Converide

Converide 150 mg/12.5 mg film-coated tablets: White, round, convex, film-coated tablets with diameter 9.5 mm.
Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Converide 300mg/12.5mg film-coated tablets: Pink, convex, film coated capsule-shaped tablets, scored on one side, embossed "MC" on the other side, with dimensions 17.5 x 8 mm.
Each film-coated tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
Excipient with known effect: lactose monohydrate.
Converide 150 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 26.65 mg of lactose (as lactose monohydrate).
Converide 300mg/12.5mg film-coated tablets: Each film-coated tablet contains 65.8 mg of lactose (as lactose monohydrate).
Excipients/Inactive Ingredients: Tablet core: Lactose Monohydrate; Pregelatinised starch; Colloidal anhydrous silica; Croscarmellose sodium E468; Cellulose microcrystalline PH-102, E460; Magnesium stearate E572.
Film-coating: Hypromellose E464, Lactose monohydrate, Magrogol 6000, Titanium dioxide E171, Red iron oxide E172 (only for the 300/12.5 mg strength).

Pharmacotherapeutic group: Angiotensin-II antagonists, combinations. ATC code: C09DA04.
Pharmacology: Pharmacodynamics: Converide 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 antihypertensive 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 tends to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces 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 mmHg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide 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 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an incremental blood pressure lowering effect was observed for both SBP and DBP (13.3 and 8.3 mmHg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mmHg in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. When measured by ambulatory blood pressure monitoring, the trough to peak effects of irbesartan/hydrochlorothiazide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and 76% for irbesartan/ hydrochlorothiazide 150 mg/12.5 mg and irbesartan/hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour 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 25 mg hydrochlorothiazide 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 over one year. Although not specifically studied with the irbesartan/hydrochlorothiazide, 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 irbesartan/hydrochlorothiazide, regardless of age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of non-black patients.
The choice of Converide as initial therapy for hypertension should be based on an assessment of potential benefits and risks.
Patients with stage 2 (moderate or severe) hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy.
Two studies evaluated Converide as initial hypertension therapy. The first study was conducted in patients with a mean baseline blood pressure of 162/98 mmHg and compared the change from baseline in SeSBP at 8 weeks between the combination group (irbesartan and HCTZ 150/12.5 mg), to irbesartan (150 mg) and to HCTZ (12.5 mg). These initial study regimens were increased at 2 weeks to Converide 300/25 mg, irbesartan 300 mg, or to HCTZ 25 mg, respectively. Mean reductions from baseline for SeDBP and SeSBP at trough were 14.6 mmHg and 27.1 mmHg for patients treated with irbesartan and HCTZ, 11.6 mmHg and 22.1 mmHg for patients treated with irbesartan, and 7.3 mmHg and 15.7 mmHg for patients treated with HCTZ at 8 weeks, respectively. For patients treated with the combination group, the mean change from baseline in SeDBP was 3.0 mmHg lower (p=0.0013) and the mean change from baseline in SeSBP was 5.0 mmHg lower (p=0.0016) compared to patients treated with irbesartan, and 7.4 mmHg lower (p<0.0001) and 11.3 mmHg lower (p<0.0001) compared to patients treated with HCTZ, respectively.
The types and incidences of adverse events reported for patients treated with irbesartan and HCTZ were similar to the adverse events profile for patients treated with irbesartan alone or hydrochlorothiazide alone as initial therapy. During the 12-week treatment period, there were no reported cases of syncope in the combination therapy group, and there was one reported event in the hydrochlorothiazide monotherapy 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 irbesartan and HCTZ compared to the irbesartan and hydrochlorothiazide groups, respectively.
The second study was conducted in patients with a mean baseline blood pressure of 172/113 mmHg and compared trough SeDBP at 5 weeks between the combination group (irbesartan and HCTZ 150/12.5 mg) and irbesartan (150 mg). These initial study regimens were increased at 1 week to irbesartan and HCTZ 300/25 mg or to irbesartan 300 mg, respectively.
At 5 weeks, mean reductions from baseline for SeDBP and SeSBP at trough were 24.0 mmHg and 30.8 mmHg for patients treated with irbesartan and HCTZ and 19.3 mmHg and 21.1 mmHg for patients treated with irbesartan, respectively. The mean SeDBP was 4.7 mmHg lower (p<0.0001) and the mean SeSBP was 9.7 mmHg lower (p<0.0001) in the group treated with irbesartan and HCTZ than in the group treated with irbesartan. Patients treated with irbesartan and HCTZ 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 types and incidences of adverse events reported for patients treated with irbesartan and HCTZ were similar to the adverse events profile for patients treated with irbesartan as initial therapy. During the 7-week treatment period, 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 irbesartan and HCTZ and the group treated with irbesartan, respectively.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide 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 hydrochlorothiazide 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 hydrochlorothiazide: 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 either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Following oral administration of irbesartan/hydrochlorothiazide, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of irbesartan/hydrochlorothiazide. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours 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 litres. 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 to 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 clearance are 157-176 and 3.0-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. 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 hours.
Following oral or intravenous 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 oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous administration of ¹⁴C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. 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 hours.
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 haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with creatinine clearance <20 ml/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.
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 one of the two medicinal products 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, haemoglobin, haematocrit); stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in a 6 months 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 angiotensin converting enzyme 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 non-clinical 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, haemoglobin, haematocrit). At very high doses (≥500 mg/kg/day) degenerative changes in the kidneys (such as 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 oedema) in rat foetuses, 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.

Treatment of essential hypertension: This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone.
This fixed dose combination is also indicated as initial therapy in patients with moderate to severe essential hypertension for whom the benefit of a prompt blood pressure reduction exceeds the risk of initiating combination therapy in these patients (see Pharmacology: Pharmacodynamics under Actions).

Posology: Converide can be taken once daily, with or without food.
Add on therapy: Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) can be recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be considered: Converide 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone; Converide 300 mg/12.5 mg may be administered in patients whose blood pressure is insufficiently controlled by irbesartan 300 mg or by Converide 150 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. When necessary, Converide may be administered with another antihypertensive medicinal product (see Interactions).
Initial therapy: The usual starting dose is Converide 150/12.5mg once daily. The dosage can be increased after 1 to 2 weeks therapy to a maximum of one 300/25mg tablet once daily as needed to control blood pressure (see Pharmacology: Pharmacodynamics under Actions). Converide is not recommended as initial therapy in patients with intravascular volume depletion (see Precautions).
Replacement therapy: Converide may be substituted for the titrated components.
Renal impairment: Due to the hydrochlorothiazide component, Converide 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 Converide.
Hepatic impairment: Converide 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 Converide is necessary in patients with mild to moderate hepatic impairment (see Contraindications).
Elderly patients: No dosage adjustment of Converide is necessary in elderly patients.
Paediatric population: Converide is not recommended for use in children and adolescents due to lack of data on safety and efficacy.
Method of administration: For oral use.

No specific information is available on the treatment of overdose with irbesartan/hydrochlorothiazide. 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 overdose. 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 overdose are expected to be hypotension and tachycardia; bradycardia might also occur.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

Hypersensitivity to the active substances, to any of the excipients listed Description, or to other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance).
Second and third trimesters of pregnancy (see Precautions and Use in Pregnancy & Lactation).
Lactation (see Use in Pregnancy & Lactation).
The following contraindications are associated with hydrochlorothiazide: Severe renal impairment (creatinine clearance <30 ml/min).
Refractory hypokalaemia, hypercalcaemia.
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Co-administration of Converide 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) (see Precautions and Interactions).
Co-administration of Converide with angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetic nephropathy (see Precautions and Interactions).

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 exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide 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 hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC.
Hypotension - Volume-depleted patients: Converide 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, diarrhoea or vomiting. Such conditions should be corrected before initiating therapy with Converide.
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 inhibitors or angiotensin-II receptor antagonists. While this is not documented with Converide, a similar effect should be anticipated.
Renal impairment and kidney transplantation: When Converide 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 Converide in patients with a recent kidney transplantation. Converide 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.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Dual blockade of the RAAS by combining Converide with an angiotensin-converting enzyme inhibitor (ACEI) or with aliskiren is not recommended since there is an increased risk of hypotension, hyperkalaemia, and changes in renal function. The use of Converide in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²) (see Interactions). The use of Converide in combination with an ACEI is contraindicated in patients with diabetic nephropathy (see Interactions).
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 Converide 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 medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Converide 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.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however at the 12.5 mg dose contained in Converide, minimal or no effects were reported. Hyperuricaemia 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 electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting. Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia 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 Converide, hyperkalaemia 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 Converide (see Interactions).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. 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 hypercalcaemia 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 hypomagnaesemia.
Lithium: The combination of lithium and Converide is not recommended (see Interactions).
Anti-doping test: Hydrochlorothiazide contained in this medication 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 (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme 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 a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see Adverse Reactions). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Acute myopia and secondary acute angle-closure glaucoma: Sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma have been reported so far with hydrochlorothiazide. 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 (see Adverse Reactions).
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, Converide 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 Pregnancy: Angiotensin II receptor antagonists including Converide should not be initiated during pregnancy. Unless continued therapy with angiotensin-II receptor antagonists is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin-II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see Contraindications and Use in Pregnancy & Lactation).

Pregnancy: Converide is not recommended during the first trimester of pregnancy (see Precautions). The use of angiotensin-II receptor antagonists is contraindicated during the second and third trimesters of pregnancy (see Contraindications and Precautions).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued therapy with angiotensin-II receptor antagonists is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin-II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Angiotensin-II receptor antagonists therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See Pharmacology: Toxicology: Preclinical safety data under Actions.)
Thiazides cross the placental barrier and appear in cord blood. They may cause decrease placental perfusion and foetal electrolyte disturbances. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy. Since Converide contains hydrochlorothiazide, it is not recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.
Lactation: Because of the potential adverse effects on the nursing infant, Converide is contraindicated during breast-feeding (see Contraindications). It is not known if irbesartan is excreted in human milk. It is excreted in the milk of lactating rats. Thiazides appear in human milk and may inhibit lactation.

The frequency of adverse reactions listed as follows is defined using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Irbesartan/hydrochlorothiazide 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: 37.5mg/6.25mg to 300 mg/25mg irbesartan/hydrochlorothiazide), the following adverse reactions were reported: Neoplasms benign, malignant and unspecified (incl cysts and polyps): Frequency 'not known': Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma).
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed.
Nervous system disorders: Common: dizziness.
Uncommon: orthostatic dizziness.
Cardiac disorders: Uncommon: hypotension, oedema, syncope, tachycardia.
Vascular disorders: Uncommon: flushing.
Gastrointestinal disorders: Common: nausea/vomiting.
Uncommon: diarrhoea.
Musculoskeletal, connective tissue and bone disorders: Uncommon: swelling extremity.
Renal and urinary disorders: Common: abnormal urination.
Reproductive system and breast disorders: Uncommon: libido changes, sexual dysfunction.
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 BUN, creatinine and creatine 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 such as angioedema, rash, urticaria have been reported.
Metabolism and nutrition disorders: Very rare: hyperkalaemia.
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: dysgeusia, dyspepsia.
Hepato-biliary disorders: Uncommon: jaundice.
Very rare: abnormal liver function, hepatitis.
Musculoskeletal, connective tissue and bone disorders: Very rare: arthalgia, 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 adverse reactions listed previously for the combination product, other adverse events previously reported with one of the individual components may be potential undesirable effects with Converide.
Irbesartan: Adverse events reported with the use of irbesartan alone include: General disorders and administration site conditions: Uncommon: chest pain.
Hydrochlorothiazide: Adverse events (regardless of relationship to medicinal product) reported with the use of hydrochlorothiazide alone include: Blood and lymphatic system: Aplastic anemia, bone marrow depression, haemolytic anaemia, leucopenia, neutropenia/agranulocytosis, thrombocytopenia.
Psychiatric disorders: Depression, sleep disturbances.
Nervous system disorders: Light-headedness, paraesthesia, restlessness, vertigo.
Eye disorders: Transient blurred vision, xanthopsia, acute myopia and secondary acute angle-closure glaucoma.
Cardiac disorders: Cardiac arrhythmias.
Vascular disorders: Postural hypotension.
Respiratory, thoracic and mediastinal disorders: Respiratory distress (including pneumonitis and pulmonary oedema).
Gastrointestinal disorders: Pancreatitis, anorexia, constipation, diarrhoea, gastric irritation, loss of appetite, sialadenitis.
Hepatobiliary disorders: Jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Anaphylactic reactions, toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, necrotising angitis (vasculitis, cutaneous vasculitis), photosensitivity reactions, rash, reactivation of cutaneous lupus erythematosus, urticaria.
Musculoskeletal, connective tissue and bone disorders: Muscle spasm, weakness.
Renal and urinary disorders: Interstitial nephritis, renal dysfunction.
General disorders and administration site conditions: Fever.
Investigations: Electrolyte imbalance (including hypokalaemia and hyponatremia, (see Precautions), glycosuria, hyperglycemia, hyperuricemia, increases in cholesterol and triglycerides.
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may increase when titrating the hydrochlorothiazide.

Other antihypertensive agents: The antihypertensive effect of Converide may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents including calcium channel blockers and beta-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).
Aliskiren-containing products: The combination of Converide 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.
Angiotensin-converting enzyme inhibitors (ACEIs): the use of Converide in combination with an ACEI is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan. Monitor lithium levels in patients receiving irbesartan and lithium. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with Converide. Therefore, the combination of lithium and Converide 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 medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives). Conversely, based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium, sometimes severe. 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 Converide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists 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 pre-existing 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 pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a drug metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic 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 medicinal products may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic medicinal products (oral agents and insulins): Dosage adjustment of the antidiabetic medicinal product may be required (see Precautions).
Colestyramine and Colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Converide should be taken at least one hour before or four hours after these medications.
Corticosteroids, ACTH: Electrolyte depletion, particularly hypokalaemia, may be increased.
Digitalis glycosides: Thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalis-induced cardiac arrhythmias (see Precautions).
Non-steroidal anti-inflammatory drugs: The administration of a non-steroidal anti-inflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.
Pressor amines (e.g. noradrenaline): The effect of pressor amines may be decreased, but not sufficiently to preclude their use.
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Antigout medicinal products: Dosage adjustments of antigout medicinal products 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 medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
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.
Other interactions: The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, beperiden) 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 medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Shelf life: 36 months.
When the product is packed in opaque PVC/PVDC-Alu blisters: Store below 30°C in the original package in order to protect from moisture and light.

Angiotensin II Antagonists / Diuretics

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.

POM