Cross-Reactivity Between Sulfonamides and Loop or Thiazide Diuretics: Is it a Theoretical or Actual Risk?

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Allergy Clin Immunol Int. Author manuscript; available in PMC 2012 Jun 1.

Published in final edited form as:

Allergy Clin Immunol Int. 2000; 12(1): 26–28.

doi: 10.1027/0838-1925.12.1.26

PMCID: PMC3365608

NIHMSID: NIHMS351978

PMID: 22661885

and

Author information Copyright and License information Disclaimer

This is a case report of furosemide use in a woman with acute renal transplant rejection and history of anaphylaxis to sulfonamide and a review of the literature.

Allergists are consulted about the question of hypersensitivity to loop or thiazide diuretics in patients with a history of sulfonamide allergy because it is thought that there is a risk of cross-reactivity from common sulfonamide constituents of these compounds. In text references and drug-package inserts, reference is made to this risk. For example, the package insert for furosemide states that “patients allergic to sulfonamides may also be allergic to furosemide” [1]. Therefore, in clinical practice, the use of thiazide or some loop diuretics is often avoided in patients with a prior history of sulfonamide allergy. The literature on this topic, however, is sparse and not well documented. We report an instructive case of a woman with a history of anaphylaxis to sulfonamides who subsequently received furosemide while undergoing acute renal transplant rejection.

A 30-year-old woman was the recipient of a cadaveric renal transplant because of end-stage renal disease secondary to insulin-dependent diabetes mellitus. She tolerated the transplant well, and for 3 years was maintained on cyclosporin at 4 mg/kg/day without complications.

At age 33, she developed an acute onset of fever, hematuria, headaches, progressive weight gain, and pain in the allograft area. She was admitted to the hospital with elevated creatinine levels and presumed organ rejection. She was given two doses of 3 mg/kg intravenous solumedrol 12 h apart on hospital day 1. A single dose of 1.3 mg/kg intravenous furosemide was administered after the patient became oliguric on day 2. She was then transferred to our institution for further management.

After transfer, she was given a 5 mg/kg intravenous loading dose of solumedrol and started 1 mg/kg oral prednisone. In addition, tacrolimus (FK506) rescue was given at 0.075 mg/kg per day. A renal biopsy was performed and showed widespread polymorphonuclear infiltrate with many eosinophils and a lymphocytic tubulitis consistent with acute rejection.

Twenty years previously, the patient had anaphylaxis after taking one oral dose of sulfamethoxazole and trimethoprim. She immediately developed urticaria and shortness of breath. At the emergency room she was hypotensive. Her symptoms resolved several hours later after treatment with epinephrine, diphenhydramine, steroids, and intravenous fluids. She had no further use of the medication and had no history of other drug allergies. There was no family history of medication allergies.

On transfer her complete cell blood count (CBC) was normal. Because of her history of sulfonamide allergy, loop and thiazide diuretics were avoided and she was given ethacrynic acid at 1 mg/kg intravenously daily to improve her urine output. After 2 weeks of therapy, she developed pancytopenia, a known complication of ethacrynic acid, which was then discontinued. Within 2 weeks, her CBC returned to normal in all indices.

Because of her sensitivity to the ethacrynic acid, her history of sulfonamide allergy, and evidence of numerous eosinophils on the renal biopsy, an allergy consultation was requested. Of particular concern was an appropriate diuretic to use for this patient. The drug of choice was furosemide, but there was concern about her history of sulfonamide allergy and the eosinophilia on renal biopsy which was taken within 2 days of a single dose of intravenous furosemide given at the referring medical center.

After review of the clinical history and pertinent literature, we offered the opinion that furosemide may be safely tried in this patient [2–4]. We concluded that it was unlikely that furosemide caused the eosinophilia on renal biopsy since eosinophilia is a pathologic finding consistent with acute allograft rejection [5, 6]. Furosemide was given repeatedly during the admission with no evidence of acute allergy, rashes, or eosinophilia.

It has long been taught that loop and thiazide diuretics pose a theoretical risk of cross sensitivity in a patient with allergy to sulfonamide antimicrobials due to their common SO₂-NH_x structure (see ) [1]. In an extensive review of the literature, we found only four published cases of possible cross-reactivity between loop or thiazide diuretics and sulfonamides [2–4]. summarizes these cases. All of these cases involved only a circumstantial reaction between reactions to drugs in the two categories.

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Structural formulas for the sulfonamide antimicrobials and diuretics used in the reported cases. SO₂-NH_x groups are highlighted.

Table 1

Published cases of putative sulfonamide-diuretic cross sensitivity

Case	Age (years) and sex	Case
1	56, F	Papular rash developed 17 days after one dose oral sulfadimethoxine. One year later developed papular pigmented rash after oral chloramidobenzole. Four weeks later developed rash after oral acetazolamide. Two years later developed rash after oral hydrochlorthiazide [2]
2	66, F	Exanthem developed shortly after sulfamethoxypyridazine. Five years later developed blisters 24 hours after oral quinethazon [2]
3	55, M	Patient was on glisoxepid, a oral hypoglycemic. One tablet of furosemide caused nausea, edema, vomiting, and diarrhea. Addition of glibenclamid, an oral hypoglycemic caused worsening symptoms. Skin tests by scratch weakly positive to sulfamethoxazole but no documented challenge done [3]
4	68, F	Indapamide caused fixed drug eruption and was confirmed with repeat oral challenge. Oral challenge with sulfamethoxazole and sulfadiazine were positive but were negative to furosemide [4]

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In case 1 the subject developed a papular rash 17 days after one oral dose of sulfadimethoxine. One year later, a papular pigmented rash developed after oral chloramidabenzole and acetazolamide. Two years later a similar papular rash developed while taking oral hydrochorothiazide [2]. In case 2, an exanthem developed shortly after sulfamethoxypyridazine. Five years later, blisters developed after oral quinethazon, a thiazide diuretic [2]. These reactions were not consistent with immunoglobulin E (IgE)-mediated hypersensitivity. They could reflect T-cell cross-reactivity, in a delayed-type hypersensitivity reaction. The cases are also consistent with multiple independent drug allergy. No immunologic or challenge studies were performed. In case 3, a patient on oral glisoxepid (an oral hypoglycemic), edema and gastrointestinal symptoms developed after one tablet of furosemide. Glibenclamide, another oral hypoglycemic, was started with worsening of symptoms. Skin tests were weakly positive to sulfamethoxazole, but no oral challenge was done [3]. The weakly positive skin test is difficult to interpret since most investigators have failed to elicit positive skin tests to sulfamethoxazole even in patients with good history of IgE-dependent reactions [5]. It is also interesting to note that the patient tolerated the oral hypoglycemic glisoxepide but did not tolerate glibenclamide, which both have internal SO₂-NH_x moieties (see ). In case 4, a fixed drug eruption developed on the oral diuretic, indapamide. Subsequent oral challenges to sulfonamide antimicrobials were positive, but the more structurally similar furosemide failed to elicit a response to oral challenge [4]. The patient could have had an independent allergy to the sulfonamide antimicrobial.

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Structural formulas for some oral hypoglycemics. SO₂-NH_x groups are highlighted.

compares the chemical structures of the sulfonamide antimicrobials with the thiazide and loop diuretics reported in these cases [1–3]. The common structural component of a SO₂-NH_x moiety is the theoretical basis for presumed cross-reactivity between such compounds [6].

The use of thiazide or loop diuretics in the general population is quite common, especially in geriatric, renal, and cardiac patients, and allergy to sulfonamide antimicrobials has been estimated to have a prevalence of only 5% [6]. It seems reasonable that if there were appreciable cross-reactivity between these medications, clearer cases of clinical cross-sensitivity would be more numerous. It remains possible that many such cases go unreported. Furthermore, what the published cases do illustrate is that putative cross-sensitivity was most often manifest as cutaneous rashes and late onset signs suggestive of T-cell pathogenesis rather than IgE antibody-dependent reactions.

Celecoxib is the first of a new family of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cycloxy-genase 2 while sparing cycloxygenase 1, and thas clinically been shown to have less side effects of gastrointestinal bleeding than currently available NSAIDs [7]. Celecoxib also has a SO₂-NH_x side group [7] (see ). While clinical experience is still limited, if we accept the lack of substantial evidence for cross-reactivity among common SO₂-NH_x, structures, we might anticipate that the actual risk of cross-reactions with this medication may also be small.

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Structural formula for the new cycloxygenase 2 inhibitor, celecoxib. The SO₂-NH_x group is highlighted.

Another instructive point in our current case is that while eosinophils on pathologic biopsy may suggest drug hypersensitivity, alternative explanations must also be considered. Acute renal transplant rejection can manifest eosinophil infiltrates, as we believe is illustrated in this case [8, 9]. How eosinophils participate in allograph rejection is not clear [8].

In conclusion, this case reports an uneventful treatment with furosemide in a patient with a history of anaphylaxis to a sulfonamide antibiotic. A review of the literature suggests that while there is a theoretical concern about cross-reactivity among sulfonamide antibiotics, loop or thiazide diuretics, and oral hypoglycemics, the actual risk will likely be small. Further immunochemical research will be needed to define more clearly the frequency and degree of cross reactivity attributable to various drugs with common SO₂-NH_x structures.

We wish to thank Anna Nowak-Wegrzyn, MD, for providing translation of German language publications. Supported by NIH Institutional Training Grant # A107007.

Wanda Phipatanakul, Division of Allergy and Immunology, Departments of Pediatrics, CMSC 1102, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore MD, 21287-3923, USA (tel. +1 410 955-5883, fax +1 410 955-0229, ude.uhj.hclew@pihpw)

N. Franklin Adkinson, Jr, Division of Allergy and Immunology, Department of Medicine, Johns Hopldns University School of Medicine, Baltimore MD, 21287-3923, USA.

1. Physician’s Desk Reference. 53rd Edition. Montavale, NJ: Medical Economics Data Production Company; 1999. [Google Scholar]

2. Goerz G, Ippen H, Meiers HG. Sulfonamide hypersensitivity. Cross-reactivity between antibacterial sulfonamides and diuretics. Dtsch Med Wochenschr. 1964;89:1301. [PubMed] [Google Scholar]

3. Ummenhofer B, Djawari D. Cross-allergy between sulfonamide diuretics, probenecid, sulfamethoxazole and sulphonyl-urea compounds. Dtsch Med Wochenschr. 1979;104:514–517. [PubMed] [Google Scholar]

4. De Barrio M, Tornero P, Zubeldia JM, Sierra Z, Matheu V, Herrero T. Fixed drug eruption induced by indapamide. Cross-reactivity with sulfonamides. J Invest Allerg Clin Immunol. 1998;8:253–255. [PubMed] [Google Scholar]

5. Macy E. Current sulfamethoxazole skin test reagents fail to predict recurrent adverse reactions. J Allergy Clin Immunol. 1995;95:121. [Google Scholar]

6. Weinstein L, Madoff MA, Samer CM. The sulfonamides. New Engl J Med. 1960;263:952–957. [PubMed] [Google Scholar]

7. Mandell BG. COX2-selective NSAIDS: Biology, promises, and concerns. Clevel Clin J Med. 1999;66:285–292. [PubMed] [Google Scholar]

8. Hongwei W, Nanra RS, Stein A, Avis L, Price A, Hibberd AD. Eosinophils in acute renal allograft rejection. Transplant Immunol. 1994;2:41. [PubMed] [Google Scholar]

9. Magil A, et al. Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathological observations in three cases. Am J Med. 1980;69:939. [PubMed] [Google Scholar]

Which diuretics are safe and effective for patients with a sulfa allergy?

Clinical Inquiries

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References

1. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628-1635.

2. Lee AG, Anerson R, Kardon RH, Wall M. Presumed “sulfa allergy” in patients with intracranial hypertension treated with acetazolamide or furosemide: Cross-reactivity, myth or reality? Am J Ophthalmol 2004;138:114-118.

3. Johnson KK, Green DL, Rife JP, Limon L. Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother 2005;39:290-301.

4. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Drug Safe 2001;24:239-247.

5. Furosemide Tablets, USP. Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson; 2007:2155.

6. Dyazide. Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson; 2007:1424.

EVIDENCE-BASED ANSWER

Diuretics that do not contain a sulfonamide group (eg, amiloride hydrochloride, eplerenone, ethacrynic acid, spironolactone, and triamterene) are safe for patients with an allergy to sulfa. The evidence is contradictory as to whether a history of allergy to sulfonamide antibiotics increases the risk of subsequent allergic reactions to commonly used sulfonamide-containing diuretics (eg, carbonic anhydrase inhibitors, loop diuretics, and thiazides) (strength of recommendation: C, based on case series and poor quality case-control and cohort studies).

Clinical commentary

Are all sulfa drugs created equal?
Brian Crownover, MD, FAAFP
96 MDG Family Medicine Residency, Eglin Air Force Base, Fla

Historical bromides commonly fall by the wayside as better evidence becomes available. Who would have thought 15 years ago that we would be promoting beta-blockers for patients with congestive heart failure?

Likewise, with closer inspection, we have learned that not all sulfa drugs are created equal. The stereospecificity due to the absence of aromatic amines in common diuretics means they are safe for patients with known sulfa antibiotic allergies. Given that diuretics are older agents and off-patent, with no company to take up their cause, no one has been willing to challenge outdated package insert warnings.

As clinicians who regularly work without a net, we are accustomed to prescribing medications in less than ideal circumstances. Thankfully, reasonable evidence is available to support what many of us are already doing—using cheap thiazides for patients despite a history of sulfa allergy.

Evidence summary

Little research has been performed on sulfonamide antibiotic and sulfonamide diuretic allergic cross-reactivity. What we do know is that there are 2 classes of sulfonamides—those with an aromatic amine (the antimicrobial sulfonamides) and those without (eg, the diuretics acetazolamide, furosemide, hydrochlorothiazide, and indapamide). Hypersensitivity reactions occur when the aromatic amine group is oxidized into hydroxylamine metabolites by the liver. Sulfonamides that do not contain this aromatic amine group undergo different metabolic pathways, suggesting that allergic reactions that do occur in this group are not due to cross-reactivity in sulfa-allergic patients. But that point is far from settled by the research.

On one side, a large cohort study shows some cross-reactivity

A large retrospective cohort study using Britain’s General Practice Research Database identified 20,226 patients seen from 1987 through March 1999 who were prescribed a systemic sulfonamide antibiotic, and then at least 60 days later received a nonantibiotic sulfonamide (eg, thiazide diuretic, furosemide, oral hypoglycemic).¹ Researchers reviewed records to determine whether patients described as having an allergic reaction to a sulfonamide antibiotic were at increased risk of having a subsequent allergic reaction to a sulfonamide nonantibiotic.

Patients were identified as being allergic using both narrow definitions (anaphylaxis, bronchospasm, urticaria, laryngospasm, or angioedema) and broad ones. As only 18 patients out of the 20,226 patients were reported as having an allergic reaction using the narrow definition, analysis was based on the broad definition. Added to the broad category were asthma, eczema, and other “adverse” drug effects that were not specified by the author.

Using this broad definition, researchers identified allergies to sulfonamide antibiotics in 969 patients. Of this group, 96 patients (9.9%) had a subsequent reaction to a sulfonamide nonantibiotic, which included drugs from the loop and thiazide diuretic classes (including bumetanide, chlorothiazide, furosemide, hydrochlorothiazide, indapamide, and torsemide). It was unclear if any patients taking a carbonic anhydrase inhibitor experienced an allergic reaction. For comparison purposes, of the 19,257 patients who were not identified as having an allergy to a sulfonamide antibiotic, again using the broad definition, 315 (1.6%), had a subsequent allergic reaction to a sulfonamide nonantibiotic, for an unadjusted odds ratio of 6.6 (95% confidence interval [CI], 5.2–8.4).

When the results were adjusted for age, sex, history of asthma, use of medications for asthma or corticosteroids, the adjusted odds ratio for individuals experiencing an allergy to a nonantibiotic sulfonamide in those persons with a history of allergy to a sulfonamide antibiotic was 2. 8 (95 % CI, 2.1–3.7). Of note, the adjusted odds ratio for the occurrence of a penicillin allergy in a patient with a history of sulfonamide antibiotic allergy was significantly higher at 3.9 (95% CI, 3.5–4.3).

Some limitations of the study included uncertainty of cause and effect of prescribed medications and subsequent reactions, possible inconsistency of physician diagnosis and coding, and lack of precision in the diagnosis of allergic reactions. There is also the possibility of “suspicion bias,” where patients with a history of allergies may be more closely monitored for subsequent reactions than nonallergic patients.

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• Immunology

Chlorthalidone | is.

.. What is chlorthalidone?

Chlorthalidone (oxodoline, hygroton) is a diuretic thiazide-like drug used both as a separate active substance and as part of combined drugs.

Randomized study of the drug was carried out in the framework of ALLHAT, THOMS, All-Russian multicenter study VOSTOK.

Suppresses active reabsorption of Na ⁺ , mainly in the peripheral renal tubules (cortical segment of the loop of Henle), increasing the excretion of Na ⁺ , Cl ⁻ and water. The excretion of K ⁺ and Mg ²⁺ through the kidneys increases, while the excretion of Ca ²⁺ decreases. It causes a slight decrease in blood pressure, the severity of the hypotensive effect gradually increases and manifests itself in full 2-4 weeks after the start of therapy. At the beginning of therapy causes a significant decrease in the volume of extracellular fluid, BCC and IOC; however, after several weeks of use, these indicators return to levels close to the original. Like thiazide diuretics, it causes a decrease in polyuria in patients with renal diabetes insipidus. The onset of action is 2-4 hours after ingestion, the maximum effect is 12 hours later, the duration of action is 2-3 days.

Indications: chronic heart failure stage II, arterial hypertension, cirrhosis of the liver with portal hypertension, nephrosis, nephritis, late preeclampsia (nephropathy, edema, eclampsia), fluid retention on the background of premenstrual syndrome, diabetes insipidus, dysproteinemic edema, obesity. With prolonged use, as well as with its simultaneous use with cardiac glycosides, glucocorticosteroids, ACTH, in order to prevent hypokalemia, it is recommended to prescribe potassium preparations (contraindicated when taking ACE inhibitors) or potassium-sparing diuretics (half dose of veroshpiron 12.5 instead of 25 with simultaneous administration of ACE inhibitors and chlorthalidone).

Contraindications: Hypersensitivity (including to sulfonamide derivatives, which include thiazide diuretics), hypokalemia, acute renal failure (anuria), hepatic coma, acute hepatitis, diabetes mellitus (severe forms), gout, lactation. With caution in renal and / or liver failure, allergic reactions, bronchial asthma, systemic lupus erythematosus. Side effects: From the digestive system: nausea, vomiting, gastrospasm, constipation or diarrhea, intrahepatic cholestasis, jaundice, pancreatitis. From the nervous system: dizziness, paresthesia, asthenia (excessive fatigue or weakness), disorientation, apathy, From the senses: xanthopsia, visual impairment. On the part of the hematopoietic organs: thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, aplastic anemia. From the cardiovascular system: orthostatic hypotension (may increase under the influence of ethanol, anesthetics and sedative drugs), arrhythmia (due to hypokalemia). Laboratory indicators: hypokalemia, hyponatremia (including accompanied by neurological symptoms – nausea), hypomagnesemia, hypochloremic alkalosis, hypercalcemia, hyperuricemia (gout), hyperglycemia, glucosuria, hyperlipidemia. Allergic reactions: urticaria, photosensitivity. Other: muscle spasm, decreased potency. Overdose symptoms: dizziness, nausea, drowsiness, hypovolemia, excessive decrease in blood pressure, arrhythmia, convulsions. Treatment: gastric lavage, oral administration of activated charcoal; symptomatic therapy (including intravenous administration of saline solutions to restore the electrolyte balance of the blood).

Dosage and administration: Inside. With long-term therapy, it is recommended to prescribe the lowest effective dose sufficient to maintain the optimal effect, especially in elderly patients. With a mild degree of arterial hypertension – 25 mg 1 time per day or 50 mg 3 times a week; if necessary, it is possible to increase the dose to 50 mg / day. With edematous syndrome, the initial dose is 100-120 mg every other day; in severe cases – 100-120 mg / day for the first few days (doses above 120 mg usually do not cause an increase in the diuretic effect), then it is necessary to switch to a maintenance dose – 100-50-25 mg / day 3 times a week. Renal diabetes insipidus (in adults): initial dose – 100 mg 2 times a day, maintenance dose – 50 mg per day. The average daily dose for children is 2 mg/kg.

Special instructions: During the period of treatment, it is necessary to periodically determine blood electrolytes, especially in patients taking digitalis preparations. It is not recommended to prescribe a very strict salt-free diet to patients. If signs of hypokalemia appear (myasthenia gravis, rhythm disturbances) or if patients have an additional possibility of K + loss (with vomiting, diarrhea, malnutrition, liver cirrhosis, hyperaldosteronism, ACTH therapy, GCS), K + replacement therapy is indicated. In patients with hyperlipidemia, serum lipids should be constantly monitored (in case of an increase in their concentration, therapy should be discontinued). While taking thiazide diuretics, an exacerbation of SLE was noted. Although no such effects have been observed with chlorthalidone, caution should be exercised when prescribing it to patients with SLE.

Interaction: Increases the concentration of Li + in the blood (in the case when Li + causes polyuria, chlorthalidone may not have a diuretic, but an antidiuretic effect) and therefore increases the risk of intoxication with Li + drugs. (Chlorthalidone, like thiazide diuretics, is used for diabetes insipidus, including patients who are prescribed lithium.) Enhances the effect of curare-like muscle relaxants and antihypertensive drugs (including guanethidine, methyldopa, ACE inhibitors, beta-blockers, vasodilators, calcium antagonists, MAO inhibitors). Against the background of taking cardiac glycosides, it can aggravate rhythm disturbances resulting from digitalis intoxication. The hypokalemic effect of the drug is enhanced by the concomitant administration of glucocorticosteroids, amphotericin and carbenoxolone. Non-steroidal anti-inflammatory drugs weaken the diuretic and hypotensive effect of the drug. Patients with diabetes may need to adjust (increase or decrease) the dose of insulin and increase the dose of oral hypoglycemic drugs.

Template:ATC code C03

The use of Chlorthalidone

Chlortalidone – composition and form of release of the drug

Chlortalidone: how to take the drug

Chlortalidone – contraindications, side effects

Chlorthalidone’s analogs

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity.

Application of Chlorthalidone

Indications.

Treatment of hypertension, essential or nephrogenic, or isolated systolic hypertension.

Treatment of stable, chronic mild to moderate heart failure (NYHA functional class II or III).

Treatment of edema.

Chlorthalidone – composition and form of release of the drug

1 tablet contains 25 mg or 50 mg of chlorthalidone;

excipients: microcrystalline cellulose, pregelatinized starch, quinoline yellow (E104), sodium starch glycolate, anhydrous colloidal silicon dioxide, stearic acid.

Dosage form. Pills.

Chlorthalidone: how to take the drug

Dosage and administration.

Arterial hypertension.

Monotherapy. For the treatment of hypertension, the recommended starting dose of chlorthalidone for adults is 25 mg daily. This is sufficient to cause the maximum hypotensive effect in most patients. If a decrease in blood pressure does not occur at a dose of 25 mg / day, it can be increased to 50 mg / day. If additional antihypertensive therapy is used, increasing the dose of the drug to more than 50 mg increases metabolic complications and rarely has a therapeutic effect.

Combination therapy. If combination therapy is needed for the treatment of arterial hypertension, the dosage can be adjusted, first of all, when using each drug separately.

Stable chronic heart failure (NYHA functional class II or III).

The recommended starting dose is 25 to 50 mg/day, in severe cases the dose may be increased to 100 to 200 mg/day. The usual maintenance dose is the lowest effective dose, eg 25 to 50 mg daily or every other day. If the response is insufficient, digitalis preparations and/or ACE inhibitors may be added.

Children. The drug is not used in children.

Chlortalidone – contraindications, side effects

Contraindications.

• Hypersensitivity to chlorthalidone or other drugs derived from sulfonamides.
• Anuria.
• Severe hepatic or renal insufficiency (creatinine clearance <30 ml/min).
• Refractory hypokalemia, hypercalcemia and hyponatremia.
• Symptomatic hyperuricemia (history of gout or uric acid stones).
• Hypertension during pregnancy.
• Untreated Addison’s disease.
• Lithium concomitant therapy.
• Children’s age.
• Pregnancy, lactation.
• Intoxication with cardiac glycoside preparations.

Adverse reactions.

From the digestive tract: anorexia, nausea, vomiting, spasms, diarrhea, constipation, jaundice, pancreatitis.

From the side of the nervous system: dizziness, vertigo, paresthesia, headache, xanthopsia.

On the part of the blood system: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, eosinophilia.

Skin: purpura, photosensitivity, rash, urticaria, necrotizing angiitis vasculitis (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).

From the side of the cardiovascular system: orthostatic hypotension, which may be aggravated by alcohol, barbiturates or drugs.