SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Moxaid SR 250mg Prolonged-release capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 250 mg acetazolamide Excipient(s): For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release capsule, hard

Orange spherical pellets contained in a size ‘1 ’ capsule with clear body and opaque orange cap. ‘GS 250’ is printed on the orange cap in black text

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Glaucoma

4.2 Posology and method of administration

There is no relevant indication for use of Acetazolamide in children.

Use in Elderly Patients: Acetazolamide should 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.

Use in Patients with Renal Impairment: In patients with moderate to severe renal impairment, the dose should not exceed 250mg per day or the dosage interval should be increased to every 12 hours.

Adults: One or two 250mg capsules a day.

Capsules should be swallowed whole. Do not chew or crush.

4.3 Contraindications

Hypersensitivity to Acetazolamide, or to any of the excipients in the formulation or to sulphonamides or other sulphonamide derivatives.

Acetazolamide is contra-indicated in situations in which sodium and/or potassium blood levels are depressed, in cases of marked renal impairment and liver disease or dysfunction, suprarenal gland failure, and hyperchloremic acidosis. Acetazolamide should not be used in patients with liver disease or impairment of liver function including cirrhosis as this may increase the risk of hepatic encephalopathy. Acetazolamide is contra-indicated in patients with hypokalemia and hyponatraemia.

Long-term administration of acetazolamide 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 lowered intra-ocular pressure

4.4 Special warnings and precautions for use

Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or paraesthesia.

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo 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 Acetazolamide.

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.

When acetazolamide is prescribed for long-term therapy, special precautions are advisable. The patient should be cautioned to report any unusual skin rash. Prior to initiating therapy and at regular intervals during therapy monitoring of 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 acetazolamide therapy.

Hypersensitivity reactions may recur if a sulphonamide or sulphonamide derivative is re- administered, irrespective of the route of administration. If signs of hypersensitivity reactions or other serious reactions occur, acetazolamide must be discontinued.

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, emphysema, patients with diabetes mellitus and patients with impaired alveolar ventilation. Severe metabolic acidosis has been reported in patients with normal renal function during treatment with acetazolamide and salicylates.

Both, increase 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.

4.5 Interaction with other medicinal products and other forms of interaction

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 may occur. Concurrent administration of acetazolamide and acetylsalicylic acid may result in severe toxicity and increase central nervous system toxicity. Severe metabolic acidosis has been reported in patients with normal renal function during treatment with acetazolamide and salicylates. Adjustment of dose may be required when acetazolamide 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.

Concomitant use with other carbonic anhydrase inhibitors is not advisable because of possible additive effects.

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 antidiabetic 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.

Interference with Laboratory and other Diagnostic Tests:

Acetazolamide may produce an increased level of crystals in the urine.

Acetazolamide interferes with the HPLC method of assay for theophylline. Interference with the theophylline assay by acetazolamide depends on the solvent used in the extraction; acetazolamide may not interfere with other assay methods for theophylline.

4.6 Fertility, Pregnancy and lactation

Use in pregnancy: Acetazolamide should not be used in pregnancy, especially during the first trimester. (See section 5.3)

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

4.7    Effects on ability to drive and use machines

Acetazolamide has minor or moderate influence on the ability to drive and use machines.

Some adverse reactions to acetazolamide, such as drowsiness, fatigue and myopia, may impair the ability to drive and operate machinery.

4.8    Undesirable effects

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

Blood and Lymphatic system disorder:

Uncommon: Thrombocytopenia, Aplastic anaemia, Pancytopenia, Bone marrow depression, Leukopenia.

Not known: Agranulocytosis

Metabolism and Nutrition Disorders:

Common: Acidosis. The acidosis can usually be corrected by the administration of bicarbonate.

Uncommon: Metabolic acidosis, Hypokalaemia

Rare: Appetite disorders, Hyponatraemia, Hypoglycaemia, Hyperglycaemia and hypoglycaemia may occasionally occur during long term therapy.

Very rare: Electrolyte imbalance.

Not known: Thirst

Psychiatric Disorders:

Uncommon: Depression

Rare: Confusional state

Very rare: Irritability, libido decreased

Nervous system disorders:

Very common: Paraesthesia, Tingling of extremity Uncommon: Dizziness

Very rare: Headache, Ataxia, Sensory disturbances, Paralysis flaccid, Convulsion. Not known: Excitement, Occasional instances of drowsiness

Eye Disorders:

Not known: Myopia transient. This condition invariably subsides upon diminution or discontinuation of the medication.

Ear and Labyrinth Disorder:

Rare: Uncommon: Tinnitus, Hearing impaired

Gastrointestinal disorders:

Uncommon: Nausea, Vomiting, Melaena Rare: Diarrhoea

Hepatobiliary disorders:

Rare: Hepatitis orJaundice cholestatic, Fulminant hepatic necrosis,

Skin and subcutaneous tissue disorders :

Uncommon: Rash (including Erythema multiforme, Stevens-Johnson Syndrome, Toxic epidermal necrolysis), Urticaria

Rare: Photosensitivity reaction,

Very rare: Thrombocytic _purpura.

Musculoskeletal and connective tissue disorders:

Very rare: Osteomalacia with long-term phenytoin therapy

Renal and urinary disorders:

Very common: Nephrolithiasis.

Common: Haematuria

Uncommon: Crystalluria, Renal and ureteral colic, Renal lesions, Renal failure, nephrolithiasis , Calculus formation, Haematuria

Very rare:, Renal tubular necrosis

Not known: Polyuria, Ureteral pain, Glycosuria

General disorders and administration site conditions:

Very rare: Fatigue, Anaphylactic reaction, Flushing, Fever

Investigations:

Uncommon: Liver function test abnormal

Injury, poisoning and procedural complications:

Not known: Renal injury

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.

By reporting side effects you can help provide more information on the safety of this medicine.

4.9 Overdose

Electrolyte imbalance, development of an acidotic state and central nervous effect might be expected to occur.

Despite its high intra-erythrocytic distribution and plasma protein binding properties, acetazolamide is dialyzable. This may be particularly important in the management of acetazolamide overdosage when complicated by the presence of renal failure.

Treatment should be symptomatic and supportive. Serum electrolyte levels, (particularly potassium) and blood pH should be monitored.

Supportive measures are required to restore electrolyte and pH balance. The acidotic state can usually be corrected by the administration of bicarbonate.

No specific antidote is available.

Treatment should be symptomatic and supportive.

No case of overdose has been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Carbonic anhydrase inhibitors

ATC Code: S01EC01

Acetazolamide is a potent inhibitor of the enzyme carbonic anhydrase; the enzyme that catalyses the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In the eye, this inhibitory action of acetazolamide

decreases the secretion of the aqueous humor and results in a drop of intraocular pressure and is thus used to treat glaucoma.

5.2 Pharmacokinetic properties

Moxaid SR is a sustained release formulation designed to obtain a smooth and continuous clinical response. Acetazolamide is readily absorbed after oral administration

and binds tightly to plasma proteins as well as to the enzyme carbonic anhydrase. The drug begins to accumulate in tissues in which this enzyme is present, notably red blood cells and the renal cortex. It is also bound to plasma proteins.

Peak plasma levels of the drug are reached 1 - 3 hours after oral administration with whole blood levels reaching peak concentrations approximately one hour later.

Plasma levels decay more rapidly than red blood cell or whole blood levels with the elimination frequently being biphasic. The first phase having a half-life in 2 hours and the second phase in 13 hours. This terminal phase half-life corresponds to the leakage from red blood cells.

Acetazolamide is completely cleared by the renal route with the measured unbound renal clearance being some 5 - 6 times greater than creatinine clearance. Overall, clearance is dependent also on plasma protein binding.

5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels to clinical exposure levels and with possible relevance to clinical use were as follows:

Acetazolamide has been reported to be teratogenic (defects of the limbs) 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. (See section 4.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Film coated Pellets: Cellulose Microcrystalline, Sodium Lauryl sulphate,

Water purified,

Ethyl cellulose,

Hydroxypropylmethyl cellulose (E464),

Mineral oil light,

Opaspray K-1R-2506 orange [hydroxypropyl cellulose(E463), titanium dioxide (E171) and FD & C yellow No 6 (E110)]

Capsule shell:

Gelatin

Titanium dioxide (E171),

Yellow iron oxide (E172),

Erythrosine (E127).

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

36 months

6.4    Special precautions for    storage

Store below 30 °C

Store in the original package in order to protect from light and moisture.

6.5    Nature and contents    of    container

Blister Packs: 28 and 30 Capsules/ Pack

Opaque UPVC/PVDC blister Pack heat sealed with aluminium foil backing in an outer carton.

Not all pack sizes may be marketed.

Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd No. 1 Croydon,

12-16 Addiscombe Road,

Croydon CR0 0XT, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 12762/0218

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/10/2011

10    DATE OF REVISION OF THE TEXT

15/01/2015