Diacarb

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIACARB (DIACARB)

Composition:

active substance: acetazolamide;

1 tablet contains 250 mg of acetazolamide;

excipients: microcrystalline cellulose, povidone, colloidal anhydrous silicon dioxide, croscarmellose sodium, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, biconvex tablets.

Pharmacotherapeutic group. Anti-glaucoma agents and miotics. Carbonic anhydrase inhibitors. ATC code S01E C01.

Pharmacological Properties

Pharmacodynamics

A diuretic, antiglaucoma, and antiepileptic agent. The mechanism of action is due to selective inhibition of carbonic anhydrase—an enzyme that catalyzes the reversible reaction of hydration of carbon dioxide and subsequent dissociation of carbonic acid. The diuretic effect is caused by inhibition of carbonic anhydrase activity in the kidneys (primarily in the proximal renal tubules), leading to reduced reabsorption of bicarbonate, sodium and potassium ions, enhanced diuresis, increased urine pH, and increased ammonia reabsorption. It does not affect chloride ion excretion. As a result of inhibition of carbonic anhydrase in the ciliary body, secretion of aqueous humor is reduced and intraocular pressure is lowered. Inhibition of carbonic anhydrase in the brain leads to accumulation of CO₂ in the brain tissue and suppression of excessive paroxysmal neuronal discharges, which underlies the antiepileptic activity of the drug. The use of the drug in conditions with elevated intracranial pressure is associated with inhibition of carbonic anhydrase in the choroid plexuses of the brain ventricles and reduction of cerebrospinal fluid production.

Pharmacokinetics

Absorption

Acetazolamide is well absorbed from the gastrointestinal tract. Maximum plasma concentration (Cmax) is reached within 1–3 hours after administration. Low concentrations of acetazolamide persist in the blood for up to 24 hours.

Distribution

Acetazolamide is distributed into many tissues. Due to its high affinity for carbonic anhydrase, it accumulates predominantly in tissues containing this enzyme, particularly in erythrocytes, kidneys, muscles, ocular tissues, and the central nervous system. The drug does not accumulate in tissues.

Protein binding ranges from 70% to 90% of the total acetazolamide content in blood. The elimination half-life ranges from 4 to 9 hours.

Acetazolamide crosses the placental barrier.

It passes into breast milk in small amounts.

Metabolism

Acetazolamide is not metabolized.

Excretion

The drug is excreted by the kidneys unchanged. After oral administration, approximately 90% of the administered dose is excreted in the urine within 24 hours.

Clinical characteristics.

Indications.

Treatment of glaucoma:

• chronic open-angle glaucoma;
• secondary glaucoma;
• closed-angle glaucoma (for short-term preoperative therapy and prior to ophthalmic procedures, to reduce intraocular pressure).

Treatment of edema:

• in heart failure;
• drug-induced edema.

Treatment of epilepsy (in combination with other anticonvulsant agents):

• petit mal (absence seizures) in children;
• grand mal (tonic-clonic seizures) in adults;
• mixed forms.

Treatment of altitude sickness (the drug shortens the time of acclimatization, but its effect on the symptoms of this condition is insignificant).

Contraindications.

Hypersensitivity to the components of the drug and sulfonamides, hepatic and renal dysfunction, acute renal failure, hepatic failure, hyponatremia and/or hypokalemia, Addison's disease, adrenal insufficiency, hyperchloremic acidosis. Acetazolamide is contraindicated in patients with liver cirrhosis, as it may increase the risk of hepatic encephalopathy.

Long-term use of acetazolamide is contraindicated in patients with chronic decompensated closed-angle glaucoma, since in case of complete closure of the anterior chamber angle, the progression of glaucoma may be masked by reduced intraocular pressure.

Nephrolithiasis (in the presence of hypercalciuria), diabetes mellitus, uremia.

Interaction with other medicinal products and other types of interactions.

• Acetazolamide may enhance the effects of folic acid antagonists, oral hypoglycemic agents, and anticoagulants.
• Concomitant use of acetazolamide with acetylsalicylic acid may lead to severe acidosis and toxic effects on the central nervous system, with risk of developing anorexia, tachypnea, lethargy, coma, and potentially fatal outcome.
• When acetazolamide is used concomitantly with cardiac glycosides or antihypertensive agents, the dosage of the latter may need to be adjusted.
• Acetazolamide interferes with phenytoin metabolism, increasing its serum concentrations. Severe osteomalacia has been observed in patients receiving acetazolamide together with certain anticonvulsants (phenytoin, primidone).
• Concomitant use of acetazolamide with amphetamines, atropine, or quinidine may enhance their adverse effects. Excretion of amphetamine and quinidine is reduced, potentially prolonging the action of amphetamine and enhancing the effect of quinidine due to increased urinary pH in renal tubules.
• Acetazolamide may increase or decrease blood glucose concentrations; this should be considered during treatment of diabetes mellitus. Dosage adjustment of insulin or oral hypoglycemic agents may be required.
• Acetazolamide enhances lithium excretion and may reduce plasma lithium levels.
• Acetazolamide may increase plasma carbamazepine concentrations.
• Concomitant use of acetazolamide increases the risk of toxic effects of salicylates, digitalis preparations, carbamazepine, ephedrine, and non-depolarizing muscle relaxants.
• The diuretic effect of acetazolamide is enhanced by theophylline and reduced by acidifying diuretics.
• Isolated reports exist of decreased serum primidone levels and increased carbamazepine levels when used concomitantly with acetazolamide.
• Due to possible additive effects, concomitant use with other carbonic anhydrase inhibitors is not recommended.
• Cyclosporine: acetazolamide may increase cyclosporine levels.
• Methenamine: acetazolamide may interfere with the urinary antiseptic effect of methenamine.
• Sodium bicarbonate: concomitant use of acetazolamide with sodium bicarbonate increases the risk of renal stone formation.

Special precautions for use.

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude the possibility of an increased risk with acetazolamide.

Therefore, monitoring for signs of suicidal thoughts and behavior is recommended, and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek immediate medical attention if symptoms of suicidal thoughts or behavior occur.

Acetazolamide, when administered in doses higher than recommended, does not lead to increased diuresis, but may cause somnolence and paresthesia, and in some cases may even reduce diuresis. However, under certain conditions, very high doses in combination with other diuretics may be necessary to achieve diuresis in patients with refractory congestive heart failure.

Both decreases and increases in plasma glucose levels have been observed during acetazolamide therapy. This should be taken into account when prescribing the drug to patients with impaired glucose tolerance or diabetes mellitus.

Special precautions are required during prolonged therapy. Patients should be warned to report any skin changes. Periodic monitoring of blood counts and serum electrolyte levels (especially potassium and blood pH) as well as peripheral blood picture is recommended. Fatal outcomes due to severe reactions to sulfonamides have been reported, although such cases are rare. The drug must be discontinued immediately in case of a sudden drop in blood cell counts or the appearance of toxic skin reactions.

Use with caution in pulmonary embolism and pulmonary emphysema, as well as in lower airway obstruction, conditions in which alveolar ventilation may be reduced, in renal insufficiency, and in elderly patients due to an increased risk of metabolic acidosis.

Non-cardiogenic pulmonary edema

Severe cases of non-cardiogenic pulmonary edema have been reported following acetazolamide administration, including after a single dose (see section "Adverse reactions"). Non-cardiogenic pulmonary edema typically develops within minutes or hours after taking acetazolamide. Symptoms include dyspnea, hypoxia, and respiratory failure. If non-cardiogenic pulmonary edema is suspected, acetazolamide should be discontinued and supportive treatment initiated. Acetazolamide should not be administered to patients who have previously experienced non-cardiogenic pulmonary edema after taking acetazolamide.

In patients with a history of kidney stones, the risk-benefit ratio for further stone formation should be evaluated.

The drug alkalinizes urine.

Development of generalized erythema during treatment, accompanied by pustules and fever, may be a sign of acute generalized exanthematous pustulosis. If this condition is diagnosed, treatment with acetazolamide should be discontinued, and further use of the drug is contraindicated.

In cases of hypersensitivity, life-threatening symptoms may occur, such as Stevens-Johnson syndrome, Lyell's syndrome, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and hemorrhagic diathesis.

If skin or hematological manifestations develop, the drug should be discontinued immediately.

Acetazolamide should be prescribed with caution to patients taking high-dose acetylsalicylic acid, as there is a risk of developing anorexia, hyperventilation, lethargy, coma, and even fatal outcomes.

If a dose is missed, the next dose should not be doubled.

If a patient takes acetazolamide for more than 5 days, there is a risk of developing metabolic acidosis.

Cases of choroidal effusion/detachment have been reported following acetazolamide use. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Acetazolamide should be discontinued as soon as possible if choroidal effusion/detachment is suspected.

Laboratory tests

Monitoring of blood counts and platelet levels at the beginning of treatment and periodically during therapy is recommended. Monitoring of plasma electrolyte levels is also recommended.

Use during pregnancy or breastfeeding.

Pregnancy

Acetazolamide crosses the placental barrier. Use of the drug during pregnancy is contraindicated.

Breastfeeding

Acetazolamide passes into breast milk in small amounts. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

High doses of acetazolamide may cause somnolence; less frequently, fatigue, dizziness, ataxia, and disorientation. Therefore, patients should avoid driving or operating potentially hazardous machinery during acetazolamide therapy.

Method of administration and dosage.

The drug is taken orally.

Glaucoma treatment

The dosage of the drug should be individually determined based on intraocular pressure.

Recommended doses for adults:

Epilepsy treatment

Treatment of edema in heart failure and drug-induced edema

Initial dose: 250 mg (1 tablet) once daily in the morning.

The best diuretic effect is observed when the drug is administered every other day or every two days with a one-day break.

When treating heart failure, acetazolamide should be administered against the background of standard therapy (e.g., administration of digitalis glycosides, low-salt diet, and potassium supplementation).

Treatment of altitude sickness

The recommended daily dose is 500–1000 mg (2–4 tablets), divided into several doses. In case of anticipated rapid ascent (more than 500 m per day), the recommended dose is 1000 mg (4 tablets), divided into several doses.

The drug should be taken 24–48 hours before ascending. If symptoms of the illness appear, treatment should be continued for another 48 hours or longer, if necessary.

Children

The drug should be used for the treatment of children aged 3 years and older only as an adjunctive therapy in epilepsy.

Overdose

Symptoms of overdose and acute poisoning have not been described in humans. In case of overdose, disturbances in electrolyte balance, acidosis, and central nervous system disorders (drowsiness, paresthesias) may occur; occasionally, decreased diuresis may be observed. Therefore, plasma electrolyte concentrations, especially potassium, and urine pH should be monitored.

Treatment

Discontinue the drug, symptomatic therapy. In case of acidosis, administer bicarbonates. Hemodialysis is effective. There is no specific antidote.

Side effects

The following adverse reactions have been observed during treatment with acetazolamide, listed below according to frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (≥ 1/100,000, < 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Rare: aplastic anemia, thrombocytopenia, agranulocytosis, leukopenia, thrombocytopenic purpura, bone marrow depression, pancytopenia.

In isolated cases during long-term use – hemolytic anemia.

Metabolism and nutrition disorders

Common: anorexia, metabolic acidosis, disturbances in water-electrolyte balance (in combination with hyponatremia and hypokalemia).

Frequency not known: hypocalcemia, weight loss (with long-term use).

Psychiatric disorders

Uncommon: depression.

Nervous system and sensory organs disorders

Common: dizziness, taste disturbances, paresthesia (tingling sensations in extremities).

Uncommon: flushing, thirst, headache, irritability, decreased libido.

There have been reports of isolated cases: somnolence, confusion, flaccid paralysis, convulsions.

Frequency not known: ataxia; with long-term use – disorientation, disturbances in touch and sensitivity, general weakness, peripheral paralysis; in isolated cases – sensation of hair on the tongue.

Eye disorders

Rare: reversible myopia.

Frequency not known: choroidal effusion, choroidal detachment.

Ear and labyrinth disorders

Rare: tinnitus, hearing disturbances.

Respiratory, thoracic and mediastinal disorders

Frequency not known: non-cardiogenic pulmonary edema.

Gastrointestinal disorders

Uncommon: nausea, vomiting, diarrhea, melena.

Hepatobiliary disorders

Uncommon: liver function abnormalities.

Rare: fulminant hepatic necrosis, hepatitis, mechanical jaundice.

Frequency not known: liver failure, hepatic colic.

Skin and subcutaneous tissue disorders

Rare: erythema multiforme, Stevens-Johnson syndrome, photosensitization, skin rash, Lyell's syndrome (toxic epidermal necrolysis), urticaria.

Frequency not known: acute generalized exanthematous pustulosis, pruritus, erythema.

Renal and urinary disorders

Uncommon: nephrolithiasis, crystalluria, renal colic, kidney damage, polyuria, hematuria, renal failure.

Rare: glucosuria.

Frequency not known: frequent urination.

General disorders

Common: fatigue.

Uncommon: fever.

Immune system disorders

Rare: hypersensitivity reactions, including anaphylactic reactions.

Investigations

Very rare: hypoglycemia, hyperglycemia.

Acetazolamide, being a sulfonamide derivative, may cause adverse reactions typical of sulfonamides.

Shelf life: 5 years.

Storage conditions:

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of the reach of children.

Packaging:

10 tablets in a blister pack; 3 blisters per cardboard box.

Prescription status: Prescription only.

Manufacturer:

Pharmaceutical Works «Polpharma» S.A., Poland.

Manufacturer's address and place of business:

Pelplinska Street 19, 83-200 Starogard Gdanski, Poland / 19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.