CoAprovel Mechanism of Action

irbesartan + hydrochlorothiazide




Full Prescribing Info
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.
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