CILZEC PLUS Tablet

Indications

indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy.

Dosage

this tablet should be taken once daily with liquid, with or without food in patients whose blood pressure is not adequately controlled by telmisartan alone. Individual dose titration with each or the two components is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

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. The side effects of telmisartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of telmisartan and hydrochlorothiazide will be associated with moth sets of dose independent side effects. These tables may be administered with other antihypertensive agents.

Patients with Renal Impairment

The usual regimens of this tablet, once daily may be followed as long as the patient’s creatinine clearance is >30mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so these tablets are not recommended.

Patients with Hepatic Impairment

These tablets are not recommended for patients with severe hepatic impairment. Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision using the 40/12.5mg combination.

in patients who are hypersensitive to any component of this product.

Telmisartan

- hypersensitivity to the active ingredient or any of other excipients

- second and third trimesters of pregnancy and lactation

- severe hepatic impairment

Hydrochlorothiazide- Hypersensitivity to thiazides and derivatives of sulfonamides, manifest gout, anuria, Addison’s disease, hypercalcemia, hyperuricemia, severe renal and hepatic insufficiency.

Side effects

2% or greater in patients: pain, headache, cough, urinary tract infection.

less than 2% in patients: back pain, dyspepsia, vomiting, tachycardia, hypokalemia, bronchitis, pharyngitis, rash, hypotension postural, abdominal pain.

Telmisartan

Autonomic Nervous System: impotence, increased sweating, flushing

Body as Whole: allergy, fever, leg pain, malaise, chest pain

Cardiovascular: palpitation, dependent edema, angina pectoris, leg edema, abnormal ECG, hypertension, peripheral edema.

CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia

Gastrointestinal: flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastro esophageal reflux, toothache, non-specific gastrointestinal disorders

Metabolic: gout, hypercholesterolemia, diabetes mellitus

Musculoskeletal: arthritis, arthralgia, leg cramps, myalgia

Psychiatric: anxiety, depression, nervousness

Resistance Mechanism: infection, fungal infection, abscess, otitis media

Respiratory: asthma, rhinitis, dyspnea, epistaxis

Skin: dermatitis, eczema, pruritus

Urinary: micturition frequency, cystitis

Vascular: cerebrovascular disorder

Special Senses: abnormal vision, conjunctivitis, tinnitus, earache A single case of angioedema was reported (among a total of 3781 patients treated with telmisartan).

Hydrochlorothiazide

Other adverse experiences 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

Telmisartan

Digoxin, Lithium, Ramipril and Ramiprilat, Other drugs (Co-administration of Telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzyme, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.)

Hydrochlorothiazide

When administered concurrently, the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin),

Cholestyramine and colestipol resins,

Corticosteroids, ACTH,

Pressor amines (e.g., norepinephrine),

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine),

Lithium,

Non-steroidal anti-inflammatory drugs.

Pregnancy

(see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

Nursing Mothers

It is not known whether Telmisartan is excreted in human milk, but Telmisartan was shown to be present 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 of discontinue the drug, taking into account the importance of the drug to the mother.

Precautions

Fetal/ Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected. Telmisartan tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensinⅡreceptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of this tablet as soon as possible.

If oligohydramnios is observed, these tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensinⅡreceptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If Oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Hypotension in Volume-Depleted Patients

Initiation of antihypertensive therapy in patients whose renin-angiotensin system are activated such as patients who are intravascular volume- or sodium-depleted, e.g., in patients treated vigorously with diuretics, should only be approached cautiously. These conditions should be corrected prior to administration of these tablets. Treatment should be started under close medical supervision. If hypotension occurs, the patients should be placed in the supine position and, if necessary, given 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.

Hydrochlorothiazide

Hepatic Impairment: Thiazide diuretics should be used with caution in patients with impaired hepatic function of progressive liber disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Hypersensitivity Reaction: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Serum electrolytes

Telmisartan and Hydrochlorothiazide

No discontinuations due to hypokalemia reported during treatment with the telmisartan//hydrochlorothiazide combination. The absence of significant changes in serum potassium levels may be due to the opposing mechanisms of action of telmisartan and hydrochlorothiazide on potassium excretion on the kidney.

Hydrochlorothiazide

Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient experiences excessive vomiting or receives parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments of Insulin or oral hypoglycemic agents may be required.

Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the post sympathectomy patient.

If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Hepatic Function

Telmisartan

As the majority of Telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance.

Telmisartan tablets should be used with caution in these patients.

Impaired Renal Function

Telmisartan

As a consequence of inhibiting the renin-angiotensin- aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan.

There has been no long-term use of telmisartan in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide

Thiazides should be used with caution in 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.

Dual Blockage of the Renin-angiotensin-aldosterone System

Telmisartan

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensinⅡreceptor antagonist) should be used with caution and should include close monitoring of renal function.

Mechanism of action

AngiotensinⅡis formed from angiotensinⅠin a reaction catalyzed by angiotensin-converting enzyme (ACE, kininaseⅡ). AngiotensinⅡis 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. Telmisartan blocks the vasoconstrictor and aldosterone secreting effects of angiotensinⅡto the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensinⅡsynthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensinⅡfrom angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Telmisartan does not inhibit ACE (kininaseⅡ), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensinⅡreceptor inhibits the negative regulatory feedback of angiotensinⅡon rennin secretion, but the resulting increased plasma renin activity and angiotensinⅡcirculating levels do not overcome the effect of Telmisartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt 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 angiotensinⅡ, so coadministration of loss angiotensinⅡreceptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is not fully understood.