CoAprovel

CoAprovel

irbesartan + hydrochlorothiazide

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Irbesartan, hydrochlorothiazide.
Description
Each tablet contains irbesartan 150 or 300 mg and hydrochlorothiazide 12.5 or 25 mg.
Action
Pharmacology: CoAprovel is a combination of an angiotensin II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Irbesartan is a potent, orally active, selective angiotensin II receptor (AT1 subtype) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II AT1 receptors results in increases in plasma renin levels and angiotensin II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses in patients without risk of electrolyte imbalance (see Precautions and Interactions). Irbesartan does not inhibit ACE (kininase II), an enzyme which generates angiotensin II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensivve effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of irbesartan tend to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hrs, and peak effect occurs at about 4 hrs, while the action persists for approximately 6-12 hrs.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in blood pressure across their therapeutic dose ranges. The addition of hydrochlorothiazide 12.5 mg to irbesartan 300 mg once daily in patients not adequately controlled on irbesartan 300 mg alone, resulted in further placebo-corrected diastolic blood pressure reduction at trough (24 hrs post-dosing) of 6.1 mmHg. The combination of irbesartan 300 mg and hydrochlorothiazide 12.5 mg resulted in an overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mmHg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300/12.5-mg combination may respond when uptitrated to 300/25 mg. In these patients, an incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 13.3 and 8.3 mmHg, respectively.
Once-daily dosing with irbesartan 150 mg and hydrochlorothiazide 12.5 mg gave systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hrs post-dosing) of 12.9/6.9 mmHg in patients with mild to moderate hypertension. Peak effects occurred at 3-6 hrs. When assessed by ambulatory blood pressure monitoring (ABPM), the combination irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily produced consistent reduction in blood pressure over the 24-hr period with mean 24-hr placebo-subtracted systolic/diastolic reductions of 15.8/10 mmHg. When measured by ABPM, the trough to peak effects of CoAprovel 150/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and 76% for CoAprovel 150/12.5 mg and 300/12.5 mg, respectively. These 24-hr effects were observed without excessive blood pressure lowering at peak and are consistent with safe and effective blood pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on hydrochlorothiazide 25 mg alone, the addition of irbesartan gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mmHg.
The blood pressure-lowering effect of irbesartan in combination with hydrochlorothiazide is apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide was maintained for >1 year. Although not specifically studied with the CoAprovel, rebound hypertension has not been seen with either irbesartan or hydrochlorothiazide.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
There is no difference in response to CoAprovel, regardless of age or gender. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (eg, 12.5 mg daily), the antihypertensive response in black patients approaches that of non-black patients.
Two (2) studies evaluated CoAprovel as initial hypertension therapy. The first study investigated 697 patients with severe hypertension (seated diastolic blood pressure [SeDBP] >110 mmHg) randomized to irbesartan 150 mg or irbesartan/hydrochlorothiazide 150/12.5 mg and force-titrated after 1 week to irbesartan 300 mg or irbesartan/hydrochlorothiazide 300/25 mg, respectively. In this study, the mean baseline blood pressure was approximately 172/113 mmHg in each treatment group and decrease of seated systolic blood pressure (SeSBP)/seated diastolic blood pressure (SeDBP) at 5 weeks were 30.8/24 mmHg and 21.1/19.3 mmHg for irbesartan/hydrochlorothiazide and irbesartan, respectively (p<0.0001). A greater proportion of the patients on CoAprovel achieved a diastolic blood pressure <90 mmHg (47.2% for CoAprovel, 33.2% for irbesartan; p=0.0005) and a greater proportion of the patients on the CoAprovel achieved simultaneous control of SeSBP <140 mmHg and SeDBP <90 mmHg (34.6% versus 19.2%;p<0.0001). Furthermore, at 5 weeks severe blood pressure levels (SeSBP ≥180 mmHg or SeDBP ≥110 mmHg) were less common on irbesartan/hydrochlorothiazide than irbesartan (5.4% versus 13.8%; p=0.0003). The types and incidences of adverse events reported for patients treated with CoAprovel were similar to the adverse events profile for patients treated with irbesartan as initial therapy. There were no reported cases of syncope in either treatment group. There were 0.6% and 0% patients with hypotension and 2.8% and 3.1% patients with dizziness adverse reactions reported in the group treated with CoAprovel and the group treated with irbesartan, respectively.
The second study investigated 538 patients with moderate hypertension randomized to irbesartan 150 mg, hydrochlorothiazide 12.5 mg or irbesartan/hydrochlorothiazide 150/12.5 mg and force-titrated after 2 weeks to irbesartan 300 mg, hydrochlorothiazide 25 mg or irbesartan/hydrochlorothiazide 300/25 mg, respectively. In this study the mean baseline blood pressure was approximately 162/98 mmHg in each group. The types and incidences of adverse events reported for patients treated with CoAprovel were similar to adverse events profile for patients treated with irbesartan alone or hydrochlorothiazide alone as initial therapy. There were no reported cases of syncope in the combination therapy group. There were 0.9%, 0% and 0% of patients with hypotension and 2.4%, 1.9% and 0% of patients with dizziness adverse reactions reported in the group treated with CoAprovel compared to the irbesartan and hydrochlorothiazide groups, respectively.
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either drug.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Following oral administration of CoAprovel, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of CoAprovel. Peak plasma concentration occurs at 1.5-2 hrs after oral administration for irbesartan and 1-2.5 hrs for hydrochlorothiazide.
Plasma protein-binding of irbesartan is approximately 96%, with negligible binding to cellular blood components. The volume of distribution for irbesartan is 53-93 L. Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 L/kg.
Irbesartan exhibits linear and dose-proportional pharmacokinetics over the dose range of 10-600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the mechanism for this is unknown. The total body and renal clearances are 157-176 and 3-3.5 mL/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hrs. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in elderly subjects (≥65 years) than those of young subjects (18-40 years). However, the terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients. The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hrs.
Following oral or IV administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidized by the cytochrome P-450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the feces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated unchanged within 24 hrs. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast milk.
Renal Impairment: In patients with renal impairment or those undergoing hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis. In patients with creatinine clearance <20 mL/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hrs.
Hepatic Impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.
Toxicology: Preclinical Safety Data: Irbesartan/Hydrochlorothiazide: The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration was evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings observed of relevance to human therapeutic use. The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide combination at 10/10 and 90/90 mg/kg/day, were also seen with 1 of the 2 drugs alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions were observed):
Kidney changes, characterized by slight increases in serum urea and creatinine, and hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the interaction of irbesartan with the renin-angiotensin system; slight decreases in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit); stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in a 6-month toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques; decreases in serum potassium due to hydrochlorothiazide and partly prevented when hydrochlorothiazide was given in combination with irbesartan.
Most of the previously mentioned effects appear to be due to the pharmacological activity of irbesartan (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and occur also with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combination on fertility have not been evaluated in animal studies, as there is no evidence of adverse effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone. However, another angiotensin II antagonist affected fertility parameters in animal studies when given alone. These findings were also observed with lower doses of this other angiotensin II antagonist when given in combination with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been evaluated in animal studies.
Irbesartan: There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In nonclinical safety studies, high doses of irbesartan (≥250 mg/kg/day in rats and ≥100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit). At very high doses (≥500 mg/kg/day), degenerative changes in the kidneys (eg, interstitial nephritis, tubular distention, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the drug which led to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥90 mg/kg/day, in macaques at ≥10 mg/kg/day). All of these changes were considered to be caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema) in rat fetuses, which were resolved after birth. In rabbits, abortion or early resorption was noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.
Hydrochlorothiazide: Although equivocal evidence for a genotoxic or carcinogenic effect was found in some experimental models, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasms.
Indications/Uses
Treatment of essential hypertension.
This fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone. It is also indicated as initial treatment when hypertension is severe and rapid control of blood pressure (within days to weeks) is of primary clinical importance (see Pharmacodynamics under Actions).
Dosage/Direction for Use
CoAprovel can be used once daily, with or without food in patients whose blood pressure is not adequately controlled by irbesartan or hydrochlorothiazide alone. In patients with severe hypertension, CoAprovel 150/12.5 mg once daily may be initiated.
Dose titration with the individual components (ie, irbesartan and hydrochlorothiazide) can be recommended.
When clinically appropriate, direct change from monotherapy to the fixed combinations may be considered: CoAprovel 150/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone; CoAprovel 300/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by CoAprovel 150/12.5 mg; CoAprovel 150/12.5 mg, 2 tabs once a day or CoAprovel 300/25 mg, 1 tab once daily, may be administered in patients insufficiently controlled by CoAprovel 300/12.5 mg; CoAprovel 150/12.5 mg, 2 tabs once daily, may be administered in patients insufficiently controlled by CoAprovel 150/12.5 mg (see Pharmacodynamics under Actions).
Doses higher than irbesartan 300 mg/hydrochlorothiazide 25 mg once daily are not recommended. When necessary, CoAprovel may be administered with another antihypertensive drug (see Interactions).
Renal Impairment: Due to the hydrochlorothiazide component, CoAprovel is not recommended for patients with severe renal dysfunction (creatinine clearance <30 mL/min). Loop diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients with renal impairment whose renal creatinine clearance is ≥30 mL/min (see Contraindications and Precautions).
Intravascular Volume Depletion: Volume and/or sodium depletion should be corrected prior to administration of CoAprovel.
Hepatic Impairment: CoAprovel is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function. No dosage adjustment of CoAprovel is necessary in patients with mild to moderate hepatic impairment (see Contraindications).
Elderly: No dosage adjustment of CoAprovel is necessary in elderly patients.
Overdosage
No specific information is available on the treatment of overdosage with CoAprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.
The most likely manifestations of irbesartan overdosage are expected to be hypotension and tachycardia; bradycardia might also occur.
Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
Irbesartan is not removed by hemodialysis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Contraindications
Hypersensitivity to irbesartan and hydrochlorothiazide, to any of the excipients of CoAprovel, or to other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance).
The following are the contraindications associated with hydrochlorothiazide: Severe renal impairment (creatinine clearance <30 mL/min); refractory hypokalemia, hypercalcemia; severe hepatic impairment, biliary cirrhosis and cholestasis.
Use in pregnancy: Thiazides cross the placental barrier and appear in cord blood. They may cause fetal electrolyte disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal thrombocytopenia, or fetal or neonatal jaundice have been reported with maternal thiazide therapy. Since CoAprovel contains hydrochlorothiazide, it is not recommended during the 1st trimester of pregnancy. A switch to a suitable alternative treatment should be carried-out in advance of a planned pregnancy.
CoAprovel is contraindicated in the 2nd and 3rd trimesters of pregnancy.
In the 2nd and 3rd trimesters, substances that act directly on the renin-angiotensin system can cause fetal or neonatal renal failure, fetal skull hypoplasia and even fetal death. If pregnancy is diagnosed, CoAprovel should be discontinued as soon as possible skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.
Use in lactation: Because of the potential adverse effects on the nursing infant, CoAprovel is contraindicated during lactation. It is not known if irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Thiazides appear in human milk and may inhibit lactation.
Special Precautions
Hypotension: Volume-Depleted Patients: CoAprovel has been rarely associated with symptomatic hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhea or vomiting. Such conditions should be corrected before initiating therapy with CoAprovel.
Renal Artery Stenosis: Renovascular Hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists. While this is not documented with CoAprovel, a similar effect should be anticipated.
Renal Impairment and Kidney Transplantation: When CoAprovel is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. There is no experience regarding the administration of CoAprovel in patients with a recent kidney transplantation. CoAprovel should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Contraindications). Thiazide diuretic-associated azotemia may occur in patients with impaired renal function. No dosage adjustment is necessary in patients with renal impairment whose creatinine clearance is ≥30 mL/min. However, in patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min but <60 mL/min), this fixed dose combination should be administered with caution.
Hepatic Impairment: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with CoAprovel in patients with hepatic impairment.
Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary Aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of CoAprovel is not recommended.
Metabolic and Endocrine Effects: Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.
Increase in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however at the 12.5 mg dose contained in CoAprovel, minimal or no effects were reported.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Electrolyte Imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolyte should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Warning signs of fluid electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances eg, nausea and vomiting.
Although hypokalemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the irbesartan component of CoAprovel hyperkalemia might occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes should be co-administered cautiously with CoAprovel (see Interactions).
There is no evidence that irbersartan would reduce or prevent diuretic-induced hyponatremia.
Chloride deficit is generally mild and usually does not require treatment.
Thiazides may decrease 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 hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia.
Lithium: The combination of lithium and CoAprovel is not recommended (see Interactions).
Anti-Doping Test: Hydrochlorothiazide contained in CoAprovel could produce a positive analytic result in an anti-doping test.
General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with ACE inhibitors or angiotensin II receptor antagonists that affect this system has been associated with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Lactose: CoAprovel contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take CoAprovel.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, CoAprovel is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that occasionally, dizziness or weariness may occur during treatment of hypertension.
Use in children: Safety and efficacy of CoAprovel have not been established in children (<18 years).
Use In Pregnancy & Lactation
Use in pregnancy: Thiazides cross the placental barrier and appear in cord blood. They may cause fetal electrolyte disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal thrombocytopenia, or fetal or neonatal jaundice have been reported with maternal thiazide therapy. Since CoAprovel contains hydrochlorothiazide, it is not recommended during the 1st trimester of pregnancy. A switch to a suitable alternative treatment should be carried-out in advance of a planned pregnancy.
CoAprovel is contraindicated in the 2nd and 3rd trimesters of pregnancy.
In the 2nd and 3rd trimesters, substances that act directly on the renin-angiotensin system can cause fetal or neonatal renal failure, fetal skull hypoplasia and even fetal death. If pregnancy is diagnosed, CoAprovel should be discontinued as soon as possible skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.
Use in lactation: Because of the potential adverse effects on the nursing infant, CoAprovel is contraindicated during lactation. It is not known if irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Thiazides appear in human milk and may inhibit lactation.
Adverse Reactions
The frequency of adverse reactions listed as follows is defined using the following convention: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Irbesartan/Hydrocholorothiazide Combination: In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan/hydrochlorothiazide and the placebo groups. Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan/hydrochlorothiazide-treated patients than for placebo-treated patients. The incidence of adverse events was not related to gender, age, race, or dose within the recommended dose range. In placebo-controlled trials in which 898 hypertensive patients received various doses (range: irbesartan/hydrochlorothiazide 37.5/6.25 mg to 300/25 mg), the following adverse reactions were reported:
Nervous System Disorders: Common: Dizziness. Uncommon: Orthostatic dizziness.
Cardiac Disorders: Uncommon: Syncope, hypotension, tachycardia, edema.
Vascular Disorders: Uncommon: Flushing.
Gastrointestinal Disorders: Common: Nausea and vomiting. Uncommon: Diarrhea.
Musculoskeletal, Connective Tissue and Bone Disorders: Uncommon: Swelling extremity.
Renal and Urinary Disorders: Common: Abnormal urination.
Reproductive System and Breast Disorders: Uncommon: Sexual dysfunction, libido changes.
General Disorders and Administration Site Conditions: Common: Fatigue.
Investigations: Patients treated with irbesartan/hydrochlorothiazide had changes in laboratory test parameters which were rarely clinically significant. Common: Increases in blood urea nitrogen (BUN), creatinine and creatinine kinase. Uncommon: Decreases in serum potassium and sodium.
In addition, since introduction of irbesartan/hydrochlorothiazide in the market the following adverse reactions have also been reported:
Immune System Disorders: Rare: As with other angiotensin-II receptor antagonists, rare cases of hypersensitivity reactions eg, angioedema, rash, urticaria have been reported.
Metabolism and Nutrition Disorders: Very Rare: Hyperkalemia.
Nervous System Disorders: Very Rare: Headache.
Ear and Labyrinth Disorders: Very Rare: Tinnitus.
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Cough.
Gastrointestinal Disorders: Very Rare: Dyspepsia, dysgeusia.
Hepatobiliary Disorders: Very Rare: Hepatitis, abnormal liver function.
Musculoskeletal, Connective Tissue and Bone Disorders: Very Rare: Arthralgia, myalgia.
Renal and Urinary Disorders: Very Rare: Impaired renal function including isolated cases of renal failure in patients at risk (see Precautions).
Additional Information on Individual Components: In addition to the mentioned adverse reactions for the combination product, other undesirable effects previously reported with one of the individual components may be potential undesirable effects with CoAprovel.
Irbesartan: General Disorders and Administration Site Conditions: Uncommon: Chest pain.
Hydrochlorothiazide: Adverse events (regardless of relationship to drug) reported with the use of hydrochlorothiazide alone include:
Blood and Lymphatic System: Aplastic anemia, bone marrow suppression, neutropenia/agranulocytosis, hemolytic anemia, leucopenia, thrombocytopenia.
Psychiatric Disorders: Depression, sleep disturbances.
Nervous System Disorders: Vertigo, paraesthesia, lightheadedness, restlessness.
Eye Disorders: Transient blurred vision, xanthopsia.
Cardiac Disorders: Cardiac arrhythmias.
Vascular Disorders: Postural hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Respiratory distress (including pneumonitis and pulmonary edema).
Gastrointestinal Disorders: Pancreatitis, anorexia, diarrhea, constipation, gastric irritation, sialadenitis, loss of appetite.
Hepatobiliary Disorders: Jaundice (intrahepatic cholestatic jaundice).
Skin and Subcutaneous Tissue Disorders: Anaphylactic reactions, toxic epidermal necrolysis, necrotizing angiitis (vasculitis, cutaneous vasculitis), cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, photosensitivity reactions, rash, urticaria.
Musculoskeletal, Connective Tissue and Bone Disorders: Weakness and muscle spasm.
Renal and Urinary Disorders: Interstitial nephritis and renal dysfunction.
General Disorders and Administration Site Conditions: Fever.
Investigations: Electrolyte imbalance (including hypokalemia and hyponatremia, see also Precautions), hyperuricemia, glycosuria, hyperglycemia, increases in cholesterol and triglycerides.
The dose-dependent side effects of hydrochlorothiazide (particularly electrolyte disturbances) may increase when titrating the hydrochlorothiazide.
Drug Interactions
Other Antihypertensive Agents: The antihypertensive effect of CoAprovel may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to irbesartan 300 mg/hydrochlorothiazide 25 mg) have been safely administered with other antihypertensive agents including calcium-channel blockers, β-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion is corrected first (see Precautions).
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with CoAprovel. Therefore, the combination of lithium and CoAprovel is not recommended (see Precautions). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal Products Affecting Potassium: The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other drugs associated with potassium loss and hypokalemia (eg, other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other drugs that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (eg, heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see Precautions).
Medicinal Products Affected by Serum Potassium Disturbances: Periodic monitoring of serum potassium is recommended when CoAprovel is administered with drugs affected by serum potassium disturbances (eg, digitalis glycosides, antiarrhythmics).
Nonsteroidal Anti-Inflammatory Drugs: When angiotensin II antagonists are administered simultaneously with nonsteroidal anti-inflammatory drugs [ie, selective cyclooxygenase (COX)-2 inhibitors, acetylsalicylic acid (>3 g/day) and nonselective NSAIDs], attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor preexisting renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Additional Information on Irbesartan Interactions: In clinical studies, the pharmacokinetics of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolized by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, a drug metabolized by CYP2C9.
The effects of CYP2C9 inducers eg, rifampicin, on the pharmacokinetics of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of irbesartan.
Additional Information on Hydrochlorothiazide Interactions: When administered concurrently, the following drugs may interact with thiazide diuretics:
Alcohol: Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulins): Dosage adjustment of the antidiabetic drug may be required (see Precautions).
Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Corticosteroids, ACTH: Electrolyte depletion, particularly hypokalemia, may be increased.
Digitalis Glycosides: Thiazide-induced hypokalemia or hypomagnesemia favor the onset of digitalis-induced cardiac arrhythmias (see Precautions).
Nonsteroidal Anti-Inflammatory Drugs: The administration of a nonsteroidal anti-inflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.
Pressor Amines (eg, Noradrenaline): The effect of pressor amines may be decreased, but not sufficiently to preclude their use.
Nondepolarizing Skeletal Muscle Relaxants (eg, Tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Antigout Medication: Dosage adjustments of antigout medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.
Calcium Salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium-sparing drugs (eg, vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Other Interactions: The hyperglycemic effect of β-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (eg, atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic drugs (eg, cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C.
Shelf-Life: 3 years.
ATC Classification
C09DA04 - irbesartan 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
Tab 150/12.5 mg (peach, biconvex, oval-shaped, with a heart engraved on one side and the number "2875" on the other side) x 28's. 300/12.5 mg (peach, biconvex, oval-shaped, with a heart engraved on one side and the number "2876" on the other side) x 28's. 300/25 mg (pink, biconvex, oval-shaped, with a heart engraved on one side and the number "2788" on the other side) x 28's.
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