Fu Ao Tan

Each film-coated tablet contains Olmesartan Medoxomil (Fu Ao Tan) 20 mg or 40 mg and Hydrochlorothiazide (Fu Ao Tan) 12.5 mg, or Olmesartan Medoxomil (Fu Ao Tan) 40 mg combined with hydrochlorthiazide 25 mg. It also contains the following excipients: Hydroxupropylcellulose, hypromellose, lactose low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide and yellow iron oxide.

Fu Ao Tan is a combination of an angiotensin II receptor antagonist (AT₁ subtype), Olmesartan Medoxomil (Fu Ao Tan) and a thiazide diuretic, Hydrochlorothiazide (Fu Ao Tan) (HCTZ).

Olmesartan Medoxomil (Fu Ao Tan), a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. It is 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.

Olmesartan Medoxomil (Fu Ao Tan) is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.6. It is practically insoluble in water and sparingly soluble in methanol.

Hydrochlorothiazide (Fu Ao Tan) is 6-chloro-3,4-dihydro-2H-1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide.

Its empirical formula is C₇H₈ClN₃O₄S₂.

Hydrochlorothiazide (Fu Ao Tan) is a white or practically white, crystalline powder with a molecular weight of 297.7.

It is slightly soluble in water but freely soluble in sodium hydroxide solution.

Fu Ao Tan tablets are indicated for the treatment of hypertension, to lower blood pressure. Fu Ao Tan tablets are not indicated for the initial therapy of hypertension.

​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 Fu Ao Tan tablets.

​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.

Fu Ao Tan tablets may be used alone, or in combination with other antihypertensive drugs.

Usual Recommended Starting Dose: 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose may be increased to 40 mg. Doses >40 mg do not appear to have greater effect. Twice daily dosing offers no advantage over the same total dose given once daily.

No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (CrCl <40 mL/min) or with moderate to marked hepatic dysfunction. For patients with possible depletion of intravascular volume (eg, patients treated with diuretics, particularly those with impaired renal function), Olmetec should be initiated under close medical supervision and consideration should be given to use of a lower starting dose.

Hydrochlorothiazide (Fu Ao Tan) is effective in doses between 12.5 mg and 50 mg once daily.

The side effects of Olmetec are generally rare and independent of dose; those of Hydrochlorothiazide (Fu Ao Tan) are most typically dose-dependent (primarily hypokalemia). Some dose-independent phenomena (eg, pancreatitis) do occur with Hydrochlorothiazide (Fu Ao Tan). Therapy with any combination of Fu Ao Tan will be associated with both sets of dose-independent side effects.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

Replacement Therapy: Fu Ao Tan may be substituted for its titrated components.

Dose Titration by Clinical Effect: A patient whose blood pressure is inadequately controlled by Olmetec or Hydrochlorothiazide (Fu Ao Tan) alone may be switched to once daily Fu Ao Tan.

Dosing should be individualized. Depending on the blood pressure response, the dose may be titrated at intervals of 2-4 weeks.

If blood pressure is not controlled by Olmetec alone, Hydrochlorothiazide (Fu Ao Tan) may be added starting with a dose of 12.5 mg and later titrated to 25 mg once daily.

If a patient is taking Hydrochlorothiazide (Fu Ao Tan), Olmetec may be added starting with a dose of 20 mg once daily and titrated to 40 mg, for inadequate blood pressure control. If large doses of Hydrochlorothiazide (Fu Ao Tan) have been used as monotherapy and volume depletion or hyponatremia is present, caution should be used when adding Olmetec or switching to Fu Ao Tan as marked decreases in blood pressure may occur. Consideration should be given to reducing the dose of Hydrochlorothiazide (Fu Ao Tan) to 12.5 mg before adding Olmetec. The antihypertensive effect of Fu Ao Tan is related to the dose of both components over the range of 10 mg/12.5 mg to 40 mg/25 mg. The dose of Fu Ao Tan is 1 tablet once daily. More than 1 tablet daily is not recommended.

Fu Ao Tan may be administered with other antihypertensive agents.

Renal Impairment: The usual regimens of therapy with Fu Ao Tan may be followed provided the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Fu Ao Tan is not recommended.

Hepatic Impairment: No dosage adjustment is necessary with hepatic impairment.

Hypersensitivity to Olmesartan Medoxomil (Fu Ao Tan), Hydrochlorothiazide (Fu Ao Tan) or to other sulfonamide-derived substances and to any of the excipients of Fu Ao Tan.

Patients with anuria, because of the Hydrochlorothiazide (Fu Ao Tan) component.

Patients who become pregnant should discontinue the use of Olmesartan Medoxomil (Fu Ao Tan)/Hydrochlorothiazide (Fu Ao Tan) as soon as possible unless no alternative to a drug acting on the renin-angiotensin system can be found.

Do not co-administer aliskiren with Olmesartan Medoxomil (Fu Ao Tan)/Hydrochlorothiazide (Fu Ao Tan) in patients with diabetes.

Use in pregnancy: There is no experience with the use of Fu Ao Tan in pregnant women. Studies in mice and rats using Olmesartan Medoxomil (Fu Ao Tan)/Hydrochlorothiazide (Fu Ao Tan) combinations do not indicate a teratogenic effect, but fetotoxicity has been shown in rats. Thiazides cross the placental barrier and appear in cord blood. They may cause fetal electrolyte disturbances and possible other reactions that have occurred in adults. Cases of neonatal thrombocytopenia, or fetal or neonatal jaundice have been reported with maternal thiazide therapy.

If pregnancy occurs during therapy, Fu Ao Tan must be discontinued as soon as possible.

General: Other Antihypertensive Agents: The blood pressure-lowering effect of Fu Ao Tan can be increased by concomitant use of other antihypertensive medications.

Olmesartan Medoxomil (Fu Ao Tan): Use with Aliskiren: Do not co-administer aliskiren with Olmesartan Medoxomil (Fu Ao Tan) in patients with diabetes because dual use is associated with increased risks of hypotension, hyperkalemia and changes in renal function (including acute renal failure) compared to monotherapy.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs and angiotensin receptor blockers (ARBs) may act synergistically by decreasing glomerular filtration. The concomitant use of NSAIDs and ARBs may increase the risk of worsening renal function.

Additionally, the antihypertensive effect of ARBs including olmesartan, may be attenuated by NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors.

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 hrs prior to colesevelam hydrochloride decreased the drug interaction effect.

Hydrochlorothiazide (Fu Ao Tan): Alcohol, Barbiturates, Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustment of the antidiabetic drug may be required.

Cholestyramine and Colestipol Resins: Absorption of Hydrochlorothiazide (Fu Ao Tan) is impaired in the presence of anionic exchange resins.

Corticosteroids and Adrenocorticotropic Hormone (ACTH): Patients taking corticosteroids or ACTH are at a greater risk of hypokalemia.

Pressor Amines (eg, Noradrenaline): The effect of pressor amines may be decreased.

Nondepolarizing Skeletal Muscle Relaxants (eg, Tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by Hydrochlorothiazide (Fu Ao Tan).

Lithium: Renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore, use of Olmesartan Medoxomil (Fu Ao Tan)/Hydrochlorothiazide (Fu Ao Tan) and lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Nonsteroidal Anti-Inflammatory Drugs: The administration of NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.

The following adverse reactions with Fu Ao Tan tablets are described elsewhere:

Clinical Trials Experience

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.

Fu Ao Tan

The concomitant use of Fu Ao Tan was evaluated for safety in 1243 hypertensive patients. Treatment with Fu Ao Tan was well tolerated, with an incidence of adverse events similar to that of placebo. Adverse reactions were generally mild, transient and not dependent on the dose of Fu Ao Tan.

The rate of withdrawals for adverse events in all trials of hypertensive patients was 2.0% (25/1243) on Olmesartan Medoxomil (Fu Ao Tan) plus Hydrochlorothiazide (Fu Ao Tan) and 2.0% (7/342) on placebo.

In a placebo-controlled, factorial clinical trial of Olmesartan Medoxomil (Fu Ao Tan) (2.5 mg to 40 mg) and Hydrochlorothiazide (Fu Ao Tan) (12.5 mg to 25 mg), the following adverse reactions reported in Table 1 occurred in > 2% of patients, and more often on the Fu Ao Tan combination than on placebo.

Other adverse reactions that have been reported with an incidence of greater than 1.0%, whether or not attributed to treatment, in the more than 1200 hypertensive patients treated with Fu Ao Tan in controlled or open-label trials are listed below.

Body as a Whole: chest pain, back pain, peripheral edema

Central and Peripheral Nervous System: vertigo

Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, diarrhea

Liver and Biliary System: SGOT increased, GGT increased, ALT increased

Metabolic and Nutritional: creatine phosphokinase increased

Musculoskeletal: arthritis, arthralgia, myalgia

Respiratory System: coughing

Skin and Appendages Disorders: rash

Urinary System: hematuria

Facial edema was reported in 2/1243 patients receiving Fu Ao Tan. Angioedema has been reported with angiotensin II receptor antagonists, including Fu Ao Tan tablets.

Hydrochlorothiazide (Fu Ao Tan)

Other adverse reactions that have been reported with Hydrochlorothiazide (Fu Ao Tan) 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: glycosuria, hyperuricemia

Musculoskeletal: muscle spasm

Nervous System/Psychiatric: restlessness

Renal: renal dysfunction, interstitial nephritis

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

Special Senses: transient blurred vision, xanthopsia

Clinical Laboratory Test Findings

Creatinine/blood urea nitrogen (BUN)

Minor elevations in creatinine and BUN occurred in 1.7% and 2.5% respectively, of patients taking Fu Ao Tan tablets and 0% and 0% respectively, given placebo in controlled clinical trials.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Fu Ao Tan tablets. 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:

Body as a Whole: Asthenia

Gastrointestinal: Vomiting

Metabolic: Hyperkalemia

Musculoskeletal: Rhabdomyolysis

Skin and Appendages: Alopecia, pruritus

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 nonfatal 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.