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Tribenzor by is a Prescription medication manufactured, distributed, or labeled by Daiichi Sankyo Inc.. Drug facts, warnings, and ingredients follow.
Warnings and Precautions (5.6) 11/2016
Tribenzor is a combination of an angiotensin II receptor blocker, a dihydropyridine calcium channel blocker, and a thiazide diuretic indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1).
Limitations of Use
Tribenzor is not indicated for initial therapy.
Tablets: (olmesartan medoxomil/amlodipine/hydrochlorothiazide) 20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, 40 /10 /25 mg (3)
Most common adverse reactions (incidence ≥2%) are dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Olmesartan medoxomil (7.1):
Amlodipine (7.2):
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 7/2017
Tribenzor (olmesartan medoxomil, amlodipine, hydrochlorothiazide) is indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Tribenzor.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Limitations of Use
This fixed combination drug is not indicated for the initial therapy of hypertension.
Because of the hydrochlorothiazide component, Tribenzor is contraindicated in patients with anuria, hypersensitivity to any component, or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with Tribenzor in patients with diabetes [see Drug Interactions (7.2)].
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tribenzor as soon as possible [see Use in specific Populations (8.1].
Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with Tribenzor under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.
Amlodipine. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Impaired renal function was reported in 2.1% of subjects receiving Tribenzor compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartan medoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide.
If progressive renal impairment becomes evident consider withholding or discontinuing Tribenzor.
Olmesartan medoxomil Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Tribenzor due to the olmesartan medoxomil component [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with Tribenzor because of the olmesartan medoxomil component.
Hydrochlorothiazide. Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.
Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.
Tribenzor contains hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Tribenzor also contains olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.
The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
Hydrochlorothiazide. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Olmesartan medoxomil. Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Tribenzor in cases where no other etiology is identified.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
In the controlled trial of Tribenzor, patients were randomized to Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg), olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received Tribenzor for 8 weeks.
The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with Tribenzor 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 mg. The most common reason for discontinuation with Tribenzor was dizziness (1%).
Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to Tribenzor.
The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:
|Adverse Reaction
HCTZ25 mg
n (%)
AML10 mg
n (%)
n (%)
HCTZ25 mg
n (%)
|Edema peripheral
|44 (7.7)
|42 (7.0)
|6 (1.0)
|46 (8.3)
|37 (6.4)
|42 (7.0)
|38 (6.6)
|33 (6.0)
|24 (4.2)
|34 (5.7)
|31 (5.3)
|36 (6.5)
|20 (3.5)
|11 (1.8)
|20 (3.4)
|16 (2.9)
|Muscle spasms
|18 (3.1)
|12 (2.0)
|14 (2.4)
|13 (2.4)
|17 (3.0)
|12 (2.0)
|22 (3.8)
|12 (2.2)
|Upper respiratory tract infection
|16 (2.8)
|26 (4.4)
|18 (3.1)
|14 (2.5)
|15 (2.6)
|14 (2.3)
|12 (2.1)
|9 (1.6)
|Urinary tract infection
|14 (2.4)
|8 (1.3)
|6 (1.0)
|7 (1.3)
|Joint swelling
|12 (2.1)
|17 (2.9)
|2 (0.3)
|16 (2.9)
Syncope was reported by 1% of Tribenzor subjects compared to 0.5% or less for the other treatment groups.
Olmesartan medoxomil
Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.
The following adverse reactions occurred in <1% but >0.1% of patients in controlled clinical trials under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert physicians to a possible relationship:
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo
Gastrointestinal: anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia
General: allergic reaction, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease
Musculoskeletal System: arthralgia, arthrosis, muscle cramps*, myalgia
Psychiatric: sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization
Respiratory: dyspnea*, epistaxis
Skin and Appendages: angioedema, erythema multiforme, pruritus*, rash*, rash erythematous, rash maculopapular
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: dry mouth, sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Hemopoietic: leukopenia, purpura, thrombocytopenia
* = events that occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
The following adverse reactions occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other adverse reactions that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole: weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia
Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: hyperglycemia, glycosuria, hyperuricemia
Musculoskeletal: muscle spasm
Nervous System/Psychiatric: restlessness
Renal: renal failure, renal dysfunction, interstitial nephritis
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: transient blurred vision, xanthopsia
The following adverse reactions have been identified during post-approval use of the individual components of Tribenzor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:
Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema
Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions (5.10)]
Metabolic and Nutritional Disorders: hyperkalemia
Musculoskeletal: rhabdomyolysis
Urogenital System: acute renal failure, increased blood creatinine
Skin and Appendages: alopecia, pruritus, urticaria
Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).
The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.
Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.
Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or
aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Tribenzor and other agents that affect the RAS.
Do not co-administer aliskiren with Tribenzor in patients with diabetes [See Contraindications (4)]. Avoid use of aliskiren with Tribenzor in patients with renal impairment (GFR <60 ml/min).
Use with Colesevelam Hydrochloride
Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3)].
Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithium levels in patients receiving Tribenzor and lithium.
Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].
CYP3A Inhibitors
Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.
CYP3A Inducers
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.
When administered concurrently the following drugs may interact with thiazide diuretics:
Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.
Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single dose of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Non-steroidal Anti-inflammatory Drugs: In some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tribenzor as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Tribenzor, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Tribenzor for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].
It is not known whether amlodipine or olmesartan are excreted in human milk, but thiazides appear in human milk and olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Neonates with a history of in utero exposure to Tribenzor:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
The safety and effectiveness of Tribenzor in pediatric patients have not been established.
Tribenzor. In a controlled clinical trial, 123 hypertensive patients treated with Tribenzor were ≥65 years of age and 18 patients were ≥75 years of age. No overall differences in the efficacy or safety of Tribenzor were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out. The recommended initial dose of amlodipine in patients ≥ 75 years of age is 2.5 mg, a dose not available with Tribenzor.
There are no studies of Tribenzor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with Tribenzor [see Warnings and Precautions (5.5)].
Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function.
Olmesartan medoxomil. Increases in AUC0-∞ and peak plasma concentration (Cmax) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.
Hydrochlorothiazide. In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
There are no studies of Tribenzor in patients with renal impairment. Avoid use in patients with severe renal impairment (creatinine clearance <30 mL/min).
Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.
Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hydrochlorothiazide. Thiazide should be used with caution in patients with severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
There is no information on overdosage with Tribenzor in humans.
Olmesartan medoxomil. Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.
Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Hydrochlorothiazide. The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, more than 1000-fold the highest recommended human dose.
Tribenzor provided as a tablet for oral administration, is a fixed combination of olmesartan medoxomil (ARB), amlodipine (CCB), and hydrochlorothiazide (thiazide diuretic).
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
The olmesartan medoxomil component of Tribenzor is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C29H30N6O6.
The amlodipine besylate component of Tribenzor is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5C6H6O3S.
The hydrochlorothiazide component of Tribenzor is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2.
The structural formula for olmesartan medoxomil is:
The structural formula for amlodipine besylate is:
The structural formula for hydrochlorothiazide is:
Tribenzor contains olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder, amlodipine besylate, a white to off-white crystalline powder, and hydrochlorothiazide, a white or practically white, crystalline powder. The molecular weights of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are 558.6, 567.1, and 297.7, respectively. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.
Each tablet of Tribenzor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating contains polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), iron oxide red (20 /5 /12.5 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), and iron oxide black (20 /5 /12.5 mg tablets).
The active ingredients of Tribenzor target three separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium on cardiac and vascular smooth muscle cells; olmesartan medoxomil blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume. For a more detailed description of the mechanisms of action for each individual component, see below.
Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction catalyzed by ACE, kininase II. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. Angiotensin-converting enzyme inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.
Amlodipine. Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine 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.
Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Tribenzor has been shown to be effective in lowering blood pressure. The three components of Tribenzor (olmesartan medoxomil, amlodipine, and hydrochlorothiazide) lower the blood pressure through complementary mechanisms, each working at a separate site and blocking different effects or pathways. The pharmacodynamics of each individual component is described below.
Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.
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 oral 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 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive patients experienced no clinically significant change in blood pressures (+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 man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. 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.
Hydrochlorothiazide. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.
Drug Interactions
Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.
Skeletal muscle relaxants, non-depolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.
Tribenzor. After oral administration of Tribenzor in normal healthy adults, peak plasma concentrations of olmesartan, amlodipine, and hydrochlorothiazide are reached in about 1.5 to 3 hours, 6 to 8 hours, and 1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine, and hydrochlorothiazide from Tribenzor are the same as when administered as individual dosage forms. Food does not affect the bioavailability of Tribenzor.
Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the Cmax of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan medoxomil.
Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated between 64% and 90%.
Hydrochlorothiazide. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Olmesartan medoxomil. The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Amlodipine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Hydrochlorothiazide. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Metabolism and Excretion
Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Amlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine.
Hydrochlorothiazide. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Specific Populations
Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCѕѕ, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Amlodipine. Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%, and a lower initial dose may be required.
Population pharmacokinetic analysis indicated that gender had no effect on the clearance of olmesartan and amlodipine. Female patients had approximately 20% smaller clearances of hydrochlorothiazide than male patients.
Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. Area under the curve and Cmax were 10% to 15% higher in women than in men.
Renal Insufficiency
Olmesartan medoxomil. In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied.
Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hepatic Insufficiency
Olmesartan medoxomil. Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Amlodipine. Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
Heart Failure
Amlodipine. Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
Drug Interactions
Simvastatin: Co-administration 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 [see Drug Interactions (7.2)].
CYP3A inhibitors: Co-administration 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 co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7.2)].
Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed in the presence of amlodipine [see Drug Interactions (7.2)].
Colesevelam: Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7.1)].
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration 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): Co-administration 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: Co-administration 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: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
No significant drug interactions were reported in studies in which olmesartan medoxomil was coadministered with digoxin in healthy volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time. No significant drug interactions were reported in studies in which olmesartan medoxomil was coadministered with warfarin in healthy volunteers.
Antacids: The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2].
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.
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/m2 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/m2 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/m2 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/m2 basis, similar to the MRHD of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m2 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/m2 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/m2 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 Drosophilla 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 Aspergillus 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/m2 basis. (Calculations based on a 60 kg patient.)
No reproductive 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, and olmesartan medoxomil and hydrochlorothiazide together.
Olmesartan medoxomil. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
Olmesartan medoxomil and Hydrochlorothiazide. No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the MRHD on a mg/m2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 times the MRHD on a mg/m2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m2 basis, the MRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.)
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 maximum recommended human dose of 10 mg amlodipine on a mg/m2 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) in 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 gestational 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.
Hydrochlorothiazide. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
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.
|Start on
|BP reduction*
|Olmesartan medoxomil 40 /
amlodipine 10 mg
|HCTZ 25 mg
|8.4/4.5 mmHg
|Olmesartan medoxomil 40 /
HCTZ 25 mg
|Amlodipine 10 mg
|7.6/5.4 mmHg
|Amlodipine 10 /
HCTZ 25 mg
|Olmesartan medoxomil 40 mg
|8.1/5.4 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 [see 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 2: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour
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.
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
|Product Code
|Tablet Color
|20 /5 /12.5 mg
|Bottle of 30
Bottle of 90
10 blisters of 10
|Orange white
|40 /5 /12.5 mg
|Bottle of 30
Bottle of 90
10 blisters of 10
|Light yellow
|40 /5 /25 mg
|Bottle of 30
Bottle of 90
10 blisters of 10
|Light yellow
|40 /10 /12.5 mg
|Bottle of 30
Bottle of 90
10 blisters of 10
|Grayish red
|40 /10 /25 mg
|Bottle of 30
Bottle of 90
10 blisters of 10
|Grayish red
Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF) [see USP Controlled Room Temperature].
See FDA-Approved Patient Labeling
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.
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.
FDA-Approved Patient Labeling
Patient Information
Tribenzor (TRY-BEN-ZOR)
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) Tablets
Read the Patient Information that comes with Tribenzor before you take it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.
What is the most important information I should know about Tribenzor?
What is Tribenzor?
Tribenzor is a prescription medicine used to lower blood pressure (hypertension). Medicines that lower blood pressure lower your chance of having a stroke or heart attack. Tribenzor is not for use as the first medicine to treat your high blood pressure.
Tribenzor contains 3 different prescription medications:
It is not known if Tribenzor is safe and works in children.
Who should not take Tribenzor?
Do not take Tribenzor if you:
What should I tell my doctor before taking Tribenzor?
Before taking Tribenzor, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some of your other medicines and Tribenzor could affect each other, causing serious side effects.
Especially tell your doctor if you are taking:
Know the medicines you take. Keep a list of your medicines and show it to your doctor or pharmacist when you get a new medicine.
How should I take Tribenzor?
What should I avoid while taking Tribenzor?
Drinking alcohol. Drinking alcohol during treatment with Tribenzor can cause you to have low blood pressure. See "What are the possible side effects of Tribenzor?"
What are the possible side effects of Tribenzor?
Tribenzor may cause serious side effects, including:
The most common side effects of Tribenzor used to treat people with high blood pressure include:
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all of the possible the side effects of Tribenzor. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effect to the FDA at 1-800-FDA1088.
How do I store Tribenzor?
General Information about Tribenzor
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Tribenzor for a condition for which it was not prescribed. Do not give Tribenzor to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Tribenzor. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tribenzor that is written for health professionals. For more information go to www.Tribenzor.com or call 1-877-437-7763.
What are the ingredients in Tribenzor?
Active ingredients: olmesartan medoxomil, amlodipine, and hydrochlorothiazide
Inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating contains polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), iron oxide red (20 /5 /12.5 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), and iron oxide black (20 /5 /12.5 mg tablets).
What is high blood pressure (hypertension)?
Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much.
High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. Tribenzor can help your blood vessels relax so your blood pressure is lower.
Manufactured for Daiichi Sankyo, Inc., Basking Ridge, NJ 07920
Manufactured by Daiichi Sankyo Europe GmbH, Germany
Copyright © Daiichi Sankyo, Inc. 2017. All rights reserved.
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets
20 mg/5 mg* 12.5 mg
30 Tablets
Rx Only
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets
40 mg/5 mg* 12.5 mg
30 Tablets
Rx Only
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets
40 mg/5 mg* 25 mg
30 Tablets
Rx Only
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets
40 mg/10 mg* 12.5 mg
30 Tablets
Rx Only
(olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets
40 mg/10 mg* 25 mg
90 Tablets
Rx Only
olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide tablet, film coated
olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide tablet, film coated
olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide tablet, film coated
olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide tablet, film coated
olmesartan medoxomil / amlodipine besylate / hydrochlorothiazide tablet, film coated
|Labeler - Daiichi Sankyo Inc. (068605067)


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A spokesman for Casey Kasem's daughter says the famous radio host's unburied body remains at a funeral home in Tacoma, Washington, a month after his death.
Danny Deraney, publicist for Kerri Kasem, says Kasem's children from his first marriage hope he will be buried at Forest Lawn cemetery in Glendale, California, as he wished.
Kasem died June 15 at a hospital in Washington state. Deraney says the celebrity's second wife, Jean Kasem, has the rights to his body but has not yet arranged for him to be buried.
U.S. & World
Stories that affect your life across the U.S. and around the world.
Hospital spokesman Scott Thompson with St. Anthony Hospital says Kasem's wife collected his remains from the hospital after he died, but Thompson did not know what arrangements she made.
A call to Jean Kasem's attorney was not immediately returned Tuesday.

subset: commoncrawl


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68 Posts
Discussion Starter • #1 •
Has anyone seen any research studies on chalkbrood resistance? From what I understand, there are bees that seem to show good resistance to chalkbrood. Is this because the larva are more resistant to the spores or is it related to hygienic behavior of the nurse bees? Maybe both? Any thoughts?


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Academy flight training craft were types of spacecraft flown by Starfleet Academy cadets.
A type of sublight vessel was flown in the 2360s by such groups as Nova Squadron, who in 2368 attempted a highly dangerous, banned (as of the 2260s) five craft formation, the Kolvoord Starburst maneuver, near Titan. (TNG: "The First Duty")
The Academy cadet ships were small, one-pilot, blunt-winged vessels, with a fairly flat cross-section; pilots had to wear flight helmets. The craft were equipped with landing struts, proximity alarms, and emergency transporters.
Warp-capable Federation attack fighter-type flight trainer schematics were part of an information download package aboard the USS Voyager. When One was assimilating as much information as he could, the flight trainer could be seen on a screen he was learning from. It was later seen when Seven used a new device on her Borg alcove to upload information directly into her brain. (VOY: "Drone", "The Voyager Conspiracy")
- TNG: "The First Duty"
- "Favor the Bold" (display graphic)
- "Sacrifice of Angels" (display graphic)
- "Tears of the Prophets" (display graphic)
- "Drone" (display graphic)
- "The Voyager Conspiracy" (display graphic)
- "Life Line" (display graphic)
Background information
Two versions of the Academy flight trainer have appeared on screen. The actual, original ships seen in "The First Duty" and the side view of the Federation attack fighter, first (and only) seen as an okudagram in "Drone". The port profile of the vehicle was created by Doug Drexler and appeared in the Star Trek Encyclopedia (4th ed., vol. 1, p. 9), accompanying the main entry "Academy Flight Range". The craft bore the registry SFA-TR4707. On page 483 of the first volume, this particular vehicle was identified as "Locarno's Academy Trainer" and accompanied the main entry "Locarno, Cadet First Class Nicholas".
The Academy's space force consisted of at least three academy training wings headed by wing commanders. The wings were divided further into squadrons commanded by squadron leaders. For example, the Third Academy Training Wing was commanded by Captain David Livingston. The Falcon Squadron, commanded by Captain Brad Yacobian, was assigned to this training wing. The operations of these wings were managed by Academy Flight Ops. Pilots who successfully completed their training were awarded the Flight Proficiency Award. [1]
Studio model
The original flight trainer, merely described as "five small SHIPS of the Nova Squadron" in scene 18 of the script, and simply referred to as a "Trainer craft" by its designer, was designed and signed off on in January 1992 by Senior Illustrator Rick Sternbach. [2] A studio model was actually built by Gregory Jein but was only seen in two brief scenes and used only in "The First Duty". "Greg Jein built a physical miniature about 14" in length. There was no major CG version that I know of aside from five tiny diagramatic ships (...)", Sternbach remarked. [3] The otherwise indiscernible symbol in front of the cockpit was that of Cobra from the G.I. Joe franchise, which Jein, a fan, added as a subtle homage. [4](X)
A copy of the model, made by Jein for Sternbach and painted and detailed by the latter, along with five of Sternbach's sketches of the design, was later offered as Lot 298 in the The Ultimate Sci-Fi Auction of 26 April 2003, estimated at US$800-$1,200, where it sold for US$900.
The original studio model itself, having escaped the 40 Years of Star Trek: The Collection and It's A Wrap! sale and auctions, is still in the possession of CBS Consumer Products and has been on tour as a display piece, starting with the Star Trek: The Adventure tour [5], and subsequently appearing in the Star Trek The Exhibition tour, as late as 2012. [6] Worn from years on the tours, the model was by CBS remitted into the care of ILM modeler John Goodson for some much needed restoration in 2015. [7]
The Federation attack fighter standing in for the trainer in the Encyclopedia may well have stemmed from the fact that the flight trainer was mostly depicted as a computer graphic in the episode and that it was either forgotten, or not realized by the authors due to its very brief appearance that a model had actually been built. "There was some editorial confusion over which little ship was the trainer," Sternbach conceded in 2013. [8]
External Link
- Academy flight trainer at Memory Beta, the wiki for licensed Star Trek works


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Thank you for your interest in Pillowcapers.
Yankee Peddler is deeply committed to protecting the privacy of children online. We conform with the COPPA laws and we do not knowingly collect personal information from children under 13 years of age. If you believe we may have inadvertently collected information from your child, please contact us and we will work to delete it.


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For Release in Greater China: September 2013
Release Number: 484PR13
The Cat® M300D Series German designed Wheeled Excavator models—M313D and M315D—have earned a solid reputation worldwide for reliable performance, long-term durability, versatility, fuel efficiency and low operating costs. Recent engineering updates have further strengthened these qualities with refinement of the operator's station. The new models provide a more-flexible design providing a new short boom option for ease of operation in tight jobsites, greater operator comfort with improved visibility, and reduced potential down time linked to serviceability. The new nomenclature highlights the change to this new wheeled excavator generation and is now based on the machines' weight.
Cab refinements. Simplicity and functionality.
New for the M315D2 and M317D2 is the operator station that adds increased comfort and visibility, while preserving the same sound levels, room and ergonomic layout of controls for ease of operation. The new design allows for better visibility with a new windshield and a larger skylight providing upward visibility, convenient for truck loading applications. In addition, our machines provide excellent lighting all shift long thanks to several halogen lights, a rain protector and wipers covering the entire surface of the windscreen for an easier operation when working in poor weather conditions. The front windscreen offers the possibility of storing the upper portion above the operator and is easy to release.
Accessibility to be cabin remains convenient with several well positioned handrails making ingress / egress easy, as well as anti-skid plates on top of all the steps to reduce slipping hazards.
The M315D2 and M317D2 will provide you with all the comfort you expect from a Cat machine. Several seat options give your operator the comfort they need for a long day of work and include full adjustment of all parts of the seat with lumbar support and weight adjustment. Our cabs are spacious and feature several large storage compartments. The automatic climate control further enhances this feeling in all climates with easy adjustment of the cab temperature with filtered ventilation.
Our cab has been designed with the operator in mind, focusing on the importance of an ergonomic layout, with centralized and easy to use controls. The large color LCD monitor is easy to read in the local language and keeps the operator aware of any important information. It is easy to navigate through the various menus and the tool select function (optional) lets you preset up to ten different hydraulic attachments for quick tool changes. The monitor allows managing the standard rear-view camera via quick-access buttons.
New boom, wide range of attachments and configurations for optimum flexibility and versatility.
Cat wheeled excavators are versatile by nature. Whether you operate in road construction, sewer and water or building construction, they are designed to make a significant contribution to the success of your business.
The M315D2 and M317D2 now offer you the choice between three boom options and four stick options. A new One-Piece boom will be available and will provide easy operation, especially when working in small areas where working close to the machine is necessary. The other One-Piece boom is still available and allows a better reach and digging depth, when there are no space constraints. One-piece booms fit best for all standard applications such as truck loading or digging. To make sure our wheeled excavators do fit all your applications' needs, we also offer a Variable Adjustable (VA) Boom, which improves right side visibility and roading balance. When working in tight quarters or lifting heavy loads, the VA Boom offers the best flexibility.
Our wheeled excavators allow you to reduce travel times between jobsites and therefore transportation costs by offering a high travel speed (up to 37kph). You can work on dirt or on roads, without damaging them. They are also excellent utility machines and will let you save time whenever you need to move material or items inside your jobsite. You can configure your machine with a blade for increased stability and dozing application and/or outriggers.
Cat work tools are designed to function as an integral part of the excavator and are performance-matched to Cat machines. Wheeled excavators are flexible. They offer a wide range of attachments like quick couplers, various specialized buckets, hammers, multi-grapples, vibratory plate compactors and shears to facilitate all the various jobs at hand.
Technologies, Fleet management, Serviceability
Cat wheeled excavators are designed to make maintenance quick and easy. The new design includes a new filtration system, perfectly suited for operations in challenging work conditions, even when using poor fuel quality. The new filter offers increased filtration capabilities and works in conjunction with a water separator. All daily maintenance can be done from ground level to enhance safety and maintenance points are kept centralized to reduce downtimes. Greasing points are grouped and very accessible for hard to reach locations. Cat wheeled excavators feature extended service intervals to further reduce your costs. Two large toolboxes allow you to keep all your tools and greasing devices at hand. A refueling pump is also available to allow you save time.
Product Link helps you take the guesswork out of equipment management.
The M315D2 and M317D2 can be equipped with the Cat Product Link™ system, which is deeply integrated into machine systems. With timely, useful information, you can better manage your assets and costs. Just a few clicks gives you access to comprehensive remote monitoring, asset tracking and maintenance management. The powerful, web-based VisionLink® application allows you to see information from all your assets – working time vs. idle time, fuel usage, diagnostic fault codes, security alerts and more. When you know where your equipment is, what it's doing and how it's performing, you can maximize your efficiency and lower your operating costs. It pays to know Cat Product Link.
The Cat Machine Security System (MSS) is another asset-management tool available as an option. The MSS, which uses special keys with an electronic chip, controls who can operate the machine and when.
Machine Specifications
Cat C4.4
Cat C4.4
Net Power (hp/kW)
Weight (lb/kg)
33,300/15,200 (13,500 – 15,200)
37,900/17,200 (15,000-17,200)
Max. Dig Depth (ft/mm)
Max. Bucket Capacity (yd³/m³)
1.20/0.9 (0.76m^3)
1.65/1.26 (0.91m^3)
Max. Speed (mph/kph)
# # #
Note to Editors: Caterpillar rolls-out products and services in each of its territories at different time intervals. Although every effort is made to ensure that product information is released only after Caterpillar has received confirmation from our dealer network, our plants, and our marketing subsidiaries that products and services are available in the relevant region, editors are kindly requested to verify with their local dealer for product availability and specifications.
Press Inquiries
Cat Trade Press Media Representatives
Sharon Holling: email@example.com
Europe, Africa, Middle East
Francine Shore: email@example.com
General Email: email@example.com
Reader Requests


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All News Releases By Date
EPA Responds To Pipeline Spill Near Lockport, Illinois
Release Date: 12/14/2010
Contact Information: Anne Rowan, 312-353-9391, firstname.lastname@example.com
No. 10-OPA151
Chicago, Ill. (December 14, 2010) - Earlier today, U.S. EPA responded to an oil release from a pipeline near Lockport, Ill. Although the spill appears to be largely contained, EPA will continue around-the-clock operations to clean up the affected area.
EPA is working closely with local and state responders to assess the spill's impact on nearby wetlands. The Agency is also monitoring air quality to assess any potential impacts on the health and safety of workers and residents.
In addition, EPA today issued a Notice of Federal Interest to the pipeline operator, Buckeye Partners, L.P. The pipeline is owned by West Shore Pipe Line Co.
At approximately 7 a.m. this morning, local fire officials received a complaint about petroleum odors. Buckeye shut down the pipeline by 8 a.m. Early estimates indicate that 21,000 gallons of oil may have been released as a result of the spill.
Search this collection of releases | or search all news releases
View selected historical press releases from 1970 to 1998 in the EPA History website.


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Cigar Galaxy – Messier 82
The Cigar Galaxy, also known as Messier 82 (M82), is a famous nearby starburst galaxy located in the constellation Ursa Major. M82 appears edge-on when seen from Earth. It has five times the luminosity of the Milky Way and lies at an approximate distance of 11.5 million light years. The galaxy's designation in the New … [Read more…]


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During the day, you cross a rich and varied city environment overrun by a vicious outbreak, scavenging the world for supplies and crafting weapons to defend against the growing infected population.
At night, the hunter becomes the hunted, as the infected become aggressive and more dangerous. Most frightening are the predators which only appear after sundown. You'll need to use everything in your power to survive until the morning's first light.
Take advantage of powerful weapons and traps set by other survivors to stay ahead of the infected and other desperate humans. Then use your vast and diverse surroundings to plot a savage attack or frantic escape. As the infected grow in strength from day to night, will you hide in the darkness and provoke vicious enemies to attack each other? Or go for an all-out assault using whatever tools you can find?
1 Players
Vibration Function
Remote Play
2-5 Network Players
See it in action


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Kambara implexidens
Kambara implexidens, from the early Eocene of Queensland, was a mekosuchine, an ancient group of primitive Gondwanan crocodiles. Species of Kambara are the most well known crocodiles from the Paleocene to Oligocene of Australia, as well as the oldest mekosuchines. Two closely related species of Kambara were found at Murgon in southeastern Queensland.
Mekosuchines are distinguished by a large size differential between the alveoli of the largest to smallest teeth, development of a wedge of the supraoccipital bone on the top of the skull, and reduction or loss of the anterior process of the palatines (from Willis 2006).
Species of Kambara were broad-snouted (platyrostral) mekosuchines with this disparity in size between teeth. Kambara also had distinctive sculpturing (large sculptured pits between the eyes and the supratemporal fenestrae), and a deep excavation in the skull in front of the nostrils. Kambara implexidens had large eyes (orbits) and an unusual, interlocking dentition (its species name comes from the Latin implexus, meaning 'interlocking or entwined'; and dens, meaning 'tooth'). Kambara implexidens differs from the similar Kambara murgonensis mainly in the way the teeth occlude: interlocking in Kambara implexidens and non-interlocking (an 'overbite') in Kambara murgonensis.
The Murgon fossil site during the early Eocene was a shallow swamp or lake. The vegetation and climate of the period have not yet been determined.
Kambara implexidens in known only from Murgon, southeastern Queensland. A second species of Kambara, Kambara murgonensis, was also found at Murgon although these two species may not have lived at the same time. There may be a third species of Kambara, with a longer snout, from Rundle in eastern Queensland.
Feeding and diet
Kambara species were generalist feeders. Kambara implexidens, like other crocodiles, would have fed on small vertebrates such as mammals, turtles, snakes and fish (all of which are known from the Murgon fossil site).
Life history cycle
Crocodiles and alligators (living Crocodylia) are the largest living reptiles, the only truly large reptiles apart from the Komodo Dragon to have survived to the present. Most crocodiles and alligators are restricted to tropical or subtropical regions today. The Cretaceous and Eocene crocodiles of Australia, however, lived in areas that at the time were cooler and more temperate.
Living Crocodylia are all semi-aquatic predators that lay eggs and live close to water. Hatchlings and eggshell fragments of one or both species of Kambara have been found at Murgon, suggesting that Murgon might have been a crocodile nesting ground during the Eocene.
Fossils description
Kambara implexidens is represented by a nearly complete skull (missing the posterior part of the quadrate bones and part of the palate), a second partial skull, a dentary possibly belonging to the holotype skull, a second lower jaw (partial mandible), and other referred cranial/dentary fragments. Most of the material appears to have been of large adult individuals. All material is held by the Queensland Museum, Brisbane.
Evolutionary relationships
Crocodiles are an ancient group of archosaurs, first appearing in the fossil record in the Late Triassic over 200 million years ago. The oldest 'modern' crocodile (Eusuchia) may be Isisfordia duncani, from the middle Cretaceous of Queensland. Mekosuchines are an endemic radiation of primitive Gondwanan crocodiles. Mekosuchine fossils are known from Australia and the southwestern Pacific, and there were many unusual types. The oldest mekosuchines are the Eocene Kambara species. Mekosuchines became extinct during the Pleistocene in Australia but survived much longer in New Caledonia and Vanuatu (almost to the present).
Relationships between mekosuchines and living crocodiles, all within the Crocodyloidea, are unclear. Mekosuchines may be members of Crocodylidae but alternatively may belong to their own family. 'Mekosuchinae' may in fact not be a natural group; it has been suggested that Harpacochampsa camfieldensis is instead closer to Crocodylidae (Salisbury and Willis 1996). The ancestors of mekosuchines might have reached Australia via South America, although fossil evidence for this is lacking.
Kambara murgonensis and Kambara implexidens have both been found in what appears to be the same stratigraphic horizon. This suggests that they co-existed together (i.e., were sympatric). This would be unusual in crocodiles, since they are normally quite territorial. However, it is also possible that these species might be from different time periods and that the Murgon clays are not well sorted stratigraphically. The depositional environment suggests that the waterbody might have been ephemeral at times, and these two crocodile species may have been forced together as the pond or billabong dried up.
- Molnar, R. E. 1991. Fossil reptiles in Australia. Pp. 605-701 in Vickers-Rich, P., Monaghan, J. M., Baird, R. F. and Rich, T. H. (eds) Vertebrate Palaeontology of Australasia. Pioneer Design Studio and Monash University Publications Committee, Melbourne.
- Nesbitt, S. The anatomy of Effigia okeeffeae (Archosauria, Suchia), theropod-like convergence, and the distribution of related taxa. Bulletin of the American Museum of Natural History 302, 1-84.
- Salisbury, S. W. and Willis, P. M. A., 1996. A new crocodilian from the Early Eocene of southeastern Queensland and a preliminary investigation of the phylogenetic relationships of crocodyloids. Alcheringa 20, 179-226.
- Salisbury, S., Molnar, R. E., Frey, E. and Willis, P. M. A. 2006. The origin of modern crocodyliforms: new evidence from the Cretaceous of Australia. Proceedings of the Royal Society B: Biological Sciences 273, 2439-2448.
- Willis, P. M. A., Molnar, R. E. and Scanlon, J. D. 1993. An early Eocene crocodilian from Murgon, southeastern Queensland. Kaupia Darmstädter Beiträge zur Naturgeschichte 3, 25-32.
- Willis, P. 2006. Evolution and zoogeography of Australasian crocodilians. Pp. 331-348 in Merrick, J. R., Archer, M., Hickey, G. M. and Lee, M. S. Y. (eds) Evolution and Biogeography of Australasian Vertebrates. Australian Scientific Publishing, Oatlands.
Further reading
- Kelly, L. 2007. Crocodile: Evolution's Greatest Survivor. Allen and Unwin, Sydney.


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Road crews tear down Mayan pyramid to make gravel
Belizean police are investigating a construction company that has destroyed most of one of the largest Mayan pyramids in the Caribbean nation to make gravel to dump on village roads, according to reports from the Caribbean.
Archaeologists and a local TV station witnessed the destruction Friday as bulldozers and excavators continued to demolish the 60-foot-tall main temple at Nohmul -- "great mound" -- one of the tallest structures in northern Belize, along the Mexican border in the Yucatan Peninsula.
"We can't salvage what has happened out here," John Morris, of the Institute of Archaeology, told 7 News Belize. "It is an incredible display of ignorance. I am appalled."
A news crew was threatened by a man with a machete as dump trucks hauled away rock and limestone from the temple, which has been "whittled down to a narrow core," the TV station said.
A Caterpillar excavator was photographed tearing down what was left of the limestone-rich ruins.
"It's like being punched in the stomach, it's just so horrendous," Jamie Awe, head of the institute, told the Associated Press. "These guys knew that this was an ancient structure. It's just bloody laziness."
The pre-Colombian site is about 2,500 years old and consists of twin ceremonial clusters surrounded by 10 plazas and connected by a raised causeway. Mayans used stone tools to quarry the rock and build the complex by hand. An estimated 40,000 people are believed to have lived there between 500 and 250 BC.
The complex, which was first recorded by Europeans in 1897, covers about 12 square miles in the middle of a privately owned sugar cane field in the Orange Walk district. All pre-Hispanic ruins are protected by federal law.
Police stopped the excavation. They are investigating the landowner and D-Mar Construction and said criminal charges are possible. The company owner, Denny Grijalva, a legislative candidate, told the TV station "he knew nothing about the project" and directed reporters to his foreman. Neither answered any follow-up questions.


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Create an Account - Increase your productivity, customize your experience, and engage in information you care about.
Shorebird Marsh
Swing on Muzzi Marsh
Low Canal in Town Park
Marsh Walking Path
High Canal
View of Mt. Tam from Marsh
Muzzi Marsh
View of Mt. Tam
Corte Madera Marsh
Old Morte Madera Square
Tamalpais Drive
Piccolo Pavillion
Corte Madera - Larkspur Walking Path
Piccolo Pavilion


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Disposable razors are the ultimate throwaway. Two billion of them are sold and tossed every year in the U.S. alone, along with the paper and plastic packaging they come in. So shifting your spending to one of the many green and ultimately money-saving options is something of a no-brainer.
What to look for when you shop:
Rechargeable electric razor. Rechargeables can be expensive to purchase initially, but their long life usually warrants the up-front cash outlay. If you recharge them using a solar charger, you reduce the amount of energy they use considerably. Unlike other models, the Braun Pulsonic Shaver contains no cadmium, lead or mercury in its components. Its Smart Plug technology has earned it an Energy Star rating for energy efficiency from the U.S. Environmental Protection Agency. NOTE: Though an electric razor does use electricity, it reduces the amount of trash you toss since you don't discard empty shaving cream cans or soap boxes every few weeks.
A straight razor uses no energy other than your own, but be careful! Keep a box of band aids at the ready. You can reduce scratches by sharpening your razor on a stone. In place of shaving cream, many men use a shaving brush and soap they can lather in a dish or jar, for a very low cost, low-tech approach. (NOTE: You probably can't take the straight razor on an airplane. If you travel a lot, you will still need an electric razor or a reusable razor with disposable blades. If you use a reusable razor but disposable blades, consider a "razor saver." This little gadget sharpens blades so you can extend their life from the normal 5-10 shaves per blade to 130!
If you absolutely must use a disposable, choose one like Recycline. The handle is made from recycled plastic and can be recycled in any community that allows recycling for #5 plastics.
Get more eco-friendly personal care tips here.


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2013-2014 Wyatt Lecture Series
Appalachian State University
Andrea Burns
"'A Place Unique in All the World': The Making and Unmaking of Autoworld"
Friday, February 21, 2014
Happenings, UCEN
Andrea A. Burns received her B.A. in History from Michigan State University, and her Ph. D. in History from the University of Minnesota in 2008. She is currently an assistant professor of public history at Appalachian State University in Boone, North Carolina. She recently transformed her dissertation into a book, entitled "From Storefront to Monument: Tracing the Public History of the Black Museum Movement" (University of Massachusetts Press, 2013). Andrea lived in Flint for over twenty years with her family, and graduated from Powers Catholic High School.
Peter Morris
"How Baseball Became America's National Pastime and Michigan's Game"
Friday, March 14, 2014
4:00-6:00 p.m.
Happenings, UCEN
Peter Morris of Haslett, Michigan, is the award-winning author of Baseball Fever: Early Baseball in Michigan, A Game of Inches: The Stories Behind the Innovations that Shaped the Game, and five other critically acclaimed books about baseball's early history. Peter is well-known for his research with the Society for American Baseball Research (SABR) Biographical Research Committee. In addition he has won the SABR Henry Chadwick Award and has twice won the Seymour Medal.
University of Texas at San Antonio
Andrew Highsmith
"Re-Thinking the Narrative of Corporate Abandonment: General Motors and the Politics of Metropolitan Capitalism in Flint, Michigan"
Tuesday, October 22, 2013
4:00-6:00 p.m.
Happenings, UCEN
Andrew Highsmith is Assistant Professor of Public Administration at the University of Texas at San Antonio. His scholarly work focuses on social inequality and metropolitan development in modern American history. He received his Ph. D. in U.S. history from the University of Michigan-Ann Arbor in May 2009. Highsmith's dissertation, "Demolition Means Progress: Race, Class, and the Deconstruction of the American Dream in Flint, Michigan," won the 2009 John Reps Prize for Best Dissertation in American Planning History from the Society for American City and Regional Planning History and the Urban History Association's Best Dissertation Award for 2009. Highsmith is also the auther of Demolition Means Progress: Flint, Michigan, and the Fate of the American Metropolis, a forthcoming book from the University of Chicago Press (2014). His most recent pulbication, "Prelude to the Subprime Crash: Beecher, Michigan, and the Origins of the Suburban Crisis," appeared in the Journal of Policy History in October 2012. A former resident of Flint's Mott Park neighborhood, Highsmith now lives in Braunfels, Texas, with his wife and their three children.