Composition:

Each Disartan Co capsule contains 80 mg or 160 mg valsartan & 12.5 mg hydrochlorothiazide.

Excipients: Microcrystalline cellulose, magnesium stearate, sodium lauryl sulphate, crospovidone, povidone K30.

Pharmacodynamics:

Disartan Co, is a combination of valsartan, an angiotensin II (type AT1) antagonist, & hydrochlorothiazide, a thiazide diuretic.

It is an antihypertensive agent.

Valsartan does not exhibit any partial agonist activity at the AT1 receptor & has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.

Valsartan, angiotensin II receptor antagonist (AIIRA), blocks the vasoconstrictor & aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues (eg, vascular smooth muscle, adrenal gland).  

Valsartan does not inhibit angiotensin converting enzyme ACE which is kininase II, the enzyme that converts angiotensin I to angiotensin II as well degrades bradykinin, and therefore, valsartan is not associated with cough.

Hydrochlorothiazide is a thiazide diuretic & an antihypertensive agent.

It exerts diuretic effect by reducing the reabsorption of electrolytes from the distal renal tubular & increases excretion of sodium & chloride ions, & consequently of water.

Excretion of other electrolytes, notably potassium & magnesium, is also increased.  

This contributes to its hypotensive effect in addition to a reduction in peripheral resistance.  

In Disartan Co, hydrochlorothiazide enhances the effect of valsartan as antihypertensive agent.

Pharmacokinetics:

Valsartan is rapidly absorbed following oral administration, with a bioavailability of about 25%.  

It is highly bound to plasma proteins around 95%.

It is not significantly metabolized & is excreted mainly via the bile as unchanged drug.

The terminal elimination half-life is approximately 6 hours.

Following an oral dose about 83% is excreted in the feces & 13% in urine.

Hydrochlorothiazide is fairly rapidly absorbed from the gastrointestinal tract.

It is reported to have a bioavailability of about 65% to 70%.  

It has plasma half-life of between about 5 & 15 hours & appears to be preferentially bound to red blood cells.

It crosses the placental barrier & is excreted in breast milk.

It is excreted mainly unchanged in the urine.

Therapeutic Indications:

Treatment of hypertension alone or in combination with other antihypertensive agents.

This fixed dose combination is not indicated for initial therapy.

Dosage and Administration:

In hypertension, Disartan Co is given in an initial dose of 80 mg once daily, with or without food.  

This may be increased, if necessary, to 160 mg once daily, although doses of up to 320 mg once daily may be used.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily, and can be given at doses of 12.5 mg to 25 mg.

Drug-Drug Interactions:

The antihypertensive effects may be increased with concomitant use of other antihypertensive drugs.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that may alter potassium levels (Heparin, etc.) should be used with cautions and with frequent monitoring of potassium, reversible increases in serum lithium concentrations and toxicity have been reported drugs concurrent use of ACE  inhibitors and thiazides.

There is no experience with concomitant use of valsartan and lithium, therefore, monitoring of serum lithium concentrations is recommended during concurrent use.

In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

The following potential drug-drug interactions may occur due to the thiazide component of Disartan Co: Thiazides potentiate the action of curare derivatives.

Concomitant administrations of NSAIDS (e.g. salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of Disartan Co. Concurrent hypovalemia may include renal failure. The hypokalemic effect of diuretics may be increased by kaliuretics, diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, and salicylic acid derivatives.

Thiazide-induced hypokalemia or hypomagnesemia may occur as unwanted effects, favoring the onset of digitalis-induced cardiac arrhythmias.

It may prove necessary to read just the dosage of insulin and of oral antidiabetic agents.

Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol, may increase the risk of adverse effects caused by amantadine, may enhance the hyperglycemic effect of diazoxide and may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosamide, methotrexate) and potentiate their myelosuppressive effects.

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden) apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.

There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Absorption of thiazide diuretics is decreased by cholestyramine. Administration of thiazide diuretics with vitamin D or with calcium salt may potentiate the rise in serum calcium. Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

Precautions:

Caution in renal artery stenosis.

Symptomatic hypotension may occur in rare cases after initiation of therapy with valsartan.

Should be used with caution in aortic or mitral valve stenosis & in obstructive hypertrophic cardiomyopathy.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid & electrolyte imbalance may precipitate hepatic coma.

Thiazides should be used with caution in patients with severe renal disease, as may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

 Pregnancy:

Should be avoided.

 Lactation:

Should be avoided in lactating mothers.

Contraindications:

Hypersensitivity to any of the components of Disartan Co.

Should be avoided in pregnancy & in lactating mothers.

Severe hepatic impairment, cirrhosis, or biliary obstruction.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Adverse Reactions:

They are usually mild.  Symptomatic hypotension may occur, particularly in patients with intravascular volume depletion may occur (e.g. those taking high-dose diuretics), headache, fatigue, dizziness, viral infection, urinary tract infection, upper respiratory tract infection, pharyngitis, coughing, bronchospasm, chest pain, tachycardia, increased sweating, dry mouth, increased appetite, muscle cramp, gout, muscle weakness, anxiety, decreased libido, impotence, somnolence, nausea, vomiting, abdominal pain, arthralgia, tinnitus, vertigo, abnormal vision, nasal congestion and sinus disorder.

Clinical signs of fluid & electrolyte imbalance can be observed.

Disartan Co has been evaluated for safety. Adverse experiences have generally been mild and transient in nature.

The following adverse experiences are based on controlled trials. The overall incidence of adverse experiences with Disartan Co was similar to placebo.

All adverse experiences showing an incidence of 1% or more in the Disartan Co group are: Headache, dizziness, fatigue, sinusitis, pharyngitis, upper respiratory tract infection, coughing, back pain, diarrhea, viral infection, chest pain, nausea, rhinitis, dyspepsia, urinary tract infection, abdominal pain, micturition frequency, arm pain, bronchitis, dyspnea, leg pain, sprains and strains, abnormal vision, arthritis, leg cramps, impotence, insomnia, rash.

Other adverse experiences with a frequency below 1% included edema, asthenia, & vertigo. It is unknown whether these effects were casually related to the therapy.

Post-marketing data revealed very rare cases of angioedema, elevated liver enzymes and very rare reports of hepatitis, impaired renal function, hyperkalemia, alopecia, rash, pruritis, and other hypersensitivity/allergic reactions including serum sickness, and vasculitis.

Laboratory findings: A greater than 20% decrease in serum potassium was observed in patients receiving Disartan Co as compared to placebo.

Elevations in creatinine occurred in 1.4% of patients taking Disartan Co and 1.1 given placebo in controlled clinical trials.

Valsartan: 

Other additional adverse experiences reported in clinical trials with valsartan monotherapy, irrespective of their casual association with the study drug, were, with a frequency greater than 1%: arthralgia. With a frequency below 1%: edema, asthenia, insomnia, rash, decreased libido, vertigo.

Hydrochlorothiazide: 

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in Disartan Co.  The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide:

Others Common: Urticaria and other forms of rash, loss of appetite, mild nausea and vomiting, postural hypotension, which may be aggravated by alcohol, anesthetics or sedatives and impotence.

Rare: Photosensitization, abdominal distress, constipation, diarrhea, and gastrointestinal discomfort, intrahepatic cholestasis or jaundice cardiac arrhythmias, headache, dizziness or lightheadedness, sleep disturbances, depression, Paresthesia, disturbances of vision, thrombocytopenia, sometimes with purpura.

Very rare: Necrotizing Vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematous- like reactions, reactivation of cutaneous lupus erythematous, pancreatitis, leucopenia, agranulocytosis, bone marrow, depression, hemolytic anemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary edema.

Presentation & Storage:

Disartan Co 80 mg capsules are supplied in carton box containing 1 or 2 Al/PVC STRIPS each of 7 capsules and inner leaflet.

Disartan Co 160 mg capsules are supplied in carton box containing 1 or 2 Al/PVC STRIPS each of 7 capsules and inner leaflet.  

Store at temperature not exceeding 30C.