Co-Dovel

Uses

Hydrochlorothiazide is used for-

• Edema associated with congestive heart failure, hepatic cirrohosis, various forms of renal dysfunction and corticosteroid and estrogen therapy
• Management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe form of hypertension
• Management of diabetes insipidus
• Management of proximal renal tubular acidosis
• Idiopathic hypercalciuria and calcium nephrolithiasis, osteoporosis and exercise induced hyperkalemia

Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive drug regimen.

Co-Dovel is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaDiabetic Nephropathy, High Blood Pressure (Hypertension)

How Co-Dovel works

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Irbesartan prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT₁ receptor with 8500 times more affinity than they bind to the AT₂ receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure.

Angiotensin II would otherwise bind to the AT₁ receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure.

Dosage

Co-Dovel dosage

Adults-

For Edema: The usual adult dosage is 25 to 100 mg daily as a single or divided dose.

For Control of Hypertension: The usual initial dose in adults is 25 mg daily given as a single dose. The dose may be increased to 50 mg daily, given as a single or two divided doses. Doses above 50 mg are often associated with marked reductions in serum potassium. In some patients (especially the elderly) an initial dose of 12.5 mg daily may be sufficient.

Infants and children-

For diuresis and for control of hypertension: The usual pediatric dosage is 1 to 2 mg/kg/day in single or two divided doses, not to exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children 2 to 12 years of age. In infants less than 6 months of age, doses up to 3 mg/kg/day in two divided doses may be required.

Adult: The usual recommended initial and maintenance dose is Irbesartan 150 mg once daily, withor without food. Irbesartan at a dose of 150 mg once daily generally provides a better 24 hourblood pressure control than 75 mg. However, initiation of therapy with Irbesartan 75 mg couldbe considered, particularly in haemodialysed patients and in the elderly over 75 years.In patients insufficiently controlled with Irbesartan 150 mg once daily, the dose of Irbesartancan be increased to Irbesartan 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have anadditive effect with Irbesartan.In hypertensive type 2 diabetic patients, therapy should be initiated at Irbesartan 150 mgonce daily and titrated up to Irbesartan 300 mg once daily as the preferred maintenance dosefor treatment of renal disease.The demonstration of renal benefit of Irbesartan in hypertensive type 2 diabetic patients is basedon studies where Irbesartan was used in addition to other antihypertensive agents, as needed, toreach target blood pressure.

Elderly: although consideration should be given to initiating therapy with Irbesartan 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly

Paediatric: Irbesartan is not recommended for use in children and adolescents due toinsufficient data on safety and efficacy.

Side Effects

Generally, Hydrochlorothiazide is well tolerated. However, a few side effects may occur like weakness, restlessness, dizziness, headache, fever, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia, and hypotension. In rare case hyperglycemia, glycosuria, hyperuricemia and muscle spasm may occur.

Diarrhoea, fatigue, dyspepsia or heartburn, dizziness, orthostatic hypotension, nausea, vomiting, musculoskeletal pain, thrombocytopaenia, hyperkalaemia, elevated serum creatinine.

Toxicity

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

The oral TDLO in humans is 30mg/kg/6W.

Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure.

Precaution

Thiazides should be used with caution in patients with severe renal disease, impaired hepatic function or progressive liver disease and gout.

Patients with unilateral or bilateral renal artery stenosis, depletion of intravascular volume, aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Renal impairment. Lactation.

Interaction

Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (oral agents and insulin): Thiazides can impair control of diabetes mellitus by diet and antidiabetic Drugs. Antihypertensive Drugs: Additive effect or potentiation.

Diuretics and other antihypertensive agents: prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Irbesartan.

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended.

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Additional information on irbesartan interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a drug metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

The volume of distribution of irbesartan is 53-93L.

Elimination Route

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

Irbesartan is 60-80% bioavailable with a T_max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability.

In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 16±7 hours, and a C_max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±7 hours, and a C_max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±8 hours, and a C_max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 17±7 hours, and a C_max of 5.3±1.9µg/mL.

Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 11±4 hours, and a C_max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T_max of 2.0 hours, a half life of 11±5 hours, and a C_max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T_max of 1.5 hours, a half life of 15±7 hours, and a C_max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T_max of 1.8 hours, a half life of 14±6 hours, and a C_max of 5.6±2.1µg/mL.

Half Life

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

The terminal elimination half life of irbesartan is 11-15 hours.

Clearance

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min.

Elimination Route

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. 10

Pregnancy & Breastfeeding use

Pregnancy: Evidence of fetal risk in hydrochlorothiazide therapy is found, but it is indicated if benefits outweigh risks. Thiazides are indicated in pregnancy when edema is due to pathologic causes.\

Lactation: Neonatal side effects have been seen incase of hydrochlorothiazide therapy and therefore it is not recommended.

Pregnancy: Irbesartan is contraindicated in the second and third trimesters of pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

Lactation: Irbesartan is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Precautions: Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Irbesartan.

Contraindication

Hydrochlorothiazide is contraindicated to the patients of anuria and those who are sensitive to hydrochlorothiazide or to other sulfonamide-derived drugs. Therapy is not to be initiated in diabetes mellitus.

Concomitant use with aliskiren in patients with diabetes and renal impairment (GFR <60 ml/min). Pregnancy.

Special Warning

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose of Irbesartan 75 mg should be considered for patients undergoing haemodialysis. Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Irbesartan.

Hepatic impairment: no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects.

Hyperkalaemia: as with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Irbesartan is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensinaldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Acute Overdose

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. Rarely, autoimmune hemolytic anemia and other hypersensitivity reactions may complicate the picture.

In the event of over dosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. Hemodialysis can be used successfully to treat severe intoxication.

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage with Irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Irbesartan is not removed by haemodialysis.

Storage Condition

Store between 15-30°C. Protect from light, moisture and freezing.

Store in a cool and dry place, protected from light.

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