CoAprovel 150 mg/12.5 mg tablets: Each tablet contains 150 mg irbesartan and 12.5 mg hydrochlorothiazide.
CoAprovel 300 mg/12.5 mg tablets: Each tablet contains 300 mg irbesartan and 12.5 mg hydrochlorothiazide.
CoAprovel 300 mg/25 mg tablets: Each tablet contains 300 mg irbesartan and 25 mg hydrochlorothiazide.
Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan is a specific insurmountable antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium homeostasis. Irbesartan does not require metabolic activation for its activity.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of the angiotensin II (AT1 subtype) receptors localized on vascular smooth muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (a receptor that has not been shown to be associated with cardiovascular homeostasis). Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (ie, renin, angiotensin converting enzyme [ACE]) or affect other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan blockade of AT1 receptors interrupts the feedback loop within the renin-angiotensin system, resulting in increases in plasma renin levels and angiotensin II levels. However, the resultant increase in plasma renin and angiotensin II levels does not overcome the effects of irbesartan on reducing blood pressure. Aldosterone plasma concentrations decline following irbesartan administration, however, serum potassium levels are not significantly affected (mean increase of <0.1 mEq/L) at the recommended doses. Irbesartan has no notable effects on serum triglycerides, cholesterol or glucose concentrations. There is no effect on serum uric acid or urinary uric acid excretion.
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic with diuretic, natriuretic and antihypertensive effects. The mechanism of antihypertensive effect of thiazide diuretics, such as hydrochlorothiazide is not fully known. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, increasing excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium and bicarbonate. Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.
Clinical Efficacy/Clinical Studies: Based on data from placebo-controlled clinical trials, the following effects were noted.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide was 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 over one year.
The combination of hydrochlorothiazide and irbesartan produced dose related additive reductions in blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo corrected diastolic blood pressure reductions at trough (24 hours post dosing) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in overall placebo subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg. Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide showed systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours post dosing) of 12.9/6.9 mm Hg. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, COAPROVEL 150/12.5 mg once daily produced consistent reduction in blood pressure over the 24 hour period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. The observed trough-to-peak effects were at least 68% of the corresponding placebo-subtracted peak diastolic and peak systolic responses.
In a clinical trial with patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan to the hydrochlorothiazide produced mean systolic/diastolic reductions which were 11.1/7.2 mm Hg greater than hydrochlorothiazide alone. Blood pressure was lowered to about the same extent in both standing and supine positions. Orthostatic effects were infrequent, but may be expected to occur in patients who develop intercurrent sodium and/or volume-depletion.
The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender. The overall antihypertensive response to the combination was similar for black and non-black patients.
After withdrawal of irbesartan, blood pressure gradually returned toward baseline. Rebound hypertension was not observed with irbesartan or hydrochlorothiazide.
With hydrochlorothiazide, onset of diuresis occurred in 2 hours, and peak effect occurred at about 4 hours, while the action persisted for approximately 6-12 hours.
Initial Therapy: Two clinical studies evaluated COAPROVEL as initial therapy. The first study was conducted in patients with a mean baseline blood pressure of 162/98 mm Hg (Moderate Hypertension) and compared the change from baseline in SeSBP at 8 weeks between the combination group (irbesartan and HCTZ 150 mg/12.5 mg) to irbesartan (150 mg) and to HCTZ (12.5 mg). These initial study regimens were increased at 2 weeks to COAPROVEL 300 mg/25 mg, irbesartan 300 mg, or to HCTZ 25 mg, respectively.
Mean reductions from baseline for SeDBP and SeSBP at trough were 14.6 mm Hg and 27.1 mm Hg for patients treated with COAPROVEL, 11.6 mm Hg and 22.1 mm Hg for patients treated with irbesartan, and 7.3 mm Hg and 15.7 mm Hg for patients treated with HCTZ at 8 weeks, respectively. For patients treated with COAPROVEL, the mean change from baseline in SeDBP was 3.0 mm Hg lower (p=0.0013) and the mean change from baseline in SeSBP was 5.0 mm Hg lower (p=0.0016) compared to patients treated with irbesartan, and 7.4 mm Hg lower (p<0.0001) and 11.3 mm Hg lower (p<0.0001) compared to patients treated with HCTZ, respectively.
The second clinical study was conducted in patients with a mean baseline blood pressure of 172/113 mm Hg (Severe Hypertension) and compared trough SeDBP at 5 weeks between the combination group (irbesartan and HCTZ 150 mg/12.5 mg) and irbesartan (150 mg). These initial study regimens were increased at 1 week to COAPROVEL 300 mg/25 mg or to irbesartan 300 mg, respectively.
At 5 weeks, mean reductions from baseline for SeDBP and SeSBP at trough were 24.0 mm Hg and 30.8 mm Hg for patients treated with COAPROVEL and 19.3 mm Hg and 21.1 mm Hg for patients treated with irbesartan, respectively. The mean SeDBP was 4.7 mm Hg lower (p<0.0001) and the mean SeSBP was 9.7 mm Hg lower (p<0.0001) in the group treated with COAPROVEL than in the group treated with irbesartan. Patients treated with COAPROVEL achieved more rapid blood pressure control with significantly lower SeDBP and SeSBP and greater blood pressure control at every assessment (Week 1, Week 3, Week 5, and Week 7). Maximum effects were seen at Week 7.
The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender. The overall antihypertensive response to the combination was similar for black and non-black patients.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg).
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of irbesartan.
Absorption: 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 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Distribution: Irbesartan is approximately 96% protein-bound in the plasma, and has negligible binding to cellular components of blood. The volume of distribution is 53-93 Liters (0.72-1.24 Liters/Kg). Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is 3.6-7.8 Liters/Kg.
Metabolism: In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following oral or intravenous administration of 14C irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolized by, nor does it substantially induce or inhibit most isoenzymes commonly associated with drug metabolism (ie, CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce nor inhibit isoenzyme CYP3A4.
Elimination: Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered radioactivity after an oral or intravenous dose of 14C irbesartan is recovered in urine with the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized and is eliminated by the kidneys. The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
The terminal elimination half-life (t½) of irbesartan is 11-15 hours. The total body clearance of intravenously administered irbesartan is 157-176 mL/ min, of which 3.0-3.5 mL/min is renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily dosing.
Special Populations: Gender: In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan were observed in females than in males, although, following multiple dosing, males and females did not show differences in either accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.
Elderly Patients: In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and hepatic function, the plasma AUC and peak plasma concentrations (Cmax) of irbesartan are approximately 20%-50% greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is comparable. No significant age-related differences in clinical effect have been observed. The area under the plasma concentration time curve (AUC) for hydrochlorothiazide was elevated in the elderly group following multiple dosing consistent with previously published data.
Hepatic Impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.
Renal Impairment: In patients with renal impairment (regardless of degree) and in hemodialysis patients, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis. In patients with severe renal impairment (creatinine clearance <20 mL/min), the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.
Race: In black and white normotensive subjects, the plasma AUC and t½ of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (Cmax) of irbesartan are essentially equivalent.
CoAprovel is indicated for the treatment of hypertension.
It may be used either alone or in combination with other antihypertensive agents (eg, beta-adrenergic blocking agent, long-acting calcium-channel blocking agent).
CoAprovel may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
General: In patients whose blood pressure is not adequately controlled with irbesartan 300 mg monotherapy, CoAprovel (irbesartan 300 mg/hydrochlorothiazide 12.5 mg) once daily may be administered, with or without food.
CoAprovel (irbesartan 150 mg/hydrochlorothiazide 12.5 mg) may be initiated in patients who are not adequately controlled with hydrochlorothiazide, or irbesartan 150 mg alone.
Patients not responding adequately to CoAprovel (irbesartan 150 mg/hydrochlorothiazide 12.5 mg) can have the dose increased to CoAprovel (irbesartan 300 mg/ hydrochlorothiazide 12.5 mg). Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide are not recommended.
If blood pressure is not adequately controlled with CoAprovel alone, another antihypertensive drug (eg, beta-adrenergic blocking agent, long-acting calcium channel blocking agent) may be added.
Initial Therapy: The usual starting dose for initial therapy with CoAprovel is 150 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 300 mg/25 mg tablet once daily as needed to control blood pressure.
Special Populations: Pediatric patients: Safety and effectiveness in pediatric patients have not been established.
Elderly patients: No dosage reduction is generally necessary in the elderly.
Among patients who received CoAprovel in clinical studies, no overall differences in efficacy or safety were observed between older patients (65 years or older) and younger patients.
Hepatic impairment: No dosage reduction is generally necessary in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, CoAprovel should be used with caution in patients with severe hepatic impairment. (See Warnings).
Renal impairment: No dosage reduction is generally necessary in patients with mild-to-moderate renal impairment (creatinine clearance >30 mL/min). However, due to the hydrochlorothiazide component, CoAprovel is not recommended for patients with severe renal impairment (creatinine clearance ≤ 30 mL/min). (See Warnings).
Patients with intravascular volume depletion: In severely volume-depleted and/or sodium-depleted patients, such as those treated vigorously with diuretics, the condition should be corrected prior to administration of CoAprovel. (See Warnings).
Signs and Symptoms: The most common signs and symptoms observed in adults exposed to hydrochlorothiazide are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If a cardiac glycoside (eg, digoxin) or other antiarrhythmic drugs (eg, sotalol) has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Management: Experience in adults exposed to irbesartan doses of up to 900 mg/day for 8 weeks revealed no toxicity. 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, including fluid and electrolyte replacement. Suggested measures include induction of emesis and/or gastric lavage. Irbesartan is not removed from the body by hemodialysis.
CoAprovel is contraindicated in patients who are hypersensitive to irbesartan, sulfonamide derived drugs (eg, thiazides), or to any other component of the CoAprovel formulation. In general, hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma. CoAprovel is contraindicated in patients who are anuric.
Do not co-administer CoAprovel with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (glomerular filtration rate [GFR] <60 mL/min/1.73 m2).
Do not co-administer CoAprovel with Angiotensin-Converting Enzyme Inhibitors (ACEIs) in patients with diabetic nephropathy.
Hypotension - Volume-Depleted Patients: CoAprovel has been rarely associated with hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who develop sodium or volume-depletion. Volume and/or sodium-depletion should be corrected before initiating therapy with CoAprovel. Thiazides may potentiate the action of other antihypertensive drugs (see Interactions).
Fetal/Neonatal Morbidity and Mortality: Although there is no experience with CoAprovel in pregnant women, in utero exposure to ACE inhibitors given to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing fetus. Thus, as for any drug that also acts directly on the renin-angiotensin-aldosterone system, CoAprovel should not be used during pregnancy. If pregnancy is detected during therapy, CoAprovel should be discontinued as soon as possible.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard, including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.
Impaired Hepatic and Renal Function: CoAprovel is not recommended for patients with severe renal impairment (creatinine clearance ≤30 mL/min) (see Contraindications). Hydrochlorothiazide-associated precipitation of azotemia may occur in patients with impaired renal function. CoAprovel should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations in fluid and electrolyte balance may precipitate hepatic coma.
Electrolyte and Metabolic Imbalances: Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia and hypochloremic alkalosis). Although hypokalemia may develop when thiazide diuretics are used alone, especially with higher doses, concurrent therapy with irbesartan reduces the frequency of diuretic-induced hypokalemia. Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is decreased by thiazides which may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia suggests the possibility of 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.
Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide therapy. Insulin requirements in diabetic patients may be increased and latent diabetes mellitus may become manifest during thiazide administration. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, minimal or no effects were reported at the 12.5 mg hydrochlorothiazide dose contained in COAPROVEL. Monitoring of laboratory parameters may be necessary in patients at risk for electrolyte and metabolic disturbances.
Systemic Lupus Erythematosus: Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Secondary Acute Angle-Closure Glaucoma and/or Acute Myopia: Hydrochlorothiazide is a sulfonamide. Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic reaction, which may result in secondary acute angle-closure glaucoma and/or acute myopia.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible.
Prompt medical or surgical treatments 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.
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.
Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Dual blockade of the RAAS by combining CoAprovel with an angiotensin converting enzyme inhibitor (ACEI) or with aliskiren is not recommended since there are increased risks of hypotension, hyperkalemia, and changes in renal function.
The use of CoAprovel in combination with aliskiren is contraindicated in patients with diabetes mellitus or with renal impairment (GFR <60 ml/ min/1.73 m2) (see Contraindications and Interactions).
The use of CoAprovel in combination with an ACEI is contraindicated in patients with diabetic nephropathy (see Contraindications and Interactions).
The use of CoAprovel in patients with psoriasis or a history of psoriasis should be carefully weighed as it may exacerbate psoriasis.
General: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function during therapy with CoAprovel may be anticipated in susceptible individuals. In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (eg, hypertensive patients with renal artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment with drugs that affect this system has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including CoAprovel, cannot be excluded.
The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.
Driving a Vehicle or Performing Other Hazardous Tasks: The effects of CoAprovel on the ability to drive motor vehicles or operate machinery have not been specifically studied, but based on its pharmacodynamic properties, CoAprovel is unlikely to affect this ability. When driving vehicles or operating machinery, it should be taken into account that occasionally dizziness may occur during treatment of hypertension.
Pregnancy: When pregnancy is detected, CoAprovel should be discontinued as soon as possible (see Warnings).
Lactation: Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its metabolites are excreted in human milk. Hydrochlorothiazide is excreted in human breast milk. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of CoAprovel during breastfeeding is not recommended. Because of the potential risk to the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of CoAprovel to the therapy of the mother.
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide (range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled trials.
The frequency of adverse reactions listed as follows is defined 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 1.)
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Additional information on individual components: in addition to the adverse reactions listed previously for the combination product, other adverse reactions previously reported with one of the individual components may be potential adverse reactions with CoAprovel. Tables 2 and 3 as follows detail the adverse reactions reported with the individual components of CoAprovel. (See Tables 2 and 3.)
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Non-melanoma skin cancer:
Based on available data from epidemiological studies, cumulative dose dependent association between HCTZ and NMSC has been observed (see also Warnings, Precautions and Pharmacology: Pharmacodynamics under Actions).
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may increase when titrating the hydrochlorothiazide.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Based on in vitro data, no interactions with irbesartan would be expected to occur with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4. Irbesartan is primarily metabolized by CYP2C9, however, during clinical interaction studies, no significant pharmacokinetic and pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin (a drug metabolized by CYP2C9). Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetics of irbesartan are not affected by coadministration with nifedipine or hydrochlorothiazide.
The combination of CoAprovel with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR <60 mL/min/1.73 m2) and is not recommended in other patients (see Contraindications and Precautions).
Angiotensin converting enzyme inhibitors (ACEIs): The use of CoAprovel in combination with an ACEI is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see Contraindications and Precautions).
Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase kalaemia with irbesartan may lead to increases in serum potassium, sometimes severe, and requires close monitoring of serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.
Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Alcohol, barbiturates or narcotics: Potentiation of thiazide diuretic-induced orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin): Thiazides may elevate blood glucose levels, thus, dosage adjustments of antidiabetic agents may be necessary.
Antigout medication: Dosage adjustments of antigout medication may be needed since HCTZ may raise the blood level of uric acid.
Cardiac glycosides (eg, digoxin) and other antiarrhythmic drugs (eg, sotalol): Diuretic-induced hypokalemia may accentuate cardiac arrhythmias.
Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium or a calcium sparing drug (eg, Vitamin D therapy) is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Cholestyramine resin and colestipol HCl: May delay or decrease absorption of HCTZ. CoAprovel should be taken at least one hour before or four hours after these mediations.
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan.
Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. Coadministration with CoAprovel should be approached with caution and the frequent monitoring of serum lithium levels is recommended.
Inhibitors of endogenous prostaglandin synthesis (ie, NSAIDs): In some patients, these agents can reduce the effects of thiazide diuretics.
Other diuretics and antihypertensive medications: The thiazide component of CoAprovel may potentiate the actions of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. HCTZ may interact with diazoxide; blood glucose, serum uric acid levels and blood pressure should be monitored.
Drugs used during surgery: The effects of nondepolarizing muscle relaxants, preanesthetics and anesthetics used in surgery (eg, tubocurarine) may be potentiated by HCTZ; dosage adjustments may be required. Preanesthetic and anesthetic agents should be given in reduced dosage, and if possible, HCTZ therapy discontinued one week prior to surgery.
Carbamazepine: Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used.
Store at temperatures not exceeding 30°C.
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.
150/12.5 mg tab (unscored) x 28's. 300 mg/12.5 mg tab (unscored) x 28's. 300/25 mg tab (unscored) x 28's.