Valzaar R

Uses

Ramiprilis used for the following cases:

• Mild to severe hypertension
• Congestive Heart failure.
• To reduce the risk of stroke, myocardial infarction and death from cardiovascular events in patients with a history of cardiovascular disease.
• Proteinuric non-diabetic nephropathy.

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

Valzaar R is also used to associated treatment for these conditions: Cardiovascular Events, Diabetic Nephropathy, Heart Failure, Heart Failure With Reduced Ejection Fraction (HFrEF), High Blood Pressure (Hypertension), Myocardial Infarction, Nondiabetic proteinuric chronic kidney disease, Stroke, High risk cardiovascular eventCardiovascular 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 Valzaar R works

Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT₁R) and angiotensin receptor II (AT₂R) occurs.

AT₁R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. These include G_q coupling to the inositol triphosphate pathway, activation of phospholipases C, A₂, and D which contribute to eicosanoid production, activation of Ca^{2+ These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT₂R although the bulk of its effect is mediated by MasR.}

ACE is also responsible for the breakdown of bradykinin. The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.

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

Valzaar R dosage

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25 - 2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5 - 20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

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

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

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

Symptoms of overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte disturbances, and renal failure. Cases of ACE inhibitor induced hepatotoxicity have been reported in humans and presented as acute jaundice and elevated liver enzymes. Removal of the ACE inhbitor resulted in a decline in liver enzymes and re-challenge produced a subsequent increase.

There were no observed tumerogenic effects at chronic doses up to 500mg/kg/day to rats for 24 months or at doses up to 1000mg/kg/day to mice for 18 months. For both species doses were administered by gavage and equivalent to 200 time the maximum recommended human exposure based on body surface area.

No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites of ramipril also produced negative results in the Ames test.

No effects on fertility were seen in rats at doses up to 500mg/kg/day. No teratogenicity was observed in rats and cynomolgus monkeys at doses 400 times the maximum recommended human exposure nor in rabbites at 2 times the maximum recommended human exposure.

LD₅₀ 10 g/kg (rat). LD₅₀ 10.5 g/kg (mouse). LD₅₀ 1 g/kg (dog).

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

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

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

With Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril.

With Potassium Supplements and Potassium-sparing Diuretics: Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.

Other: Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). The co-administration of ramipril and warfarin did not adversely affect the anticoagulant effects of the latter drug.

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 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

The extent of absorption is at least 50-60%.. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.

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

Plasma concentrations of ramiprilat decline in a triphasic manner. Initial rapid decline represents distribution into tissues and has a half life of 2-4 hours. The half life of the apparent elimination phase is 9-18 hours, which is thought to represent clearance of free drug. The half-life of the terminal elimination phase is > 50 hours and thought to represent clearance of drug bound to ACE due to its slow dissociation. The half life of ramiprilat after multiple daily doses (MDDs) is dose-dependent, ranging from 13-17 hours with 5-10 mg MDDs to 27-36 hours for 2.5 mg MDDs.

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 ramipril and ramiprilat was reported to be 7.2 and 77.4 mL/min/1.73m². The mean renal clearance of ramipril and ramiprilat is reported to be 10.7 and 126.8 mL/min in healthy elderly patients with normal renal function, additionally the Cmax of ramiprilat is approximately 20% higher in this population. While the pharmacokinetics of ramipril appear unaffected by reduced renal function, the plasma concentration and half-life of ramiprilat are increased. In patient's with hepatic failure the concentration of ramipril is initially increased while the tmax of ramiprilat is prolonged due to a reduced ability to metabolize the drug. However, steady state concentrations of ramiprilat are the same in hepatic failure as in healthy patients.

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

Following oral administration, about 60% of the dose is eliminated in the urine as unchanged ramipril (6

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

If pregnancy is detected, ramipril should be discontinued as early as possible unless continued use is considered life saving. Ramipril should not be used during lactation.

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

It is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with a ACE inhibitor.

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

Special Warning

Dosage in renal impairment: For the patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily. For the patients with heart failure and renal impairment, the recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Use in children: No information is yet available on the use of Ramipril in children.

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

Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Because the hypotensive effect of Ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ramipril overdosage by infusion of normal saline solution.

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 at cool & dry place, protect from light and moisture.

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

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