Moduretic^® is indicated in those patients with hypertension or with congestive heart failure who develop hypokalemia when thiazides or other kaliuretic diuretics are used alone, or in whom maintenance of normal serum potassium levels is considered to be clinically important, e.g., digitalized patients, or patients with significant cardiac arrhythmias.

 

This  fixed  combination  drug  is  not   indicated  for  the  initial  therapy  of  edema  or hypertension except in individuals in whom the development of hypokalemia cannot be risked.

 

Swallow the tablets with liquid.

 

The usual starting dosage is 1 tablet a day. The dosage may be increased to 2 tablets a day, if necessary. More than 2 tablets of MODURETIC^® daily usually are not needed and there is no controlled experience with such doses. Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. Patients usually do not require doses of hydrochlorothiazide in excess of 50 mg daily when combined with other antihypertensive agents. The daily dose is usually given as a single dose but may be given in divided doses. Once an initial diuresis has been achieved, dosage adjustment may be necessary. Maintenance therapy may be on an intermittent basis.

 

Hypertension

Initially half a MODURETIC^® tablet given once a day. If necessary increase to one MODURETIC^® tablet given once a day or in divided doses.

 

Congestive Heart Failure

Initially half a MODURETIC^® tablet a day, subsequently adjusted if required, but not exceeding two MODURETIC^® tablets a day. Optimal dosage is determined by the diuretic response and the plasma potassium level. Once an initial diuresis has been achieved, reduction in dosagemay be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.

 

Paediatric population

MODURETIC^® is contraindicated in children under 18 years because safety and efficacy have not been established (see section 4.3).

 

Elderly patients

Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance; the dosage should be carefully adjusted to renal function and clinical response.

 

Hyperkalemia MODURETIC® should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter). Antikaliuretic Therapy or Potassium Supplementation MODURETIC® should not be given to patients receiving other potassium-conserving agents, such as spironolactone or triamterene. Potassium supplementation in the form of medication, potassium-containing salt substitutes or a potassium-rich diet should not be used with MODURETIC® except in severe and/or refractory cases of hypokalemia. Such concomitant therapy can be associated with rapid increases in serum potassium levels. If potassium supplementation is used, careful monitoring of the serum potassium level is necessary. Addison’s disease Impaired Renal Function Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of MODURETIC®. Patients with evidence of renal functional impairment (blood urea nitrogen [BUN] levels over 30 mg per 100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus should not receive the drug without careful, frequent and continuing monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of an antikaliuretic agent is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia. Hypersensitivity MODURETIC® is contraindicated in patients who are hypersensitive to this product, or to other sulfonamide-derived drugs, such as suphamethoxazole.

General

 

Electrolyte Imbalance and BUN Increases

Determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

 

Patients should be observed for clinical signs of fluid or electrolyte imbalance: i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

 

Hyponatremia and hypochloremia may occur during the use of thiazides and other diuretics. Any chloride deficit during thiazide therapy is generally mild and may be lessened by the amiloride HCl component of MODURETIC^®. Hypochloremia usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

 

Hypokalemia may develop during thiazide therapy, especially with brisk diuresis, when severe cirrhosis  is  present,  during  concomitant  use  of  corticosteroids  or  ACTH,  or  after  prolonged therapy. However, this usually is prevented by the amiloride HCl component of MODURETIC^®.

 

Interference   with   adequate   oral   electrolyte   intake   will   also   contribute   to   hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

 

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Amiloride HCl, a component of MODURETIC^®, has been shown to decrease the enhanced urinary excretion of magnesium which occurs when a thiazide or loop diuretic is used alone.

 

Increases in BUN levels have been reported with amiloride HCl and with hydrochlorothiazide. These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, when MODURETIC^® is given to such patients, careful monitoring of serum electrolyte and BUN levels is important. In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and  coma,  and  increased  jaundice,  have  been  reported  in  association  with  diuretic  therapy including amiloride HCl and hydrochlorothiazide.

In patients with renal disease, diuretics may precipitate azotemia. Cumulative effects of the components of MODURETIC^® may develop in patients with impaired renal function. If renal impairment becomes evident, MODURETIC^® should be discontinued (see CONTRAINDICATIONS and WARNINGS).

 

 In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic,  natriuretic,  and  antihypertensive   effects  of  loop,   potassium-sparing  and  thiazide diuretics.

 

Therefore, when MODURETIC^® and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Since indomethacin and potassium-sparing diuretics, including MODURETIC^®, may each be associated with increased serum potassium levels, the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently.

 

When amiloride HCl is administered concomitantly with an angiotensin-converting enzyme inhibitor,  an  angiotensin  II  receptor  antagonist,  cyclosporine  or  tacrolimus,  the  risk  of hyperkalemia may be increased.  Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. (See WARNINGS.)

 

Hydrochlorothiazide

 

When given concurrently the following drugs may interact with thiazide diuretics. Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs — additive effect or potentiation. Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

 

Corticosteroids, ACTH — intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness to the muscle relaxant.

 

Lithium - generally should not be given with diuretics.  Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with MODURETIC^®.

 

 

Metabolic and Endocrine Effects

 

In diabetic patients, insulin requirements may be increased, decreased, or unchanged due to the hydrochlorothiazide component.  Diabetes mellitus that  has  been latent  may become  manifest during administration of thiazide diuretics.

 

Because calcium excretion is decreased by thiazides, MODURETIC^® should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen.

 

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.

 

Other Precautions

 

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or   bronchial   asthma.   The   possibility   of   exacerbation   or   activation   of   systemic   lupus erythematosus has  been  reported  with  the  use  of  thiazides.    Increases in  cholesterol  and triglyceride levels may be associated with thiazide diuretic therapy.

 

Pregnancy Category B

 

Nursing Mothers

 

Studies in rats have shown that amiloride is excreted in milk in concentrations higher than those found in blood, but it is not known whether amiloride HCl is excreted in human milk. However, thiazides appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

 Infrequently, patients may experience weakness, fatigue, dizziness, stupor and vertigo. Should any of these occur, the patient should be cautioned not to drive or operate machinery.

Although minor side effects are relatively common, significant side effects are infrequent. Reported side effects are generally associated with diuresis, thiazide therapy, or with the underlying disease.

No increase in the risk of adverse reactions has been seen over those of the individual components.

The following side effects have been reported with MODURETIC®:

Body as a whole: anaphylactic reaction, headache*, weakness*, fatigue, malaise, chest pain, back pain, syncope.

Cardiovascular: arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris.

Digestive: anorexia*, nausea*, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, appetite changes, abdominal fullness, flatulence, thirst, hiccups.

Metabolic: elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia (see 4.4 'Special warnings and precautions for use'), gout, dehydration, symptomatic hyponatraemia.

Integumentary: rash*, pruritus, flushing, diaphoresis.

Musculoskeletal: leg ache, muscle cramps, joint pain.

Nervous: dizzines*, vertigo, paraesthesiae, stupor.

Psychiatric: insomnia, nervousness, mental confusion, depression, sleepiness.

Respiratory: dyspnoea.

Special senses: bad taste, visual disturbance, nasal congestion.

Urogenital: impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure.

 

Additional side effects that have been reported with the individual components and may be potential side effects of MODURETIC® are listed below:

 

Amiloride:

Body as a whole: neck/shoulder ache, pain in extremities.

Digestive: abnormal liver function, activation of probable pre-existing peptic ulcer, dyspepsia, jaundice.

Integumentary: dry mouth, alopecia.

Nervous: tremors, encephalopathy.

Haematological: aplastic anaemia, neutropenia.

Cardiovascular: one patient with partial heart block developed complete heart block, palpitation. Psychiatric: decreased libido, somnolence.

Respiratory: cough.

Special senses: tinnitus, increased intra-ocular pressure.

Urogenital: polyuria, urinary frequency, bladder spasm.

 

Hydrochlorothiazide:

Body as a whole: fever.

Cardiovascular: necrotising angiitis (vasculitis, cutaneous vasculitis.)

Digestive: jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramping, gastric irritation.

Endocrine/Metabolic: glycoscuria, hyperglycaemia, hyperuricaemia, hypokalaemia.

Integumentary: photosensitivity, sialadenitis, urticaria, toxic epidermal necrolysis.

Haematological: agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia.

Psychiatric: restlessness.

Renal: interstitial nephritis.

Respiratory: respiratory distress, including pneumonitis, pulmonary oedema.

Special senses: transient blurred vision, xanthopsia. 

* Side effects that have been reported most frequently during controlled clinical trials with MODURETIC®

 

To report any side effect(s):

Saudi Arabia: National Pharmacovigilance and Drug Safety Center (NPC)

•                  Call NPC at +966-11-2038222, Exts: 2317-2356-2340

•                  Fax: +966-11-205-7662

•                  Toll-free: 8002490000

•                  Email: npc.drug@sfda.gov.sa

•                  Website: www. sfda.gov.sa/npc

No specific data are available on over dosage with MODURETIC®. No specific antidote is available, and it is not known whether the drug is dialyzable.

Treatment should be symptomatic and supportive. Therapy should be discontinued and the patient watched closely. Emesis should be induced and/or gastric lavage performed. The most common signs and symptoms of over dosage with amiloride hydrochloride are dehydration and electrolyte imbalance. Blood pressure should be monitored and corrected where necessary. If hyperkalaemia occurs, active measures should be taken to reduce the plasma potassium levels.

Electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide over dosage. If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias.

Pharmacotherapeutic group: Diuretic and potassium-sparing agent, ATC code: C03EA01

 

MODURETIC^® provides diuretic and antihypertensive activity (principally due to the hydrochlorothiazide component), while acting through the amiloride component to prevent the excessive potassium loss that may occur in patients receiving a thiazide diuretic. Due to its amiloride component, the urinary excretion of magnesium is less with MODURETIC^® than with a thiazide or loop diuretic used alone .The onset of the diuretic action of MODURETIC^® is within 1 to 2 hours and this action appears to be sustained for approximately 24 hours.

 

Amiloride HCl

 

Amiloride HCl is a potassium-conserving (antikaliuretic) drug that possesses weak (compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive activity. These effects have been partially additive to the effects of thiazide diuretics in some clinical studies. Amiloride HCl has potassium-conserving activity in patients receiving kaliuretic-diuretic agents.    Amiloride HCl exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. This mechanism accounts in large part for the potassium sparing action of amiloride.

 

Hydrochlorothiazide

 

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal  renal  tubular  mechanism  of  electrolyte  reabsorption.     Hydrochlorothiazide  increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

 

 Amiloride HCL

Amiloride HCl usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life varies from 6 to 9 hours. Effects on electrolytes increase with single doses of amiloride HCl up to approximately 15 mg.

Amiloride HCl is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of amiloride HCl is excreted in the urine and 40 percent in the stool within 72 hours.

 

Hydrochlorothiazide

After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.  Hydrochlorothiazide  crosses  the  placental  but  not  the  blood-brain  barrier  and  is excreted in breast milk.

 No particulars

Calcium hydrogen phosphate, guar gum, lactose, magnesium stearate, corn starch and aluminium lake FD&C yellow #6.

 

 Not Applicable

36 months

Do not store above 30°C

Store in the original Package

Aluminium/opaque PVC blisters.

Pack of 30 tablets.

 

No particulars