Xipogama®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSIPOGAMA® (XIPAGAMMA®)

Composition:

Active substance: xipamid;

1 tablet contains xipamid 10 mg or 20 mg; or 40 mg;

Excipients:

10 mg: starch, microcrystalline cellulose, povidone (K 25), cetyl alcohol, lactose monohydrate, highly dispersed silicon dioxide, magnesium stearate, iron(III) oxide yellow (E 172);

20 mg: starch, microcrystalline cellulose, povidone (K 25), cetyl alcohol, lactose monohydrate, highly dispersed silicon dioxide, magnesium stearate;

40 mg: starch, microcrystalline cellulose, povidone (K 25), cetyl alcohol, lactose monohydrate, highly dispersed silicon dioxide, magnesium stearate, iron(III) oxide yellow (E 172), indigo carmine dye.

Pharmaceutical form. Tablets.

Main physicochemical properties: 10 mg tablets: yellow, round tablets with a "snap-tab" on one side, practically odorless;

20 mg tablets: white, round tablets with a "snap-tab" on one side, practically odorless;

40 mg tablets: light green, round tablets with a "snap-tab" on one side, practically odorless.

Pharmacotherapeutic group. Non-thiazide diuretics with moderately expressed activity. Sulfamides, simple preparations. ATC code C03BA10.

Pharmacological properties.

Pharmacodynamics. Xipamide is a diuretic agent that inhibits reabsorption in the distal tubule of the nephron and initially leads to excretion of chloride and sodium, followed by an increase in polyuria due to osmotically bound water. Increased flow in the distal tubule stimulates potassium secretion. Excretion of bicarbonate, calcium, and magnesium is also enhanced. The mechanism of action of xipamide differs from thiazides, despite structural similarity. Xipamide does not affect renal hemodynamics or the glomerular filtration fraction. Diuretic effect begins within 1 hour and reaches its maximum between the 3rd and 6th hour. Excretion of chloride and sodium occurs over 12–24 hours; therefore, there is no rebound effect. The ceiling dose of xipamide is 5 mg (orally). When doses exceed 80 mg, no further saluresis or diuresis occurs.

The antihypertensive effect of xipamide begins at the start of treatment. Maximum reduction in arterial blood pressure is achieved within 2–3 weeks.

Pharmacokinetics. Maximum plasma concentration of xipamide is reached approximately 1 hour after administration. Protein binding capacity is 99%. The elimination half-life is about 7 hours. Oral absorption of xipamide is complete.

In renal insufficiency, the elimination half-life increases to 9 hours. In liver cirrhosis, despite elevated plasma levels of xipamide, the half-life remains unchanged.

Renal excretion of unchanged substance accounts for 30–40%. Extrarenal elimination (approximately two-thirds of administered xipamide) occurs half by glucuronidation. The inactive metabolite formed in this process is excreted by the kidneys, the remainder through the intestine.

Clinical characteristics.

Indications. Arterial hypertension.

Cardiac, renal, and hepatogenic edema.

Contraindications.

• Hypersensitivity to xipamide, to other sulfonamide derivatives or thiazides or to any of the excipients;
• severe hepatic impairment (precoma and Coma hepaticum);
• severe renal failure;
• refractory hypokalemia;
• severe hyponatremia;
• hypercalcemia;
• hypovolemia;
• gout;
• hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Interaction with other medicinal products and other forms of interactions.

The following interactions have been reported with thiazide diuretics and similar agents and may also occur with xipamide.

Combination not recommended:

Lithium. Concomitant use increases the cardiotoxic and neurotoxic effects of lithium. If diuretic therapy cannot be avoided, lithium blood levels should be monitored and dosage adjusted accordingly.

Combinations requiring special precautions:

Substances that may cause torsades de pointes arrhythmia:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol);
• others: bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinpocetine.

Increased risk of ventricular arrhythmia, including torsades de pointes (especially in the presence of hypokalemia).

Hypokalemia should be monitored and corrected prior to initiating such combination therapy. Monitoring of plasma electrolytes and ECG is required.

Preferably, substances not associated with torsades de pointes should be used if the patient has hypokalemia.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, and high-dose salicylic acid (> 3 g/day). Possible reduction of the antihypertensive effect of xipamide. Risk of acute renal failure in case of dehydration (glomerular filtration). Adequate fluid intake should be ensured and renal function monitored at the start of treatment. High-dose salicylate therapy may enhance its CNS toxicity.

ACE inhibitors. Risk of severe hypotension and/or acute renal failure when initiating ACE inhibitor therapy in patients with pre-existing sodium depletion (e.g., due to renal artery stenosis).

If xipamide treatment for arterial hypertension has led to sodium depletion, the following should be considered:

• either discontinue xipamide 3 days before starting ACE inhibitor therapy and reintroduce it later;
• or initiate ACE inhibitor therapy at low doses and gradually increase.

In patients with decompensated heart failure, very low initial doses of ACE inhibitors should be used.

In all cases, renal function (serum creatinine) should be monitored during the first weeks of ACE inhibitor therapy.

Other diuretics, antihypertensives, beta-blockers, nitrates, vasodilators, barbiturates, phenothiazines, tricyclic antidepressants, alcohol.

The antihypertensive effect of xipamide may be enhanced.

Other agents that reduce potassium levels: amphotericin B (intravenous), glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives.

Increased risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected, especially during concomitant therapy with cardiac glycosides.

Baclofen. Potentiates the antihypertensive effect. Adequate fluid intake should be ensured and renal function monitored at the start of treatment.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may increase the risk of toxic side effects of digitalis glycosides. Monitoring of serum potassium and ECG is required.

Combinations with possible additional interactions.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Although this combination may be appropriate for certain patients, it may lead to hypokalemia or hyperkalemia (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels and ECG should be checked, and therapy adjusted if necessary.

Potassium-wasting diuretics (e.g., furosemide), glucocorticoids, ACTH (adrenocorticotropic hormone), carbenoxolone, penicillin G, amphotericin, or laxatives. Concomitant use with xipamide may increase potassium loss. Combined use of xipamide with loop diuretics (e.g., furosemide) increases the risk of electrolyte and fluid imbalances. Close patient monitoring is required.

Metformin. Increased risk of metformin-induced lactic acidosis due to possible functional renal impairment associated with diuretic therapy, especially with loop diuretics.

Metformin should not be used if serum creatinine is ≥15 mg/L (135 µmol/L) in men or ≥12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. Diuretic-induced dehydration increases the risk of acute renal failure when iodinated contrast agents (especially in high doses) are administered. Adequate rehydration is required before administration of iodinated contrast media.

Tricyclic antidepressants (e.g., imipramine), neuroleptics. Enhanced hypotensive effect and increased risk of orthostatic hypotension.

Calcium (salts). Risk of hypercalcemia due to reduced urinary excretion of calcium.

Cyclosporine, tacrolimus. Risk of increased serum creatinine levels.

Corticosteroids, tetracosactide (systemic). Reduced antihypertensive effect (due to fluid and sodium retention caused by corticosteroids).

Cytostatic agents (e.g., cyclophosphamide, fluorouracil, methotrexate). Risk of toxicity, particularly granulocytopenia.

Antidiabetic agents, uric acid-lowering drugs, noradrenaline, adrenaline. The effects of these drugs may be diminished when taken concomitantly with xipamide.

Quinidine. Quinidine excretion may be reduced.

Muscle relaxants (curare-type alkaloids). Enhanced and prolonged muscle relaxant effect.

Colestipol and cholestyramine. May reduce absorption of xipamide.

Special precautions for use.

The medicinal product contains lactose monohydrate. This medicinal product must not be used in patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Water and electrolyte balance. Xipamide should not be administered in cases of uncorrected electrolyte imbalance, orthostatic disturbances in blood pressure regulation, disorders of the central nervous system, pancreatitis, blood count abnormalities (anemia, leukopenia, thrombocytopenia), acute cholecystitis, onset of vasculitis, or worsening of myopia.

In patients with liver disease, hepatic encephalopathy may occur. In such cases, the medicinal product should be discontinued immediately.

With chronic excessive use of diuretics, a pseudohyperaldosteronism (extra-adrenal hyperaldosteronism), also known as Bartter's syndrome, may develop, accompanied by edema. These edemas are manifestations of increased renin levels, leading to secondary hyperaldosteronism.

Serum sodium levels should be checked before initiating treatment and then at regular intervals thereafter. Since hyponatremia may initially be asymptomatic, patients—especially elderly patients and those with liver cirrhosis—should be monitored closely.

Serum potassium levels. Hypokalemia may occur during prolonged treatment with xipamide. Serum electrolytes (particularly potassium, sodium, calcium), bicarbonate, creatinine, urea, uric acid, and blood glucose should be monitored regularly. Potassium supplementation may be necessary in elderly patients who do not absorb sufficient potassium.

Hypokalemia (serum potassium level below 3.4 mmol/L) should be avoided, especially in cases of significant fluid loss (e.g., due to vomiting, diarrhea, or excessive sweating) and in patients at risk—i.e., elderly patients, debilitated patients, patients previously treated with multiple medications, patients with liver cirrhosis and edema or ascites, and patients with coronary heart disease or heart failure. In such patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Hypovolemia or dehydration, as well as significant electrolyte imbalances or acid-base disturbances, must be monitored. If necessary, treatment with Xipogama® should be temporarily discontinued.

Patients at risk include those with prolonged QT interval, whether congenital or acquired. The presence of hypokalemia and bradycardia may predispose to serious cardiac arrhythmias, including potentially fatal torsades de pointes.

In all the above-mentioned cases, serum potassium levels should be monitored more frequently, with the first test performed during the first week of treatment. Hypokalemia should be corrected promptly.

Calcium levels in blood. Treatment with thiazide diuretics and related medicinal products may reduce urinary calcium excretion and cause a significant, temporary increase in serum calcium levels. Marked hypercalcemia may be due to hyperparathyroidism.

Therapy should be interrupted before assessing parathyroid function.

Blood glucose. In diabetic patients, blood glucose levels should be monitored, particularly when hypokalemia is also present.

Uric acid levels. In patients with hyperuricemia, the risk of gout attacks is increased.

Kidney function and diuretics. Thiazide diuretics and their derivatives are fully effective with normal kidney function or mild impairment (serum creatinine < 25 mg/L or < 220 µmol/L in adults). In elderly patients, serum creatinine levels should be appropriate for age, body weight, and sex.

Hypovolemia caused by fluid or sodium loss due to diuretics at the beginning of treatment may lead to reduced glomerular filtration. This may result in increased blood urea and nitrogen levels. This transient functional renal insufficiency in individuals with healthy kidneys is usually without consequence, but it may exacerbate pre-existing renal impairment.

If electrolyte imbalance cannot be corrected, treatment should be discontinued.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamides or sulfonamide derivatives may induce an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks after starting the medication.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Use during pregnancy or breastfeeding. The use of xipamide during pregnancy or breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery. Since individual responses to the drug may vary, reaction speed may be altered to such an extent that the ability to drive or operate machinery, as well as balance, may be impaired. This may occur at the beginning of treatment, when the dose is increased, or when switching medications.

Dosage and Administration

For adults, take 10–20 mg of xipamid once daily, both for arterial hypertension and edema.

The dose for edema treatment may be increased to 40 mg of xipamid. In case of severe renal function impairment, the daily dose of xipamid may be increased up to 80 mg.

An increase of the dose beyond 80 mg of xipamid per day is not recommended.

After edema has resolved, the dose may be reduced to 20 mg or 10 mg of xipamid for prevention of relapses.

After prolonged treatment, xipamid should be discontinued gradually.

Tablets should be swallowed whole with sufficient amount of water (approximately 1 glass), preferably in the morning after breakfast.

Hepatic impairment. In case of hepatic dysfunction, xipamid dosage should be adjusted according to the degree of impairment.

Reduced cardiac function. In severe cardiac decompensation, absorption of xipamid may be significantly reduced.

Children. Xipamid must not be administered to children, as the safety and efficacy of the drug in this patient group have not been established.

Overdose.

Acute intoxication is primarily manifested by disturbances in water and electrolyte balance (hyponatremia, hypokalemia). Clinical symptoms may include nausea, vomiting, acute drop in blood pressure, seizures, dizziness, drowsiness, confusion, polyuria or oliguria up to anuria (due to hypovolemia).

Emergency measures: administration of activated charcoal. Restoration of water and electrolyte balance.

In case of overdose, the drug must be discontinued immediately and medical advice should be sought. Treatment is symptomatic.

Side effects.

The frequency of adverse reactions is defined as follows: very common (≥ 10%), common (≥ 1% to < 10%), uncommon (≥ 0.1% to < 1%), rare (≥ 0.01% to < 0.1%), very rare (< 0.01% or unknown).

Central nervous system and visual disorders: common – headache, dizziness, increased fatigue, dry mouth, sweating.

Cardiovascular system: common – orthostatic hypotension, palpitations; at high doses, particularly in venous disorders, the risk of thrombosis and embolism increases.

Gastrointestinal tract: common – abdominal pain, spasmodic abdominal pain, diarrhea, constipation, acute cholecystitis in the presence of cholelithiasis;

rare – hemorrhagic pancreatitis;

very rare – jaundice.

Skin: allergic reactions (including pruritus, erythema, urticaria, chronic photosensitization) (discontinuation of therapy).

Eye disorders: rare: slight visual disturbances, worsening of pre-existing myopia (discontinuation of therapy), choroidal effusion with unknown frequency.

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia (discontinuation of therapy).

Psychiatric disorders: common – apathy, lethargy, anxiety, excitement.

Metabolic disorders: rare – hyperlipidemia. Latent diabetes may become manifest. Increased blood glucose levels may indicate that the patient has diabetes.

Renal and urinary disorders: very rare – acute interstitial nephritis.

Musculoskeletal and connective tissue disorders: common – muscle spasms and cramps.

Electrolyte and fluid balance: disturbances in fluid and electrolyte balance are frequently observed during treatment with xipamide due to increased excretion of fluids and electrolytes. Therefore, monitoring of electrolyte levels (potassium, sodium, and calcium) is necessary.

Patients very commonly suffer from hypokalemia, which may manifest as nausea, vomiting, ECG changes, increased sensitivity to glycosides, cardiac arrhythmias, or skeletal muscle hypotonia.

Potassium loss may increase or potassium intake may decrease in cases of vomiting, chronic diarrhea, or excessive sweating. Increased renal potassium excretion may lead to hypokalemia, which may present with neuromuscular symptoms (muscle weakness, paresthesia, paralysis), gastrointestinal symptoms (vomiting, constipation, flatulence), renal symptoms (polyuria, polydipsia), and cardiovascular symptoms (e.g., disturbances in cardiac impulse generation and conduction). Severe hypokalemia may lead to paralytic ileus, loss of consciousness, or coma.

Hyponatremia may develop due to increased renal sodium loss. The most commonly observed symptoms of hyponatremia include apathy, convulsions, loss of appetite, weakness, drowsiness, vomiting, and confusion.

Increased renal calcium excretion may lead to hypocalcemia. Hypocalcemia may result in tetany.

Increased renal magnesium excretion may rarely cause tetany or cardiac arrhythmias.

As a consequence of fluid and electrolyte loss during xipamide therapy, metabolic alkalosis may develop or pre-existing metabolic alkalosis may worsen.

Increased serum uric acid levels may lead to gout in predisposed patients.

Excessive diuresis may cause dehydration. As a result – hypovolemia, hemoconcentration, rarely – seizures, loss of consciousness, vascular collapse, dizziness.

Other: rare – anaphylactoid reactions.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister, 3, 5, or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Artesan Pharma GmbH & Co. KG, Germany

Address.

29439, Luechow, Wendlandstrasse 1, Germany