Co-Diovan

Co-Diovan

valsartan + hydrochlorothiazide

Manufacturer:

Novartis

Distributor:

DKSH
Full Prescribing Info
Contents
Valsartan, hydrochlorothiazide.
Description
Each film-coated tablet contains valsartan 80 mg and hydrochlorothiazide 12.5 mg, or valsartan 160 mg and hydrochlorothiazide 12.5 mg, or valsartan 160 mg and hydrochlorothiazide 25 mg.
Valsartan is (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-valine. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide.
Each 80/12.5 mg film-coated tablet measures approximately 10.2 mm by 5.4 mm and 3.7 mm in thickness, and weighing approximately 156 mg; 160/12.5 mg film-coated tablet measures approximately 15.2 mm by 6.2 mm and 4.4 mm in thickness, and weighing approximately 312 mg; 160/25 mg film-coated tablet measures approximately 14.2 mm by 5.7 mm and 4.5 mm in thickness, and weighing approximately 310 mg, respectively.
Excipients/Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172) (for 80/12.5 mg and 160/25 mg only), black iron oxide (E172) (for 160/25 mg only).
Action
Pharmacotherapeutic Group: Angiotensin II antagonists combination (valsartan) with diuretic (hydrochlorothiazide). ATC Code: C09D A03.
Pharmacology: Pharmacodynamics: The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II (Ang II), which is formed from angiotensin I (Ang I) through angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, Ang II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.
Valsartan is an orally active and specific Ang II receptor antagonist. It acts selectively on the angiotensin II receptor type 1 (AT1) receptor subtype which is responsible for the known actions of Ang II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked angiotensin II receptor type 2 (AT2) receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000-fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. No potentiation of bradykinin-related adverse effects should be expected. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p<0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% vs 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (p<0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex with the primary binding site for the thiazide diuretic action and inhibition of sodium chloride (NaCl) transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter, perhaps by competing for the Cl- site, affecting mechanisms electrolyte reabsorption: Directly increasing excretion of sodium and chloride in approximately equivalent amounts and indirectly by its diuretic action reducing plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion and urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by Ang II, so co-administration of an Ang II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
Pharmacokinetics: Valsartan: Absorption: Following oral administration of valsartan alone, peak plasma concentrations (Cmax) of valsartan are reached in 2-4 hrs. Mean absolute bioavailability is 23%. When valsartan is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hrs post-dosing plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect and valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution (Vss) of valsartan after IV administration is about 17 L, indicating that valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation/Metabolism: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (<10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multi-exponential decay kinetics [half-life (t½α <1 hr and t½β about 9 hr)]. Valsartan is primarily eliminated in feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following IV administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance). The t½ of valsartan is 6 hrs.
The pharmacokinetics of valsartan is linear in the dose range tested. There is no change in the kinetics of valsartan on repeated administration and little accumulation when dosed once daily. Plasma concentrations were observed to be similar in males and females.
Hydrochlorothiazide: Absorption: The absorption of hydrochlorothiazide after an oral dose is rapid [time to reach maximum plasma concentration (Tmax) about 2 hrs]. The increase in mean AUC is linear and dose proportional in the therapeutic range. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.
Distribution: The distribution and elimination kinetics have generally been described as a bi-exponential decay function. The apparent volume of distribution is 4-8 L/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.
Biotransformation: Hydrochlorothiazide is eliminated predominantly as unchanged drug.
Elimination: Hydrochlorothiazide is eliminated from plasma with a t½ averaging 6-15 hrs in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is minimal when dosed once daily. More than 95% of the absorbed dose is excreted as unchanged compound in the urine.
Valsartan/Hydrochlorothiazide: The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. The kinetics of valsartan is not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear antihypertensive effect, greater than that obtained with either drug given alone or placebo.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Renal Impairment: As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, there is no apparent correlation between renal function [measured by creatinine clearance (CrCl)] and systemic exposure to valsartan (measured by AUC) in patients with different degrees of renal failure. A trial in 5 normotensive patients undergoing haemodialysis demonstrated that complete loss of renal function does not lead to a gross increase in the exposure to valsartan and does not have a major impact on the kinetics of valsartan. This study also confirmed that valsartan is not removed from the plasma by haemodialysis. Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see Contraindications and Precautions).
In patients with severe renal impairment (CrCl <30 mL/min) and patients undergoing dialysis, no data are available for Co-Diovan (see Contraindications).
Hepatic Impairment: About 70% of the absorbed valsartan dose is excreted in the bile, mainly as unchanged compound. The AUC with valsartan has been observed to approximately double in patients with mild or moderate hepatic impairment including patients with biliary obstructive disorders (see Precautions.) There is no data available on the use of valsartan in patients with severe hepatic dysfunction.
Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Clinical Studies: Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hrs and the peak reduction of blood pressure is achieved within 4-6 hrs. The antihypertensive effect persists over 24 hrs after dosing. During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Toxicology: Nonclinical Safety Data: Valsartan/Hydrochlorothiazide: In a variety of preclinical safety studies conducted in several animal species, there was no findings that would exclude the use of therapeutic doses of valsartan/hydrochlorothiazide in humans. High doses of valsartan/hydrochlorothiazide (100/31.25-600/187.5 mg/kg body weight) caused, in rats, a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (moderate to severe raised plasma urea, increases in plasma potassium and magnesium, and mild increases in urinary volume and electrolytes, minimal to slight tubular basophilia and afferent arteriolar hypertrophy at the highest dose level). In marmosets (30/9.375-400/125 mg/kg), the changes were fairly similar though more severe, particularly at the higher dose levels and in the kidney, where the changes developed to a nephropathy, which included raised urea and creatinine. Marmosets also had gastrointestinal mucosal changes at 30/9.373-400/125 mg/kg.
Hypertrophy of the renal juxtaglomerular cells was also seen in rats and marmosets. All changes were considered to be caused by the pharmacological action of valsartan/hydrochlorothiazide, which is synergistic (potentiation is about 10-fold compared to valsartan alone) rather than additive, producing prolonged hypotension particularly in marmosets. For therapeutic doses of valsartan/hydrochlorothiazide in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance. The main preclinical safety findings are attributed to the pharmacological action of the compounds which appear to act synergistically with no evidence of any interaction between the 2 compounds. In the clinic, the actions of the 2 compounds are additive and the preclinical findings have not been demonstrated to have any clinical significance.
The combination valsartan/hydrochlorothiazide was not tested for mutagenicity, clastogenicity or carcinogenicity as there was no evidence of any interaction between the 2 compounds.
Valsartan: Valsartan has been tested for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
Safety Pharmacology and Long Term Toxicity: In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan in humans. In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg/day body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy including raised blood urea nitrogen and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Reproductive Toxicity: Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. In embryofetal development studies (Segment II) in mice, rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats at valsartan doses of 600 mg/kg/day and in rabbits at doses of 10 mg/kg/day. In a peri- and postnatal development toxicity (segment III) study, the offspring of rats given 600 mg/kg/day during the last trimester and during lactation showed a slightly reduced survival rate and a slight developmental delay.
Mutagenicity: Valsartan was devoid of mutagenic potential at either the gene or chromosome level when investigated in various standard in vitro and in vivo genotoxicity studies.
Carcinogenicity: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for 2 years at doses up to 160 and 200 mg/kg/day, respectively.
Hydrochlorothiazide: Hydrochlorothiazide has been tested for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.Hydrochlorothiazide was not teratogenic and had no effects on fertility and conception. No teratogenic potential was revealed in 3 animal species tested, given doses that were at least 10 times greater than recommended human doses of ~1 mg/kg. A decrease in weight gain in suckling rat pups was attributed to the high dose (15 times the human dose) and diuretic effects of hydrochlorothiazide, with subsequent effects on milk production (see Use in Pregnancy & Lactation).
Indications/Uses
Treatment of hypertension in patients whose blood pressure is not adequately controlled by monotherapy. This fixed-dose combination should be used as 2nd-line therapy.
Dosage/Direction for Use
Recommended Dose: 1 tab daily. When clinically appropriate, either Co-Diovan 80/12.5 mg or 160/12.5 mg may be used.
Co-Diovan 160/12.5 mg may be administered in patients whose blood pressure is not adequately controlled after 4 weeks of treatment by valsartan 160 mg monotherapy. Treatment with Co-Diovan 160/25 mg is limited to those patients who do not show adequate blood pressure reduction with Co-Diovan 160/12.5 mg is limited to those patients who do not show adequate blood pressure reduction with Co-Diovan 160/12.5 mg after at least 4 weeks of treatment.
Children: The safety and efficacy of Co-Diovan have not been established in children.
Renal or Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (CrCl >30 mL/min). In patients with mild to moderate hepatic impairment without cholestasis, the daily dose of valsartan should not exceed 80 mg (see Precautions).
Patients with severe renal or hepatic impairment, biliary cirrhosis or cholestasis must not take Co-Diovan (see Contraindications).
Administration: Co-Diovan should be administered consistently with or without food (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
Overdosage with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be IV infusion of normal saline solution.
Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma-binding behaviour, whereas, clearance of hydrochlorothiazide will be achieved by dialysis.
Contraindications
Hypersensitivity to valsartan, hydrochlorothiazide, other sulphonamides or to any of the excipients of Co-Diovan.
Pregnancy (see Use in Pregnancy & Lactation).
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Anuria, severe renal impairment (creatinine clearance <30 mL/min).
Refractory hypokalemia, hyponatremia, hypercalcemia, and symptomatic hyperuricemia.
Concomitant use of angiotensin receptor antagonists (ARBs) including valsartan or of angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with Type 2 diabetes (see Interactions).
Warnings
Use in Pregnancy: When used in pregnancy during the 2nd and 3rd trimesters, drugs that act directly on the renin-angiotensin system (RAS) can cause injury and even death to the developing foetus. When pregnancy is detected, Co-Diovan should be discontinued as soon as possible.
Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the RAS can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in patients who were taking ACE inhibitors. When pregnancy is detected, Co-Diovan should be discontinued as soon as possible.
The use of drugs that act directly on the RAS during the 2nd and 3rd trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported although it is not clear whether these occurrences were due to exposure to Co-Diovan.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the 1st trimester.
Mothers whose embryos and fetuses are exposed to an Ang II receptor antagonist only during the 1st trimester should be informed. When patients become pregnant, physicians should advise the patient to discontinue the use of Co-Diovan as soon as possible. Rarely (probably less than often than once in every thousand pregnancies), no alternative to a drug acting on the RAS will be found. In these rare cases, the mother should be apprised of the potential hazards to their foetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, Co-Diovan should be discontinued unless it is considered life-saving for the mother. Contraction Stress Testing (CST), a Nonstress Test (NST) or Biophysical Profiling (BPP) may be appropriate depending upon the week of pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an Ang II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Special Precautions
Serum Electrolyte Changes: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (eg, heparin) should be used with caution. Thiazide diuretics can precipitate new onset hypokalemia or exacerbate preexisting hypokalemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss ie, salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalemia is accompanied by clinical signs (eg, muscular weakness, paresis or electrocardiogram alterations), Co-Diovan should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.
Thiazide diuretics can precipitate new onset hyponatremia and hypochloremic alkalosis or exacerbate preexisting hyponatremia. Hyponatremia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended.
Sodium- and/or Volume-Depleted Patients: In severely sodium- and/or volume-depleted patients eg, those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan. Co-Diovan should be used only after correction of any preexisting sodium and/or volume-depletion otherwise, the treatment should start under close medical supervision.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an IV infusion of normal saline. Treatment can be continued once the blood pressure has stabilized.
Renal Artery Stenosis: Co-Diovan should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, since blood urea and serum creatinine may increase in such patients.
Renal Impairment: Renal function has a marked effect on the kinetics of hydrochlorothiazide (Pharmacology: Pharmacokinetics: Renal Impairment under Actions). Co-Diovan should be used with caution in patients with moderate renal impairment (CrCl >30 mL/min). Periodic checks of serum potassium, creatinine and uric acid levels are advisable.
Patients with severe renal impairment (CrCl <30mL/min) should not take Co-Diovan (see Contraindications).
Hepatic Impairment: In patients with mild to moderate hepatic impairment without cholestasis, Co-Diovan should be used with caution (see Pharmacology: Pharmacokinetics: Hepatic Impairment under Actions). Patients with severe hepatic impairment, biliary cirrhosis or cholestasis should not take Co-Diovan (see Contraindications).
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Co-Diovan should be immediately discontinued in patients who develop angioedema and Co-Diovan should not be re-administered.
Systemic Lupus Erythematosus: Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other Metabolic Disturbances: Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance, and raise serum levels of cholesterol and triglycerides.
Like other diuretics, hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia, and precipitate gout in susceptible patients.
Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, it should be used with caution in patients with hypercalcaemia. Marked hypercalcaemia unresponsive to thiazide withdrawal or ≥12 mg/dL may be evidence of an underlying thiazide independent hypercalcaemic process.
Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcaemia occurs, further diagnostic clarification is necessary.
General: Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Acute Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain, and typically occur within hrs to week of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy.
Patients with Heart Failure/Post-Myocardial Infarction: In patients whose renal function may depend on the activity of the RAAS (eg, patients with severe congestive heart failure), treatment with ACE inhibitors or ARBs has been associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure, and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Dual Blockade of the Renin-Angiotensin System (RAS): Caution is required while co-administering ARBs, including valsartan, with other agents blocking the RAS eg, ACE inhibitors or aliskiren (see Interactions).
Effects on the Ability to Drive or Operate Machinery: As with other antihypertensive agents, it is advisable to exercise caution when driving or operating machinery.
Impairment of Fertility: There is no information on the effects of valsartan or hydrochlorothiazide on human fertility. Studies in rats did not show any effects of valsartan or hydrochlorothiazide on fertility (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
Use In Pregnancy & Lactation
Use in Pregnancy: As for any drug that also acts directly on the RAAS, Co-Diovan must not be used during pregnancy (see Contraindications). Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to angiotensin converting enzyme (ACE) inhibitors (a specific class of drugs acting on the renin-angiotensin-aldosterone system - RAAS) given to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
If pregnancy is detected during therapy, Co-Diovan should be discontinued as soon as possible (see Pharmacology: Toxicology: Nonclinical Safety Data under Actions).
Women of Child-Bearing Potential: As for any drug that also acts directly on the RAAS, Co-Diovan should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
Use in Lactation: It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use Co-Diovan in breast-feeding mothers.
Adverse Reactions
Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual post-marketing reports are presented below according to system organ class. Adverse reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/hydrochlorothiazide.
Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 1.)

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The following events have also been observed during clinical trials in hypertensive patients irrespective of their causal association with the study drug: Abdominal pain, abdominal pain upper, anxiety, arthritis, asthenia, back pain, bronchitis, bronchitis acute, chest pain, dizziness postural, dyspepsia, dyspnea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhydrosis, hypoesthesia, influenza, insomnia, ligament sprain, muscle spasms, muscle strain, nasal congestion, nasopharyngitis, nausea, neck pain, edema, edema peripheral, otitis media, pain in extremity, palpitations, pharyngolaryngeal pain, pollakiuria, pyrexia, sinusitis, sinus congestion, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, vision disturbance.
Additional Information on the Individual Components: Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Co-Diovan as well, even if not observed in clinical trials or during post-marketing period.
Valsartan: See Table 2.

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The following events have also been observed during clinical trials in hypertensive patients irrespective of their causal association with the study drug: Arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, libido decrease, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Hydrochlorothiazide: See Table 3.

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Drug Interactions
Valsartan-Hydrochlorothiazide: The following drug interactions may occur due to both components (valsartan and/or hydrocholorothiazide) of Co-Diovan: Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotension II receptor antagonists or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Co-Diovan. Therefore, careful monitoring of serum lithium concentrations is recommended during concomitant use.
Valsartan: The following potential drug interactions may occur due to the valsartan component of Co-Diovan: Dual blockade of the Renin-Angiotensin-System (RAS) with Angiotensin II Receptor Blockers (ARBs), Angiotensin-Converting Enzyme (ACE) Inhibitors or Aliskiren: The concomitant use of ARBs, including valsartan, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Diovan hydrochlorothiazide and other agents that affect the RAS (see Precautions).
The concomitant use of ARBs, including valsartan, or of ACE inhibitors with aliskiren should be avoided in patients with severe renal impairment [glomerular filtration rate (GFR) <30 mL/min] (see Precautions).
The concomitant use of ARBs, including valsartan, or of ACE inhibitors with aliskiren is contraindicated in patients with Type 2 diabetes (see Contraindications).
Potassium: 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 caution and with frequent monitoring of potassium.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including Selective Cyclooxygenase-2 (COX-2) Inhibitors: When Ang II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy) or have compromised renal function, concomitant use of Ang II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter organic anion transporting polypeptide (OATP1B1) and the hepatic efflux transporter multidrug resistance associated protein (MRP2). Co-administration of inhibitors of the uptake transporter (rifampin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
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.
Hydrochlorothiazide: The following potential drug interactions may occur due to the thiazide component of Co-Diovan: Other Anti-Hypertensive Drugs: Thiazides potentiate the antihypertensive action of other antihypertensive drugs [eg, guanethidine, methyldopa, β-blockers, vasodilators, calcium-channel blockers, ACE inhibitors, ARBs and direct renin inhibitors (DRIs)].
Skeletal Muscle Relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants eg, curare derivatives.
Drugs Affecting Serum Potassium Level: The hypokalemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics (see Precautions).
Drugs Affecting Serum Sodium Level: The hyponatremic effect of diuretics may be intensified by concomitant administration of drugs eg, antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs (see Precautions).
Antidiabetic Agents: Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and of oral antidiabetic agents.
Digitalis Glycosides: Thiazide-induced hypokalemia or hypomagnesemia may occur as adverse effects, favouring the onset of digitalis-induced cardiac arrhythmias (see Precautions).
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Cyclooxygenase-2 (COX-2) Selective Inhibitors: Concomitant administration of NSAIDs (eg, salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of Co-Diovan. Concurrent hypovolemia may induce acute renal failure.
Allopurinol: Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine: Co-administration of thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine.
Antineoplastic Agents (eg, Cyclophosphamide, Methotrexate): Concomitant use of thiazide diuretics may reduce the renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Anticholinergic Agents: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (eg, atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic drugs eg, cisapride may decrease the bioavailability of thiazide-type diuretics.
Ion-Exchange Resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hrs before or 4 hrs-6 hrs after the administration of resins would potentially minimize the interaction.
Vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Ciclosporin: Concomitant treatment with ciclosporine may increase the risk of hyperuricemia and gout-type complications.
Calcium Salts: Concomitant use of thiazide type diuretics may lead to hypercalcaemia by increasing tubular calcium reabsorption.
Diazoxide: Thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.
Methyldopa: There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Alcohol, Barbiturates or Narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates or narcotics may potentiate orthostatic hypotension.
Pressor Amines: Hydrochlorothiazide may reduce the response to pressor amines eg, noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
Caution For Usage
Instructions for Use and Handling: No special requirements.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C.
ATC Classification
C09DA03 - valsartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
80/12.5 mg FC tab (light orange, ovaloid, slightly convex, non-divisible, imprinted with HGH on one side and CG on the other side) 28's. 160/12.5 mg FC tab (dark red, ovaloid, slightly convex, non-divisible, imprinted with HHH on one side and CG on the other side) 28's. 160/25 mg FC tab (brown-orange, ovaloid, slightly convex, non-divisible, imprinted with HXH on one side and NVR on the other side) 28's.
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