Co-Dizant

Valsartan, hydrochlorothiazide.

Each tablet of Co-Dizant contains valsartan 80 mg and hydrochlorothiazide 12.5 mg.

Pharmacology: Toxicology: 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 and 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 and 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.
In a variety of preclinical safety studies conducted in several animal species with vals­artan, hydrochlorothiazide and valsartan:hydrochlorothiazide, there was no evidence of systemic or target organ toxicity. High doses of valsartan:hydrochlorothiazide (100:31.25 to 600:187.5 mg/kg body weight) caused in rats, a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (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 to 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.
The combination valsartan:hydrochlorothiazide was not tested for mutagenicity, clastogenicity or carcinogenicity as there was no evidence for any interaction be­tween the 2 compounds. However, both valsartan and hydrochlorothiazide have been tested individually for mutagenicity, clastogenicity and carcinogenicity with negative results.

Management of hypertension in patients whose blood pressure is not adequately-controlled by monotherapy.

Recommended Dose: 1 tablet daily. The maximum antihypertensive effect is seen within 2-4 weeks. No dose adjustment is required for patients with mild to moderate renal impairment (CrCl >30 mL/min) and hepatic impairment.
Administration: Co-Dizant can be taken with or without food and should be administered with water.

Symptoms: Overdose with valsartan may result in marked hypotension, which could lead to depressed levels of consciousness, circulatory collapse and/or shock.
Valsartan is unlikely to be removed by hemodialysis.
Limited data are available related to overdosage in humans. The most likely mani­festations of overdosage would be hypotension and tachycardia. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be IV infusion of normal saline solution.
The following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: Nausea, somnolence, hypovolemia and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms. The therapeutic measures depend on the time of ingestion and the type and severity of the symp­toms, stabilization of the circulatory condition being of prime importance.
If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly. Valsartan cannot be elimi­nated by means of hemodialysis because of its strong plasma binding behavior whereas, clearance of hydrochlorothiazide will be achieved by dialysis.
Treatment: The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms; stabilization of the circulatory condition is of prime importance. If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken.

Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients of Co-Dizant.
Severe renal impairment (CrCl <10 mL/min) and hepatic impairment.
Anuria, cirrhosis, biliary obstruction, biliary cirrhosis and cholestasis.
Refractory hypokalemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.
Use in Pregnancy: Due to the mechanism of action of AIIRAs, a risk for the fetus cannot be excluded. In utero exposure to ACE inhibitors [a specific class of drugs acting on the renin-angiotensin-aldosterone system (RAAS)] given to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, 1st 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. As for any drug that also acts directly on the RAAS, valsartan/hydrochlorothiazide should not be used during pregnancy or 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.
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, valsartan/hydrochlorothiazide should be discontinued as soon as possible.

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 valsartan or valsartan/hydrochlorothiazide.
For Co-Dizant, those patients whose diuretic dose cannot be reduced in order to correct their sodium and/or volume depletion a starting dose of 40 mg is recommended.
Valsartan/hydrochlorothiazide 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: Short-term administration of valsartan to 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal hemodynamics, serum creatinine or blood urea nitrogen (BUN). However, since other drugs that affect the RAAS may increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring is recommended as a safety measure.
In patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of valsartan/hydrochlorothiazide has not been established.
Serum Electrolyte Changes: Concomitant use with potassium supplements, potassium-sparing diuretics, salt sub­stitutes containing potassium or other agents that may increase potassium levels (heparin, etc) is not recommended. Monitoring of potassium should be undertaken as appropriate. Hypokalemia has been reported under treatment with thiazide diuretics including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended. Treatment with thiazide diuretics including hydrochlorothiazide has been associated with hyponatremia and hypochloremic alkalosis. Thiazides including hydrochlorothiazide, increase the urinary excretion of magnesium, which may result in hypomagnesemia. Calcium excretion is decreased by thiazide diuret­ics. This may result in hypercalcemia. As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
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, triglycerides and uric acid. In diabetic patients dos­age adjustments of insulin or oral hypoglycemic agents may be required. Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Laboratory Findings: A >20% decrease in serum potassium was observed in 3.7% of patients receiving valsartan/hydrochlorothiazide as compared to placebo (3.1%).
Elevations in creatinine and BUN occurred in 1.9% and 14.7%, respectively, of patients taking valsartan/hydrochlorothiazide and 0.4% and 6.3%, respectively, given placebo in controlled clinical trials.
Neutropenia was observed in 0.1% of patients treated with valsartan/hydrochlorothiazide versus 0.4% of patients treated with placebo.
Hepatic Impairment: Based on pharmacokinetic data which demonstrate significantly increased (approximately 2-fold increase) plasma concentrations of valsartan in mild to moderately hepatically-impaired patients, a lower dose is recommended in patients with hypertension. In these patients, the dose of 80 mg should not be exceeded but doses >80 mg twice daily should only be considered if the clinical benefit is likely to outweigh the possible risk associated with increased exposure of valsartan. Patients with severe hepatic impairment, cirrhosis, biliary obstruction are contraindicated from using valsartan (see Contraindications).
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg. Valsartan/hydrochlorothiazide should be used with particular caution in patients with biliary obstructive disorders and in pa­tients with severe hepatic impairment. Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Renal Impairment: As a consequence of inhibiting the RAAS, increases of blood urea and serum creatinine, and changes in renal function including renal failure (very rarely) have been reported particularly in patients with preexisting renal dysfunction or those with severe cardiac insufficiency.
Serum potassium should be monitored in renally-impaired or elderly patients if they are also taking potassium supplement.
No dosage adjustment is required for patients with renal impairment with a CrCl ≥30 mL/min.
Effects on the Ability to Drive or Operate Machinery: When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur.
As with other antihypertensive agents, it is advisable to exercise caution when driving or operating machinery.
Use in Lactation: Because no information is available regarding the use of valsartan during breastfeeding, valsartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
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 valsartan/hydrochlorothiazide in lactating mothers.
Use in Children: Valsartan and valsartan/hydrochlorothiazide is not recommended for use in children and adolescents <18 years due to a lack of data on safety and efficacy.
Use in 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. No dose adjustment is required in the elderly.

Use in Pregnancy: Due to the mechanism of action of AIIRAs, a risk for the fetus cannot be excluded. In utero exposure to ACE inhibitors [a specific class of drugs acting on the renin-angiotensin-aldosterone system (RAAS)] given to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, 1st 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. As for any drug that also acts directly on the RAAS, valsartan/hydrochlorothiazide should not be used during pregnancy or 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.
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, valsartan/hydrochlorothiazide should be discontinued as soon as possible.
Use in Lactation: Because no information is available regarding the use of valsartan during breastfeeding, valsartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
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 valsartan/hydrochlorothiazide in lactating mothers.

Valsartan/hydrochlorothiazide has been evaluated for safety in >4,300 patients. Adverse experiences have generally been mild and transient in nature. The following table of adverse experiences is based on 3 controlled trials involving a total of 7,616 patients. Of the 7,616 patients, 4,372 received valsartan in combination with hydrochlorothiazide. The overall incidence of adverse experiences with valsartan/hydrochlorothiazide was similar to placebo. All adverse experiences showing an incidence of ≥1% in the valsartan/hydrochlorothiazide group are included in the following table, irrespective of their causal association with the study drug. (See table.)

Click on icon to see table/diagram/image

Other adverse experiences with a frequency <1% included abdominal pain, anxiety, arthritis, asthenia, acute bronchitis, chest pain, postural dizziness, dyspepsia, dyspnea, dry mouth, erectile dysfunction, gastroenteritis, hyperhidrosis, hypesthesia, hypokalemia, hypotension, influenza, insomnia, muscle spasms and strain, nausea, nasal congestion, neck pain, edema, peripheral edema, otitis media, pain in extremity, palpitations, paresthesia, pharyngolaryngeal pain, pollakiuria, pyrexia, sinus congestion, sinusitis, somnolence, ligament sprain, syncope, tachycardia, tinnitus, urinary tract infection, vertigo, viral infection, blurred vision, vision disturbance. It is unknown whether these effects were casually related to the therapy.
Post-marketing data revealed very rare cases of angioneurotic edema, rash, pruritus and other hypersensitivity/allergic reactions including serum sickness and vasculitis. Very rare cases of renal impairment and myalgia have also been reported. There have also been reported several cases of hydrochlorothiazide-induced pulmonary edema with granulocytic infiltration and immunoglobulin G (IgG) deposition in alveolar membranes. Non-cardiogenic pulmonary edema may be an immunologically-mediated rare idiosyncratic reaction to hydrochlorothiazide.
Other additional adverse experiences reported in clinical trials with valsartan monotherapy, irrespective of their causal association with the study drug, were with a frequency <1%: Decreased libido, acute renal failure, occasional elevations in liver function values.
Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in valsartan/hydrochlorothiazide. The following adverse reactions have been reported in patients treated with thiazide diuretics alone including hydrochlorothiazide: Very Common: Mainly at higher doses, hypokalemia, increased blood lipids.
Common: Hyponatremia, hypomagnesemia, hyperuricemia, urticaria and other forms of rash, decreased appetite, mild nausea and vomiting, orthostatic hypotension, which may be aggravated by alcohol, anesthetics or sedatives, and impotence.
Rare: Hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic state, photosensitivity reaction, abdominal discomfort, constipation, diarrhea, cholestasis or jaundice, arrhythmias, headache, dizziness, sleep disorders, depression, paresthesia, visual impairment, thrombocytopenia, sometimes with purpura.
Very Rare: Hypochloremic alkalosis, necrotizing vasculitis, toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow failure, hemolytic anemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary edema.
Adverse Drug Reactions from Post-Marketing Experiences: The following adverse drug reactions have been identified based on post-marketing experiences. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies. Therefore, the frequency assigned is "not known".
Frequency Not Known: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma.

Valsartan and hydrochlorothiazide combination may increase the effects of other agents with antihypertensive properties.
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.
Reversible increases in serum lithium concentrations and toxicity have been reported during 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.
The following potential drug interactions may occur due to the 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.
Nonsteroidal Anti-Inflammatory Agents including Selective COX-2 Inhibitors: When angiotensin 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 an­giotensin 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.
CYP450 Interactions: In vitro metabolism studies indicate that CYP450-mediated drug interactions between valsartan and co-administered drugs are unlikely because of low extent of metabolism.
The following potential drug interactions may occur due to the thiazide compo­nent of Co-Dizant: NSAIDs and COX-2 Selective Inhibitors: Concomitant administration of NSAIDs (eg, salicylic acid derivative, indomethacin) may weaken the diuretic and antihyper­tensive activity. Concurrent hypovolemia may induce acute renal failure.
Medicinal products associated with potassium loss and hypokalemia [eg, kaliu­retic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, peni­cillin G, salicylic acid and derivatives].
Absorption of thiazide diuretics including hydrochlorothiazide is decreased by cholestyramine or colestipol.
Thiazides including hydrochlorothiazide potentiate the action of skeletal muscle relaxants eg, curare derivatives.
Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and of oral antidiabetic agents.
Co-administration of thiazide diuretics including hydrochlorothiazide may increase the incidence of hypersensitivity reactions to allopurinol and it may enhance the hyperglycemic effects of diazoxide.
Antineoplastic Agents (eg, Cyclophosphamide, Methotrexate): Concomitant use of thiazide diuretics may reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.
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.
There have been reports in the literature of hemolytic anemia occurring with con­comitant use of hydrochlorothiazide and methyldopa.
Administration of thiazide diuretics including hydrochlorothiazide with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Concomitant treatment with cyclosporin may increase the risk of hyperuricemia and gout-type complications.
Concomitant administration of thiazide diuretics with alcohol, barbiturates or narcotics may potentiate orthostatic hypotension.
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.
Thiazide-induced hypokalemia or hypomagnesemia may occur as unwanted ef­fects, favoring the onset of digitalis-induced cardiac arrhythmias.
Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Such patients should therefore be advised about the possibility of hyponatremic reactions and should be monitored accordingly.

Instructions for Use and Handling: Do not preserve in other containers in order to maintain quality of the drug and avoid misuse.

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists / Diuretics

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.

Rx

FC tab (light orange, oval, engraved with "UT" on one side and "VH80" on the other side) 98's.