Co-DIO MD

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

Valsartan is used for:

• For hypertension
• To reduce hospitalizations in patients with congestive heart failure
• To reduce death in patients who developed congestive heart failure after myocardial infarction

Co-DIO MD 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 preeclampsiaCardiovascular Mortality, Diabetic Nephropathy, High Blood Pressure (Hypertension), Left Ventricular Dysfunction, Moderate Essential Hypertension, Chronic heart failure with reduced ejection fraction (NYHA Class II), Chronic heart failure with reduced ejection fraction (NYHA Class III), Chronic heart failure with reduced ejection fraction (NYHA Class IV), Hospitalization due to cardiac failure

How Co-DIO MD 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.

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy.

The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized.

Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease.

Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor.

Dosage

Co-DIO MD 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.

Hypertension: The usual dose of Valsartan is 80 to 160 mg once daily. The maximum dose is 320 mg daily. Maximum blood pressure reduction occurs within 4 weeks.

Heart failure:The usual dose is 40 mg twice daily and may be increased to 80-160 mg twice daily.

Post-Myocardial Infarction:The initial dose after myocardial infarction is 20 mg twice daily. The dose should be increased with a target of 160 mg daily if tolerated without side effects.

Administration of Valsartan with food decreases the absorption of Valsartan by about 40%, so it should be taken on an empty stomach. No initial dosage adjustment is required for elderly patients with mild to moderate renal and hepatic insufficiency.

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.

Valsartan is generally well tolerated and side effects are rare. The most common side effects include headache, dizziness, fatigue, abdominal pain, cough, diarrhea and nausea. Patient may also experience hyperkalemia, impotency, reduced renal function, allergic reactions, dyspnea, constipation, back pain, muscle cramps, rash, anxiety, insomnia and vertigo. Hypotension may also occur if patient have been taking diuretics along with Valsartan.

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.

Approximate LD50 >2000 mg/kg (Gavage, rat) [F3139]

Reproductive Toxicology Studies

No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation.[F4607]

Pregnancy

When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible.[F4607]

Precaution

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

Impaired Hepatic Function: As the majority of Valsartan is eliminated in the bile, care should be exercised in patients with mild to moderate hepatic impairment including biliary obstructive disorder.

Impaired Renal Function: Dosage reduction or discontinuation may be required with patients having pre-existing renal impairment.

Heart Failure and Myocardial Infarction: Caution should be exercised when initiating therapy in patients with heart failure and post-myocardial infarction patients.

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.

No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include Cimetidine, Warfarin, Furosemide, Digoxin, Atenolol, Indomethacin, Hydrochlorothiazide, Amlodipine and GlibenclamideAs Valsartan is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with Valsartan. Although valsartan is highly bound to plasma proteins, in vitrostudies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as Diclofenac, Furosemide, and Warfarin. Concomitant use of potassium sparing diuretics (e.g., Spironolactone, Triamterene, Amiloride) potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium. If co medication is considered necessary, caution is advisable

Volume of Distribution

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

The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.[F3139,F3607]

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.

After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients.[F3139] Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan genereally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive administration.[F4607]

Half Life

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

After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.[F4607]

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.

Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).[F4607]

Elimination Route

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.[F4607]

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: Valsartan should not be used in pregnancy, as in 2nd and 3rd trimester it can cause injury and even death to fetus. When pregnancy is detected, Valsartan should be stopped as soon as possible.

Nursing mothers: It is not known whether Valsartan 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.

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.

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

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.

Pediatric use: Safety and effectiveness in paediatric patients have not been established.Geriatric use: No overall difference in the efficacy or safety of Valsartan was observed in this patient population, but greater sensitivity of some elderly persons cannot be ruled out.Hepatic Impairment:

• Mild to moderate: Max: 80 mg once daily.
• Severe: Contraindicated.

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.

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia, bradycardia could occur from parasympathetic (vagal) stimulation. If excessive hypotension occurs, the patient should be placed in the supine position and if necessary, has to be given an intravenous infusion of normal saline.

Storage Condition

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

Store between 15-30° C. Protect from moisture and heat.

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