Instructions for Lozap Plus film-coated tablets, blister pack No. 90
Composition
active ingredients: losartan potassium, hydrochlorothiazide;
1 tablet contains losartan potassium 50 mg, hydrochlorothiazide 12.5 mg;
excipients: mannitol (E 421), microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose, macrogol 6000, talc, simethicone emulsion, titanium dioxide (E 171), quinoline yellow (E 104), Ponceau 4R (E 124).
Dosage form
Film-coated tablets.
Main physicochemical properties: yellow oval tablets, coated, with a score on both sides.
Pharmacotherapeutic group
Medicinal products acting on the renin-angiotensin system. Angiotensin II antagonists and diuretics. ATC code C09D A01.
Pharmacological properties
Mechanism of action.
Lozap® Plus is a combination of losartan and hydrochlorothiazide. In patients with arterial hypertension and left ventricular hypertrophy, losartan, especially in combination with hydrochlorothiazide, reduces the risk of cardiovascular disease and mortality, which was proven by assessing the combined incidence of cardiovascular events, stroke and myocardial infarction.
The components of the drug have an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone. As a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), stimulates aldosterone secretion, increases angiotensin II levels, and reduces serum potassium levels. Losartan blocks all physiological effects of angiotensin II and, by inhibiting the effects of aldosterone, may help reduce diuretic-associated potassium loss.
Losartan has a moderate uricosuric effect, which disappears when the drug is discontinued.
Hydrochlorothiazide slightly increases blood uric acid levels; the combination of losartan and hydrochlorothiazide attenuates diuretic-induced hyperuricemia.
Pharmacodynamics.
Losartan
Losartan is a synthetic angiotensin II receptor (AT1 receptor) antagonist for oral administration. Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin system and a determining factor in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors, which are found in many types of tissues (for example, in vascular smooth muscle tissues, adrenal glands, kidneys and heart), which leads to a number of important biological effects, including vasoconstriction and stimulation of aldosterone secretion. Angiotensin II also stimulates the proliferation of smooth muscle cells. Losartan selectively blocks AT1 receptors. In vitro and in vivo studies have shown that losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant effects of angiotensin II, regardless of its source or origin. Losartan does not bind to or block receptors for other hormones or ion channels important for cardiovascular regulation. In addition, losartan does not inhibit ACE (kinase II), the enzyme that degrades bradykinin. Accordingly, there is no potentiation of undesirable effects mediated by bradykinin.
When losartan is used, inhibition of the negative feedback effect of angiotensin II on renin secretion leads to an increase in ARP. An increase in ARP causes an increase in the concentration of angiotensin II in the blood plasma. Despite the increase in the concentration of these substances, antihypertensive activity and a decrease in the concentration of aldosterone in the blood plasma are preserved, which indicates effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II values decrease to baseline levels within a three-day period.
Both losartan and its major active metabolite have a higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10-40 times more active than losartan on a weight-for-weight basis.
In a study specifically designed to assess the incidence of cough in patients taking losartan compared with patients taking ACE inhibitors, the incidence of cough in patients taking losartan or hydrochlorothiazide was approximately the same and statistically significantly lower than in patients taking ACE inhibitors. In addition, a pooled analysis of 16 double-blind clinical trials involving a total of 4131 patients showed that the incidence of spontaneously reported cases of cough in patients taking losartan (3.1%) was similar to that in patients taking placebo (2.6%) or hydrochlorothiazide (4.1%), while the incidence of cough in patients taking ACE inhibitors was 8.8%.
Losartan does not affect the reflexes of the autonomic nervous system and does not have a prolonged effect on the concentration of norepinephrine in the blood plasma. In patients with left ventricular failure, losartan at doses of 25 mg and 50 mg exhibits a positive hemodynamic and neurohormonal effect, which is characterized by an increase in the index of the volumetric velocity of the heart and a decrease in the pressure in the terminal capillaries of the lungs, a decrease in systemic vascular resistance, a decrease in the mean systemic arterial pressure and heart rate, as well as a decrease in the levels of circulating aldosterone and norepinephrine, respectively. In such patients with heart failure, the incidence of arterial hypotension was dose-dependent.
Studies in patients with arterial hypertension
In controlled clinical trials, once-daily administration of losartan to patients with mild to moderate essential hypertension resulted in statistically significant reductions in systolic and diastolic blood pressure. Blood pressure measurements 24 hours after dosing compared with 5-6 hours after dosing demonstrated that the blood pressure-lowering effect was maintained for
24 hours. The body's natural circadian rhythm was maintained. The reduction in blood pressure at the end of the interval between two doses was 70-80% of the effect observed 5-6 hours after the dose.
Discontinuation of losartan in hypertensive patients does not result in a sudden increase in blood pressure (rebound phenomenon). Although losartan causes a pronounced decrease in blood pressure, it does not significantly affect heart rate.
Losartan is equally effective in male and female patients, as well as in younger (under 65 years of age) and older people suffering from arterial hypertension.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazides disrupt the tubular reabsorption of electrolytes in the kidney, directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and increases aldosterone secretion, with a corresponding increase in urinary potassium and bicarbonate loss, as well as an increase in serum potassium. The renin-aldosterone chain is mediated by angiotensin II, so the concomitant use of angiotensin II receptor antagonists may reverse the potassium loss associated with thiazide diuretics.
After oral administration, diuresis begins within two hours, reaches a maximum after about 4 hours, and lasts for about 6 to 12 hours. The antihypertensive effect persists for up to 24 hours.
Non-melanoma skin cancer: Based on available epidemiological data, there is a cumulative dose-dependent association between HCT and NMSC. One study included a population consisting of 71,533 BCC cases and 8,629 PCC cases, and a control group of 1,430,833 and 172,462 cases, respectively. High HCT use (>50,000 mg cumulatively) 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 PCC. A clear cumulative dose-response relationship was observed for both BCC and PCC. Another study demonstrated a possible association between lip cancer (LC) and HRT use: 633 cases of lip cancer were found compared to 63,067 cases in the control group (a risk-adjusted sampling strategy was used). A cumulative dose-effect relationship was demonstrated with an adjusted odds ratio (OR) of 2.1 (95% CI: 1.7–2.6), increasing to an OR of 3.9 (3.0–4.9) for the high dose (25,000 mg) and an OR of 7.7 (5.7–10.5) for the highest cumulative dose (100,000 mg) (see also section 4.4).
Pharmacokinetics.
Absorption
Losartan
When administered orally, losartan is well absorbed and undergoes first-pass metabolism to form an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in tablet form is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached after 1 hour and 3-4 hours, respectively. When losartan is administered with a standard meal, there is no clinically significant effect on the plasma concentration profile of losartan.
Distribution
Losartan
Losartan and its active metabolite are more than 99% bound to plasma proteins (mainly albumin). The volume of distribution of losartan is 34 L. Animal studies have shown that losartan does not cross the blood-brain barrier.
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental (but not the blood-brain) barrier and into breast milk.
Biotransformation
Losartan
In addition to the active metabolite, biologically inactive ones are formed, including two major metabolites formed as a result of hydroxylation of the butyl side chain, and one minor one – N-2-tetrazole-glucuronide.
Breeding
Losartan
The plasma clearance of losartan and its active metabolite is approximately 600 ml/min and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, approximately 4% of the dose is excreted unchanged in the urine and approximately 6% of the dose is excreted in the urine as the active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered orally in doses up to 200 mg.
After administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with terminal half-lives of approximately 2 and 6-9 hours, respectively. When taking 100 mg of the drug once a day, neither losartan nor its active metabolite accumulate significantly in plasma.
Losartan and its metabolites are excreted in the bile and urine. After oral administration of 14C-labeled losartan, approximately 35% of the radioactivity is recovered in the urine and 58% in the feces.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. When monitoring plasma levels for at least 24 hours, the elimination half-life ranged from 5.6 to 14.8 hours. At least 61% of the administered dose was excreted unchanged within 24 hours.
Patient characteristics
Losartan-hydrochlorothiazide
Plasma concentrations of losartan and its active metabolite, as well as the absorption rate of hydrochlorothiazide in elderly patients with arterial hypertension, are not statistically significantly different from these indicators in young patients with arterial hypertension.
Losartan
In patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite after oral administration were 5 and 1.7 times higher, respectively, than in young healthy male volunteers. Neither losartan nor its active metabolite are removed by hemodialysis.
Indication
Arterial hypertension in patients whose blood pressure is not adequately controlled by losartan or hydrochlorothiazide monotherapy.
Contraindication
Hypersensitivity to losartan or to any of the components of the drug.
Hypersensitivity to sulfonamide derivatives (such as hydrochlorothiazide).
Treatment-resistant hypokalemia or hypercalcemia.
Anury.
Severe hepatic impairment: cholestasis and disorders associated with biliary obstruction.
Refractory hyponatremia.
Symptomatic hyperuricemia/gout.
Pregnant women or women planning to become pregnant (see section “Use during pregnancy or breastfeeding”).
Severe renal impairment (creatinine clearance <30 ml/minute).
The simultaneous use of Lozap® Plus with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or renal impairment (GFR [glomerular filtration rate] <60 ml/min/1.73 m2) (see sections “Pharmacodynamics” and “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Losartan
Rifampicin and fluconazole have been reported to decrease the levels of the active metabolite. The clinical consequences of these interactions have not been studied.
The combination of losartan, as well as other agents that block angiotensin II or its effects, with potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes may lead to increases in serum potassium. Concomitant use of such agents is not recommended. As with other drugs that impair sodium excretion, this drug may reduce lithium excretion. Therefore, if concomitant administration of lithium salts and angiotensin II receptor antagonists is planned, careful monitoring of serum lithium levels is necessary.
When angiotensin II receptor antagonists are used together with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. selective cyclooxygenase (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. The concomitant use of angiotensin II receptor antagonists or diuretics 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 pre-existing impaired renal function. This combination should be used with caution, especially in elderly patients. The patient should be adequately hydrated and renal function should be monitored immediately after initiation of concomitant therapy and periodically thereafter.
Other substances that cause arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen, amifostine) when used simultaneously with these agents, which contribute to a decrease in blood pressure due to a therapeutic effect or side effects, may increase the risk of arterial hypotension.
Dual blockade (e.g., the use of an ACE inhibitor with an angiotensin II receptor antagonist) should be limited to individually defined cases with careful monitoring of blood pressure, renal function, and electrolytes. Clinical trial data have shown that in patients with atherosclerosis, heart failure, or diabetes mellitus with target organ damage, dual blockade of the renin-angiotensin-aldosterone system (RAAS) is associated with a higher incidence of hypotension, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of a single agent (see sections 5.1, 5.3, and 4.4).
Aliskiren should not be used concomitantly with Lozap® Plus in patients with diabetes mellitus. Aliskiren should be avoided in patients with renal insufficiency (GFR < 60 ml/min).
Hydrochlorothiazide
When combined with thiazide diuretics:
alcohol, barbiturates, narcotics, and antidepressants may increase the risk of developing orthostatic hypotension;
Antidiabetic agents (oral and insulin) Thiazide use may affect glucose tolerance. Dose adjustment of antidiabetic agents may be necessary. Metformin should be used with caution due to the risk of lactic acidosis caused by functional renal failure that may occur under the influence of hydrochlorothiazide;
with other antihypertensive agents – additive effect;
Cholestyramine and colestipol resins - in the presence of anion exchange resins, the absorption of hydrochlorothiazide is reduced. Single doses of cholestyramine and colestipol resins bind hydrochlorothiazide and reduce its absorption in the gastrointestinal tract by 85 and 43%, respectively;
corticosteroids, adrenocorticotropic hormone (ACTH) – pronounced decrease in electrolyte levels, in particular hypokalemia;
pressor amines (e.g. adrenaline) – a decrease in the severity of the response to the use of pressor amines is possible, but not sufficient to exclude their use;
muscle relaxants of a non-depolarizing type of action (for example, tubocurarine) - possible enhancement of the effect of the muscle relaxant;
Lithium – diuretics reduce renal clearance of lithium and increase the risk of lithium toxicity; their combined use is not recommended.
Medicines for the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
Dose adjustment of uricosuric drugs (to remove uric acid from the body) may be necessary, as hydrochlorothiazide may cause an increase in serum uric acid levels. Dose increase of probenecid or sulfinpyrazone may be necessary. Concomitant administration with thiazides may increase the incidence of hypersensitivity reactions to allopurinol.
Anticholinergics (e.g., atropine, biperiden)
Increased bioavailability of thiazide diuretics due to decreased gastrointestinal motility and gastric emptying rate.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.
Salicylates
When salicylates are used in high doses in combination with hydrochlorothiazide, the toxic effect of salicylates on the central nervous system may be enhanced.
Methyldopa
There have been isolated reports of hemolytic anemia during concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine
Concomitant use with cyclosporine may increase the risk of hyperuricemia and gout-like complications.
Digitalis glycosides
Thiazide-induced hypokalemia or hypomagnesemia may precipitate digitalis-induced cardiac arrhythmias.
Drugs affected by changes in serum potassium concentration
Periodic monitoring of serum potassium and ECG is recommended when losartan/hydrochlorothiazide is used concomitantly with medicinal products that are affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and when medicinal products that induce torsades de pointes (including some antiarrhythmics) are administered concomitantly; hypokalaemia is a predisposing factor to the development of torsades de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
other agents (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).
Calcium salts
Thiazide diuretics may increase serum calcium levels by reducing its excretion from the body. If the use of calcium preparations is necessary, serum calcium levels should be monitored and the calcium dose adjusted.
Effect of the drug on laboratory test results
Due to the effect of thiazides on calcium metabolism, their administration may alter the results of parathyroid function tests (see section "Special warnings and precautions for use").
Carbamazepine
There is a risk of symptomatic hyponatremia. Clinical and biological monitoring is necessary.
Iodine-containing contrast agents
In the presence of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially when using iodine products in high doses. Before administering the drug, it is necessary to compensate for dehydration in patients.
Amphotericin B (for parenteral administration), corticosteroids, ACTH, stimulant laxatives, or glycyrrhizin (found in licorice)
Hydrochlorothiazide may worsen electrolyte imbalance, namely worsening the condition of hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (mainly in renal failure).
Beta-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Amantadine
Thiazides, including hydrochlorothiazide, may increase the risk of side effects caused by amantadine.
Application features
Losartan
Angioedema
Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be monitored closely (see section 4.8).
Arterial hypotension and intravascular hypovolemia
Symptomatic hypotension, especially after the first dose, may occur in patients with hypovolemia and/or hyponatremia due to aggressive diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected before starting Lozap Plus (see sections "Contraindications", "Method of administration and dosage").
Electrolyte imbalance
Electrolyte imbalance is common in patients with impaired renal function, with or without diabetes mellitus. Plasma potassium levels and creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance between 30 and 50 ml/min. The concomitant use of losartan/hydrochlorothiazide with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes is not recommended (see section 4.5).
Liver dysfunction
Pharmacokinetic data indicate that in patients with cirrhosis of the liver, the concentration of losartan in the blood plasma is significantly increased, therefore, the drug Lozap® Plus should be used with caution in patients with a history of mild to moderate liver dysfunction. There is no therapeutic experience with the use of losartan in patients with severe liver dysfunction. Therefore, the drug Lozap® Plus is contraindicated in patients with severe liver dysfunction (see sections "Pharmacokinetics", "Contraindications", "Method of administration and dosage").
Kidney dysfunction
Cases of deterioration in renal function, including renal failure, have been reported following RAAS inhibition, particularly in patients whose renal function is dependent on the RAAS, such as those with severe heart failure or pre-existing renal dysfunction. As with other medicinal products that affect the RAAS, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible upon discontinuation of the drug.
Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Kidney transplantation
There is no experience with the use of the drug in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that inhibit the renin-angiotensin system. Therefore, the use of Lozap Plus is not recommended in these patients.
Coronary heart disease and cerebrovascular disorders
Excessive reduction in blood pressure in patients with ischemic cardiovascular diseases and cerebrovascular disorders can lead to myocardial infarction or stroke.
In patients with heart failure, with or without renal impairment, as with other drugs that affect the renin-angiotensin system, there is a risk of severe hypotension and (often acute) renal failure.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, the drug should be used with extreme caution in patients suffering from aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
The influence of ethnic factors
As with all ACE inhibitors, losartan and other angiotensin antagonists are significantly less effective in lowering blood pressure in blacks than in non-blacks, possibly because the black population has a lower renin-angiotensin-aldosterone profile.
Pregnancy
Angiotensin II receptor antagonists (ARBs) should not be used as initial therapy during pregnancy. Unless continued ARB therapy 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, ARA II should be discontinued immediately and, if necessary, alternative therapy should be started (see sections "Contraindications", "Use during pregnancy or breastfeeding").
Dual blockade of RAAS
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS by the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections 5.1 and 5.5).
If such double blockade therapy is absolutely necessary, it should be carried out under specialist supervision and with frequent and careful monitoring of renal function, electrolytes, and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Hydrochlorothiazide
Arterial hypotension and electrolyte imbalance
As with any antihypertensive agent, symptomatic hypotension may occur in some patients. Patients should be observed for clinical signs of electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may occur with concomitant diarrhea or vomiting. Serum electrolytes should be monitored in such patients. Dilutional hyponatremia may develop in patients with edema in hot weather.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. In some cases, dose adjustment of hypoglycemic agents, including insulin, may be necessary (see section "Interaction with other medicinal products and other forms of interaction"). During thiazide therapy, latent diabetes mellitus may progress to overt.
Thiazides may reduce urinary calcium excretion and cause occasional and minor increases in serum calcium. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazide diuretics should be discontinued before parathyroid function tests are performed.
Elevations in blood cholesterol and triglyceride levels may also be associated with thiazide diuretic therapy.
In some patients, thiazide therapy may precipitate the development of hyperuricemia and/or gout. Since losartan lowers uric acid levels, losartan in combination with hydrochlorothiazide reduces the manifestations of diuretic-induced hyperuricemia.
Liver dysfunction
Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as they may induce intrahepatic cholestasis, and minor abnormalities in fluid and electrolyte balance may precipitate hepatic coma.
The drug Lozap® Plus is contraindicated in patients with severe liver dysfunction (see sections "Pharmacokinetics", "Contraindications").
Non-melanoma skin cancer
Patients taking HT should be informed of the risk of NMSC and advised to regularly check their skin for new lesions and to report any suspicious skin lesions immediately. In order to reduce the risk of developing skin cancer, patients should be advised of possible precautions, such as limiting exposure to sunlight and ultraviolet light and ensuring adequate skin protection in the event of such exposure. Suspicious skin lesions should be investigated as soon as possible, including biopsy with histological examination. The use of HT may also need to be reconsidered in patients with a history of NMSC (see also section 4.8).
Choroidal effusion, acute myopia, and/or secondary acute angle-closure glaucoma
Hydrochlorothiazide is a sulfonamide. Medicinal products that are sulfonamides or sulfonamide derivatives may cause idiosyncratic reactions that may lead to choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms are characterized by an acute onset of decreased visual acuity or eye pain and usually develop within a few hours to a few weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment involves discontinuation of the drug as soon as possible. If intraocular pressure remains uncontrolled after this time, immediate medical or surgical intervention may need to be considered. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin (see section 4.8).
Acute respiratory toxicity
Very rare cases of severe acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported following the administration of hydrochlorothiazide. Pulmonary edema usually develops within minutes to hours of hydrochlorothiazide administration. Initial symptoms include dyspnea, fever, impaired pulmonary function, and hypotension. If ARDS is suspected, the drug should be discontinued and appropriate treatment instituted. Hydrochlorothiazide should not be given to patients who have previously experienced ARDS after taking hydrochlorothiazide.
Laboratory studies
The drug may reduce the level of iodine in the blood plasma. Treatment with the drug should be discontinued before laboratory tests to assess the function of the parathyroid glands. This drug is capable of increasing the concentration of free bilirubin in the blood serum.
Other effects
Hypersensitivity reactions may occur in patients taking thiazide diuretics, even in the absence of a history of allergy or bronchial asthma. There have been reports of exacerbation or progression of systemic lupus erythematosus with thiazide diuretics.
Excipients
This medicine contains the dye Ponceau 4R, which may cause allergic reactions.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.
Use during pregnancy or breastfeeding
Pregnancy
The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.
Breastfeeding period
Angiotensin II receptor antagonists (ARBs)
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