AGIMSTAN-H 80/25

Composition: Each tablet contains:
Telmisartan . . . . . . . . . . . . . . . . . . . . . . . 80 mg
Hydrochlorothiazide . . . . . . . . . . . . . . . . . 25 mg
Presentation:
4 blisters of 7 film-coated tablets in a carton box.
Indications:
Agimstan-H 80/25 fixed dose combination of telmisartan and hydrochlorothiazide is indicated for the treatment of idiopathic hypertension in adults whose blood pressure is not adequately controlled by telmisartan alone or fixed dose combination of telmisartan/hydrochlorothiazide 80/12.5 mg.
Agimstan-H 80/25 is not indicated for initial treatment of hypertension.
If necessary, Agimstan-H 80/25 can be combined with other antihypertensive agent.

Additional information

Dosage and administration

Dosage
Adults: Take one tablet daily. (Oral administration, one tablet once daily)
Dose can be titrated up to 160 mg of telmisartan and 25 mg hydrochlorothiazide (appropriate fixed dose combination or individual dosage forms containing one or two components with proper contents.)
Prior to dose adjustment it should be noted that the maximum reduction in blood pressure is generally attained 4-8 weeks after the start of treatment.
Patients with renal impairment:
Due to the hydrochlorothiazide component, Agimstan-H 80/25 is not indicated in patients with severe renal impairment (creatinine clearance ≤ 30 ml / min). Loop diuretics are preferred to thiazides in these patients.
There is inadequate experience in patients with mild to moderate renal impairment, but no undesirable effects in the kidney have been reported and no dose adjustment is necessary. Periodic monitoring of renal function is advised.
Patients with hepatic impairment:
In patients with mild to moderate hepatic impairment the dose should not exceed ½ Agimstan-H 80/25 tablet (i.e. telmisartan 40 mg/hydrochlorothiazide 12.5 mg) once daily. Agimstan-H 80/25 is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.
Elderly patients: No dose adjustment is necessary.
Paediatric population: The safety and efficacy of Agimstan H – 80/25 tablet in children and adolescents aged below 18 have not been established.
Administration
Take the medicine once daily regardless of meals as food slightly reduces the bioavailability of Agimstan-H.

Contraindications

Hypersensitivity to telmisartan, thiazides and other sulphonamide-derivatives or with any component of the drug.
Pregnant women or breastfeeding mothers.
Patients with anuria.
Severe renal impairment, renal impairment with serum creatinine ≥ 250 micromol/L or serum potassium ≥ 5 mmol/l or Clcr ≤ 30 ml/min.
Severe hepatic impairment or biliary obstruction.
Refractory hypokalaemia, hypercalcaemia have been identified but the treatment has not achieved better results.
The concomitant use of Agimstan-H 80/25 with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2).

Warnings and precautions for use

Telmisartan:
Blood levels of potassium should be monitored, especially in the elderly and patients with renal impairment. Initial dose should be reduced in these patients.
Aortic and mitral valve stenosis.
Obstructive hypertrophic cardiomyopathy.
Severe congestive heart failure (particularly sensitive to changes in the renin-angiotensin-aldosterone system, accompanied by oliguria, progressive azotemia, acute renal failure (possibly fatal).
Dehydration (volume and/or sodium depletion due to vomiting, diarrhea, vigorous diuretic therapy, dialysis, dietary salt restriction) increases the risk of excessive reduction of blood pressure. This disorder should be corrected before telmisartan therapy or dose reduction and monitored closely when starting the treatment. Increase in telmisartan dose is not contraindicated when there is transient hypotension; however, the therapy should be monitored closely after blood pressure has been stabilized (as increase in fluid volume).
Progressive gastric and duodenal ulcers or other gastrointestinal disease (increased risk of gastrointestinal bleeding).
Mild and moderate hepatic impairment.
Agimstan H80/25 tablets should be used with caution in patients with biliary obstructive disorders as the predominant route of elimination of telmisartan is through biliary excretion and hepatic clearance for telmisartan may be reduced.
Renal artery stenosis.
Caution should be taken in patients with a history of angioedema with or without regard to administration of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers.
Telmisartan may cause porphyria and should only be used in the absence of other safer alternatives and caution should be taken in severe renal failure patients
Hydrochlorothiazide:
Due to the hydrochlorothiazide component serum and urine electrolytes should be monitored periodically in patients suffering vomiting or receiving an intravenous infusion, especially those who are taking corticosteroids, ACTH or digitalis, quinidine (risk of torsades de pointes leading to ventricular fibrillation)
Severe renal impairment: Hyperuricemia and possible exacerbation of impaired renal function.
Impaired Hepatic Function: Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease.
Gout: The disease may be aggravated.
Diabetes: Dosage adjustment of the antidiabetic drugs (insulin, oral antidiabetics) may be required because this drug can increase blood glucose.
The antihypertensive effects of hydrochlorothiazide may be enhanced in the post sympathectomy patient.
Increase in serum levels of cholesterol and triglycerides.
Caution should be taken when giving hydrochlorothiazide to the elderly because the drug may cause electrolyte imbalance.

Recommendation for pregnancy and breastfeeding

Pregnancy:
Agimstan-H 80/25 is contraindicated for pregnant women because the drug directly acts on the renin-angiotensin system, which is known to induce human fetotoxicity: hypotension, reversible or irreversible renal failure, anuria, skull ossification retardation, fetal or neonatal death. Oligohydramnios (possibly due to reduced fetal renal function) associated with limb spasticity, craniofacial deformity and fetal lung hypoplasia have been reported. When pregnancy is detected, discontinue telmisartan as soon as possible.
Lactation:
Although no information is available regarding the use of telmisartan during breast-feeding, thiazide is excreted in human milk. 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.

Effects on ability to drive and use machines

It should be taken into account that dizziness or drowsiness due to hypotension may occasionally occur when taking antihypertensive therapy. Therefore, caution should be taken when driving, using machine or engaging in activities that require complete alertness.

Interactions, incompatibilities of medicine

Other antihypertensive agents: The hypotensive effect of Agimstan-H 80/25 may increase when it was co-administered with other antihypertensive agents. Aliskiren and Agimstan-H 80/25 should not be used concomitantly in patients with diabetes or renal failure (Clcr < 60 ml/min).
Medicinal products that affect potassium: The potassium-lowering effects of hydrochlorothiazide are compensated by the potassium-sparing effects of telmisartan. However, this effect of hydrochlorothiazide on serum potassium is likely to occur when combined with other drugs that cause potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, corticosteroids, ACTH, salbutamol, amphotericin). In contrast, the combination with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that induce hyperkalaemia may increase the hyperkalaemia effect of telmisartan.
Lithium: Telmisartan increases in serum lithium concentrations, in addition, thiazide reduces the renal clearance of lithium. Concomitant use of Agimstan-H 80/25 with lithium should be cautious and serum lithium level monitoring is advisable.
More information on telmisartan interactions:
Co-administration of telmisartan with NSAIDs, including selective COX-2 inhibitors may result in deterioration of renal function, including possible acute renal failure. If needed, renal function in these patients should be monitored.
A pharmacokinetic interaction of telmisartan with drugs which inhibit or induce cytochrome P450 (CYP) isoenzymes rarely occurs. Telmisartan is not metabolized by the cytochrome P450 (CYP) isoenzymes. Telmisartan has no effects on CYP isoenzymes except for some inhibition of CYP2C19 in vitro.
Digoxin: Co-administration of telmisartan with digoxin increased digoxin peak plasma concentration. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.
Warfarin: Co-administration of telmisartan with warfarin for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in the International Normalized Ratio (INR).
Diuretics: Increases the antihypertensive effect of telmisartan.
Acetaminophen, amlodipine, glyburide, ibuprofen and simvastatin: There is almost no pharmacokinetic interaction.
More information on hydrochlorothiazide interactions: Since Agimstan-H 80/25 contains hydrochlorothiazide belonging to thiazide class of diuretics, it is possible to interact with the following drugs:
Alcohol, barbiturates and narcotics: Potentiation of orthostatic hypotension may occur.
Anti-diabetic drugs (oral hypoglycemic agents and insulin): Dosage adjustment of the antidiabetic drug may be required.
Corticosteroids, and adrenocorticotropic hormone (ACTH): Intensified electrolyte depletion, particularly hypokalemia may occur.
Pressor amines (e.g. norepinephrine): Decreased response to pressor amines may occur, but the effect is considered not sufficient to preclude their concurrent use.
Skeletal muscle relaxants (e.g. tubocurare): The drug may increase the responsiveness of some skeletal muscle relaxants.
Nonsteroidal AntiInflammatory Drugs (NSAIDs): The co-administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Therefore, when Agimstan-H 80/25 and NSAIDs are used concomitantly, the patient should be observed closely to determine whether the desired effect of the diuretic is obtained.
Quinidine: may causes torsades de pointes leading to ventricular fibrillation and death.
Anticoagulants, gout medications: The effects of these drugs may be reduced.
Anesthetics, glycosides, vitamin D: The effects of these drugs may be increased.
Cholestyramine and colestipol resins: Bile acid sequestrants bind thiazide diuretics in the gut and impair gastrointestinal absorption of hydrochlorothiazide.
Allopurinol, tetracycline: Co-administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol. Co-administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea.
Herbal medicines: Avoid concomitant use with herbal medicine such as liquorice, Angelica sinensis, Ephedra, ginseng, yohimbe because they have influence on the diuretic effect of hydrochlorothiazide.

Undesirable effects (ADRs)

Telmisartan:
ADRs have generally been mild and transient in nature and have infrequently required discontinuation of therapy.
Uncommon, 1/1000 < ADR < 1/100
Body as a whole: Fatigue, headache, hypotension, vertigo especially in volume-depleted patients (e.g. patients taking high doses of diuretics), swelling in the hands, lower legs, and feet, angioedema, increased sweating, blurred vision.
CNS: Agitation, anxiety, dizziness.
Gastrointestinal: Dry mouth, nausea, abdominal pain, gastroesophageal reflux, dyspepsia, flatulence, anorexia, diarrhea.
Urinary: Kidney failure, increases in creatinine and blood urea nitrogen, urinary tract infections.
Respiratory: Sore throat, sinusitis, upper respiratory tract infection, influenza-like symptoms (cough, congestion or earache, fever, nasal congestion, runny nose, sneezing, sore throat).
Musculoskeletal: Back pain, muscle spasms, myalgia, and tendinitis like symptoms.
Metabolic: Hyperkalemia.
Rare, ADR < 1/1000
Body as a whole: Angioedema.
Eye: Visual disturbance.
Cardiovascular: Tachycardia, hypotension or syncope (in volume-or salt-depleted patients, patients being treated with diuretics, especially upon standing posture).
Gastrointestinal: Gastrointestinal bleeding.
Skin: Skin rash, urticaria, itching.
Liver: Increase hepatic enzyme.
Hematology: Decreased hemoglobin, neutrophenia.
Metabolic: Hyperuricemia, hypercholesterolemia.
Hydrochlorothiazide:
Hydrochlorothiazide may exacerbate potassium loss (may produce excessive loss of potassium). This effect is dose-dependent and can be reduced at a low dose (when taking low dose) (12.5 mg/day), the optimum dosage for treating hypertension and minimizing adverse reactions. (the optimal dose for antihypertensive effect with the smallest occurrence of side effects). Diuretics often cause hyponatremia.
Common, ADR > 1/100
Body as a whole: Fatigue, lightheadedness, dizziness, headache.
Cardiovascular: Orthostatic hypotension.
Metabolic: Hypokalaemia, hyperuricemia, hyperglycemia, hyperlipidemia (at high doses)
Uncommon, 1/1000 < ADR < 1/100
Cardiovascular: Orthostatic hypotension, cardiac arrhythmias.
Gastrointestinal: Nausea, vomiting, anorexia, constipation, diarrhea, intestinal spasm.
Skin: Hives, rash, photosensitivity.
Metabolic: Hypomagnesaemia, hyponatremia, hypercalcemia, hypochloraemic alkalosis, hypophosphatemia.
Rare, ADR < 1/1000
Body as a whole: Anaphylactic reactions, fever.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia.
CNS: Paresthesia, sleep disorders, depression.
Skin: Necrotizing angiitis, rash, purpura, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Hepatobiliary: Hepatitis, hepatocellular cholestatic jaundice, pancreatitis.
Respiratory: Dyspnea, pneumonia and pulmonary edema (anaphylactic reaction), respiratory distress.
Genitourinary: Renal impairment, interstitial nephritis, impotence.
Eye: Blurred vision
An acute attack of gout may be precipitated by hyperuricemia. Orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressant..
Management of adverse reactions
Reduce the dose or discontine the treatment when undesirable effects occur.
Treatment of excessive fall in blood pressure: The patient should be placed in a supine position, intravenous infusion of a normal saline solution is required in patients with severe hypertension to increase fluid volume.

Overdose and management

There is limited information available for telmisartan with regard to overdose in humans.
Symptoms:
Telmisartan: Bradycardia (due to parasympathetic (vagal) stimulation) or tachycardia, vertigo, dizziness, hypotension.
Hydrochlorothiazide: Electrolyte depletion and dehydration resulting from excessive diuresis. The most common signs and symptoms observed are nausea and somnolence. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
Management:
There is no specific information on the treatment of overdose of fixed dose combination of telmisartan and hydrochlorothiazide. Symptomatic and supportive treatment should be instituted. The drug should be stop immediately and the patient should be monitored closely. Suggested measures include induction of emesis and/or gastric lavage, ingestion of activated charcoal; rehydration, electrolyte balance; management of hepatic coma, management of hypotension according to conventional procedures. The drug is not removed by hemodialysis.

Pharmacodynamic properties

Agimstan-H 80/25 is a combination of telmisartan and hydrochlorothiazide which is suitable for once-daily oral administration. The combination of these ingredients has an additive antihypertensive effect to achieve well-controlled blood pressures. Blood pressure is reduced to a greater degree than either component alone.
Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT1) antagonist, and hydrochlorothiazide is a thiazide diuretic. The combination of two drugs have synergistic effects on blood pressure. Higher efficacy in treating hypertension is achieved when combining small dose of thiazide diuretics such as hydrochlorothiazide with angiotensin II receptor antagonists).
Moreover, due to diuretic action hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, decreases serum potassium and increases angiotensin II circulating levels. Telmisartan blocks all physiological effects of angiotensin II and through blocking aldosterone secreting effects of angiotensin II, it tends to reverse the potassium loss associated with this diuretic.
Thus, the combination of telmisartan and hydrochlorothiazide increases the antihypertensive effect of the drug, which is maintained for the full 24-hour dose interval. Agimstan-H tablets are for once-daily oral administration.
Telmisartan:
Telmisartan is a benzimidazole derivative and a non-peptide angiotensin II receptor antagonist with antihypertensive property. Telmisartan selectively antagonizes angiotensin II binding to the angiotensin II AT1 subtype receptor, located in vascular smooth muscle and adrenal gland.
In the renin-angiotensin system, angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor, it stimulates the synthesis and release of aldosterone from the adrenal cortex and has effect on cardiac stimulation. Aldosterone increases sodium reabsorption and potassium excretion by the kidneys.
Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT1-receptor by binding to receptors in vascular smooth muscle and the adrenal gland resulting in vasodilation and reduction in aldosterone effects).
AT2 receptor has been 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. Unlike ACE inhibitors, which are widely used for the treatment of hypertension, angiotensin II receptor antagonist does not inhibit the degradation of bradykinin, thus does not cause persistent dry cough – an undesirable effect which is usually seen with ACE inhibitors. Telmisartan is used for people who stop using ACE inhibitor because of experiencing cough.
In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure of telmisartan. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours. After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy. In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive medicinal products.
Similar to angiotensin receptor antagonists, telmisartan shows an effect in reducing the rate of progression to renal disease or microalbuminuria in patients with diabetes and the use of telmisartan is recommended in this population.
Telmisartan is also used in treating congestive heart failure. However, similar to angiotensin II receptor antagonists, telmisartan should only be used in patients who have been prescribed ACE inhibitors but can not tolerate the drug (e.g., in patients with cough or angioedema).
Hydrochlorothiazide:
Hydrochlorothiazide is a thiazide diuretic which increases the excretion of sodium, chloride, and water by reducing sodium (Na+) and chloride (Cl-) reabsorption in the distal convoluted tubule. The excretion of other electrolytes also increases, especially potassium and magnesium, whereas calcium is reduced. Hydrochlorothiazide also inhibits carbonic anhydrase activity, which induced excretion of sodium bicarbonate, but this excretion is generally weaker than that of Cl- and does not significantly alter urinary pH. Thiazide diuretics may also reduce the glomerular filtration rate. Thiazides have a moderately diuretic effect, since about 90% of the sodium ion has been reabsorbed before reaching the distal convoluted tubule that is primary site of action of thiazide diuretics.
Hydrochlorothiazide has antihypertensive effect, firstly due to the decrease in plasma and extracellular fluid volume relating to urinary sodium excretion. Then, during treatment, the antihypertensive effect depends on the decrease of peripheral vascular resistance, through the gradual adaptation of the blood vessels to reduction of the Na+ concentration. The antihypertensive effect of hydrochlorothiazide is present after 1-2 weeks, while onset of diuresis occurs rapidly in a few hours. Hydrochlorothiazide enhances the effect of other antihypertensive drugs.

Pharmacokinetic properties

Telmisartan:
Absorption: Telmisartan is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of telmisartan is dose dependent: After oral administration of 40 and 160 mg telmisartan the bioavailability was 42% and 58%, respectively. Food slightly reduces the bioavailability of telmisartan (with a reduction of about 6% after a 40 mg dose). Following oral administration, peak plasma concentrations of telmisartan are reached in 0.5 to 1 hour after dosing.
Distribution: Telmisartan is highly bound to plasma proteins (> 99 %), mainly albumin and α1 -acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters.
Metabolism: Following oral administration, telmisartan is metabolized to form a pharmacologically inactive acyl glucuronide.
Elimination: Most of the administered dose (> 97%) was eliminated unchanged in feces via biliary excretion; only minute amounts (< 1%) were found in the urine. The elimination half-life of telmisartan is about 24 hours, trough plasma concentrations of telmisartan with once daily dosing are about 15% to 25% of peak plasma concentrations.
Telmisartan pharmacokinetics has not been investigated in patients < 18 years of age. The pharmacokinetics of telmisartan does not differ between the elderly and those younger than 65 years.
Hydrochlorothiazide
Following oral administration, hydrochlorothiazide is well absorbed, about 65 – 75% of the administered dose; however, this rate may decrease in patients with heart failure. Food may reduce the absorption of the drug. Hydrochlorothiazide accumulates in red blood cells. Hydrochlorothiazide is 40 – 68% bound to plasma proteins. Hydrochlorothiazide is excreted almost entirely as unchanged substance in urine. The elimination half-life of hydrochlorothiazide is about 9.5 – 13 hours but may be prolonged in patients with impaired liver function and dosage adjustment is required. Hydrochlorothiazide crosses the placenta, is distributed in the fetus with high concentrations.
The onset of the diuretic action of hydrochlorothiazide occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 12 hours.
Antihypertensive effect occurs much later than diuretic effect and can only be fully effective after 2 weeks, even at an optimum dose of between 12.5-25 mg/day. It is important to know that the antihypertensive effect of hydrochlorothiazide is usually optimal at a dose of 12.5 mg. Current treatment guidelines and clinical trials emphasize the requirement of taking the lowest and optimal dosage to reduce the risk of adverse effects. It is important to wait for enough time to evaluate the body's response to the hypotensive effect of hydrochlorothiazide, because the effects on peripheral resistance need time to be apparent.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.