Acetazolamide is an enzyme inhibitor which acts specifically on carbonic anhydrase. It is indicated in the treatment of:

i) Glaucoma: Diamox/Acetazolamide injection is useful in glaucoma (chronic simple (open angle) glaucoma, secondary glaucoma and perioperatively in acute angle closure glaucoma where delay of surgery is desired in order to lower intraocular pressure) because it acts on inflow, decreasing the amount of aqueous secretion.

ii) Abnormal retention of fluids: Diamox/Acetazolamide injection is a diuretic whose effect is due to the effect on the reversible hydration of carbon dioxide and dehydration of carbonic acid reaction in the kidney. The result is a renal loss of HCO₃- ion which carries out sodium, water and potassium.

Diamox/Acetazolamide injection can be used in conjunction with other diuretics when effects on several segments of the nephron are desirable in the treatment of fluid retaining states.

iii) Epilepsy: In conjunction with other anticonvulsants best results with Diamox/Acetazolamide injection have been seen in petit mal in children. Good results, however, have been seen in patients, both children and adults, with other types of seizures such as grand mal, mixed seizure patterns, myoclonic jerk patterns, etc.

Posology

i) Glaucoma (simple acute congestive and secondary):

Adults: 250 - 1000mg per 24 hours, usually in divided doses for amounts over 250mg daily.

ii) Abnormal retention of fluid: Congestive heart-failure, drug-induced oedema.

Adults: For diuresis, the starting dose is usually 250 - 375mg once daily in the morning. If, after an initial response, the patient fails to continue to lose oedema fluid do not increase the dose but allow for kidney recovery by omitting a day. Best results are often obtained on a regime of 250 - 375mg daily for two days, rest a day and repeat or merely giving Diamox/Acetazolamide injection every other day. The use of Diamox/Acetazolamide injection does not eliminate the need for other therapy, e.g. digitalis, bed rest and salt restriction in congestive heart failure and proper supplementation with elements such as potassium in drug-induced oedema.

For cases of fluid retention associated with pre-menstrual tension, a daily dose (single) of 125 - 375mg is suggested.

iii) Epilepsy

Adults: 250 - 1000mg daily in divided doses.

Children: 8 - 30mg/kg in daily divided doses and not to exceed 750mg/day.

The change from other medication to Diamox/Acetazolamide injection should be gradual.

Elderly: Diamox/Acetazolamide injection should only be used with particular caution in elderly patients or those with potential obstruction in the urinary tract or with disorders rendering their electrolyte balance precarious or with liver dysfunction.

For reconstitution please refer to section to section 6.6 below.

Method of Administration:

Intravenous or intramuscular injection. The direct intravenous route is preferred as intramuscular use is limited by the alkaline pH of the solution.

Hypersensitivity to acetazolamide or to any of the excipients listed in section 6.1.

Diamox/Acetazolamide injection should not be used in patients hypersensitive to sulphonamides.

Diamox/Acetazolamide injection is contraindicated in situations in which sodium and/or potassium blood levels are depressed, in cases of marked kidney and liver dysfunction, suprarenal gland failure and hyper-chloremic acidosis.

Diamox/Acetazolamide injection should not be used in patients with hepatic cirrhosis as this may increase the risk of hepatic encephalopathy.

Long-term administration of Diamox/Acetazolamide injection is contra-indicated in patients with chronic non-congestive angle-closure glaucoma since it may permit organic closure of the angle to occur while the worsening glaucoma is masked by lower intraocular pressure.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placeb controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Diamox/Acetazolamide injection.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or paraesthesia. Increasing the dose often results in a decrease in diuresis. Under certain circumstances, however, very large doses have been given in conjunction with other diuretics in order to secure diuresis in complete refractory failure.

When Diamox/Acetazolamide injection is prescribed for long-term therapy, special precautions are advisable. The patient should be cautioned to report any unusual skin rash.

Periodic blood cell counts, and electrolyte levels are recommended. Fatalities have occurred, although rarely, due to severe reactions to sulphonamides including acetazolamide, such as Steven-Johnson syndrome and toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia and other blood dyscrasias and anaphylaxis. A precipitous drop in formed blood cell elements or the appearance of toxic skin manifestations should call for immediate cessation of Diamox/Acetazolamide injection therapy.

Acetazolamide treatment may cause electrolyte imbalances, including hyponatraemia and transient hypokalaemia, as well as metabolic acidosis. Therefore, periodic monitoring of serum electrolytes is recommended. Particular caution is recommended in patients with conditions that are associated with, or predispose to, electrolyte and acid/base imbalances, such as patients with impaired renal function (including elderly patients), pulmonary obstruction or emphysema patients with diabetes mellitus and patients with impaired alveolar ventilation may be impaired. Severe metabolic acidosis has been reported in patients with normal renal function during treatment with acetazolamide and salicylates.

Both increases and decreases in blood glucose levels have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus.

In patients with a past history of renal calculi, benefit should be balanced against the risks of precipitating further calculi.

The pH of parenteral acetazolamide is 9.1. Care should be taken during intravenous administration of alkaline preparations to avoid extravasation and possible development of skin necrosis

The occurrence at the treatment initiation of a feverish generalized erythema associated with pustula may be a symptom of acute generalised exanthematous pustulosis (AGEP) (See section 4.8). In case of AGEP diagnosis, acetazolamide should be discontinued and any subsequent administration of acetazolamide contraindicated.

Non-cardiogenic pulmonary oedema

Severe cases of non-cardiogenic pulmonary oedema have been reported after taking acetazolamide, also after a single dose (see section 4.8). Non-cardiogenic pulmonary oedema typically developed within minutes to hours after acetazolamide intake. Symptoms included dyspnoea, hypoxia, and respiratory insufficiency. If non-cardiogenic pulmonary oedema is suspected, acetazolamide should be withdrawn, and supportive treatment should be given. Acetazolamide should not be administered to patients who previously experienced non-cardiogenic pulmonary oedema following acetazolamide intake.

Cases of choroidal effusion/detachment have been reported after the use of acetazolamide. Symptoms include acute onset of decreased visual acuity or ocular pain and can occur within hours after initiation of acetazolamide treatment. If choroidal effusion/detachment is suspected, acetazolamide should be discontinued as rapidly as possible.

Acetazolamide is a sulphonamide derivative. Sulphonamides may potentiate the effects of folic acid antagonists. Possible potentiation of the effects of folic acid antagonists, hypoglycaemics and oral anti-coagulants. Concurrent administration of acetazolamide and aspirin may result in severe acidosis and increase central nervous system toxicity. Adjustments of dose may be required when Diamox/Acetazolamide injection is given with cardiac glycosides or hypertensive agents.

When given concomitantly acetazolamide modifies the metabolism of phenytoin leading to increased serum levels of phenytoin. Severe osteomalacia has been noted in a few patients taking acetazolamide in combination with other anticonvulsants. There have been isolated reports of reduced primidone and increased carbamazepine serum levels with concurrent administration of acetazolamide.

Because of possible additive effects with other carbonic anhydrase inhibitors, concomitant use is not advisable.

Both increases and decreases in blood glucose levels have been described in patients with acetazolamide. This should be taken into consideration in patients treated with anti-diabetic agents.

By increasing the pH of renal tubular urine, acetazolamide reduces the urinary excretion of amphetamine and quinidine and so may enhance the magnitude and duration of the effect of amphetamines and enhance the effect of quinidine.

By increasing the pH of urine, acetazolamide may prevent the urinary excretion of methenamine compounds.

Acetazolamide increases lithium excretion due to impaired re-absorption of lithium in the proximal tubule. The effect of lithium carbonate may be decreased.

The use of concurrent sodium bicarbonate therapy enhances the risk of renal calculus formation in patients taking acetazolamide.

When given concomitantly, acetazolamide may elevate cyclosporine blood levels. Caution is advised when administrating acetazolamide in patients receiving cyclosporine.

Pregnancy

Acetazolamide has been reported to be teratogenic and embryotoxic in rats, mice, hamsters and rabbits at oral or parenteral doses in excess of ten times those recommended in human beings. Although there is no evidence of these effects in human beings, there are no adequate and well-controlled studies in pregnant women. Therefore, Diamox/Acetazolamide injection should not be used in pregnancy, especially during the first trimester.

Breast-feeding

Acetazolamide has been detected in low levels in the milk of lactating women who have taken Diamox/Acetazolamide injection. Although it is unlikely that this will lead to any harmful effects in the infant, extreme caution should be exercised when Diamox/Acetazolamide injection is administered to lactating women.

Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or paraesthesia. Less commonly, fatigue, dizziness and ataxia have been reported. Disorientation has been observed in a few patients with oedema due to hepatic cirrhosis. Such cases should be under close supervision. Transient myopia has been reported.

These conditions invariably subside upon diminution or discontinuance of the medication.

The following adverse reactions are classified by system organ class and ranked under heading of frequency using the following convention:

Not known (cannot be estimated from the available data).

¹ Acetazolamide is a sulphonamide derivative and therefore some side effects similar to those caused by sulphonamides have occasionally been reported.

² During long-term therapy, metabolic acidosis and electrolyte imbalance may occasionally occur. This can usually be corrected by the administration of bicarbonate.

³ Adverse reactions during short-term therapy are usually non-serious.

⁴ The condition invariably subsides upon diminution or discontinuation of the medication.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Management

No specific antidote. Supportive measures with correction of electrolyte and fluid balance. Force fluids.

Pharmacotherapeutic group: Carbonic anhydrase inhibitors.

ATC Code: S01EC01

Mechanism of action

Acetazolamide is an inhibitor of carbonic anhydrase. By inhibiting the reaction catalysed by this enzyme in the renal tubules, acetazolamide increases the excretion of bicarbonate and of cations, chiefly sodium and potassium, and so promotes alkaline diuresis.

Pharmacodynamic effects

Continuous administration of acetazolamide is associated with metabolic acidosis and resultant loss of diuretic activity. Therefore, the effectiveness of Diamox/Acetazolamide in diuresis diminishes with continuous use.

By inhibiting carbonic anhydrase in the eye acetazolamide decreases intra-ocular pressure and is therefore useful in the treatment of glaucoma.

Distribution

It is tightly bound to carbonic anhydrase and accumulates in tissues containing this enzyme, particularly red blood cells and the renal cortex. It is also bound to plasma proteins.

Elimination

Acetazolamide has been estimated to have a plasma half-life of about 4 hours. It is excreted unchanged in the urine, renal clearance being enhanced in the alkaline urine.

Nothing of note to the prescriber.

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

None.

24 months.

Do not store above 25° C.

Glass vial with butyl rubber plug and aluminium ring seal.

Pack size 500mg vial.

Reconstitute each vial of Diamox/Acetazolamide Injection with at least 5ml of water for injection prior to use. The reconstituted solution is clear and colourless and does not contain an antimicrobial preservative. Any unused solution can be stored in a refrigerator for up to 24 hours but any solution not used within this period must be discarded.

The direct intravenous route of administration is preferred. Intramuscular injection may be employed but is painful due to the alkaline pH of the solution.