBENZOR (olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets 40 mg/5 mg*/12.5 mg 30 Tablets Rx only
(click image for full-size original)

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