Moducren

Amiloride Hydrochloride:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Moducren (Amiloride Hydrochloride) reviews

INDICATIONS AND USAGE

Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets are 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.

The use of potassium-conserving agents is often unnecessary in patients receiving diuretics for uncomplicated essential hypertension when such patients have a normal diet.

Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets may be used alone or as an adjunct to other antihypertensive drugs, such as methyldopa or beta blockers. Since Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide enhances the action of these agents, dosage adjustments may be necessary to avoid an excessive fall in blood pressure and other unwanted side effects.

The 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.

CONTRAINDICATIONS

Hyperkalemia

Moducren hydrochloride and hydrochlorothiazide tablets should not be used in the presence of elevated serum potassium levels (greater than 5.5 mEq per liter).

Antikaliuretic Therapy or Potassium Supplementation

Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide 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 this product 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.

Impaired Renal Function

Anuria, acute or chronic renal insufficiency, and evidence of diabetic nephropathy are contraindications to the use of Moducren hydrochloride and hydrochlorothiazide. Patients with evidence of renal function 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

Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets is contraindicated in patients who are hypersensitive to this product, or to other sulfonamide-derived drugs.

WARNINGS

Hyperkalemia

Like other potassium-conserving diuretic combinations, Moducren and hydrochlorothiazide may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter). In patients without renal impairment or diabetes mellitus, the risk of hyperkalemia with this combination product is about 1 to 2 percent. This risk is higher in patients with renal impairment or diabetes mellitus (even without recognized diabetic nephropathy). Since hyperkalemia, if uncorrected, is potentially fatal, it is essential to monitor serum potassium levels carefully in any patient receiving Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide, particularly when it is first introduced, at the time of dosage adjustments, and during any illness that could affect renal function.

The risk of hyperkalemia may be increased when potassium-conserving agents, including Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide, are administered concomitantly with an angiotensin-converting enzyme inhibitor, cylosporine or tacrolimus. Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities. Monitoring of the serum potassium level is essential because mild hyperkalemia is not usually associated with an abnormal ECG.

When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression.

Treatment of Hyperkalemia

If hyperkalemia occurs in patients taking Moducren (Amiloride Hydrochloride) and hydrochlorothiazide, the drug should be discontinued immediately. If the serum potassium level exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such measures include the intravenous administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. Patients with persistent hyperkalemia may require dialysis.

Diabetes Mellitus

In diabetic patients, hyperkalemia has been reported with the use of all potassium-conserving diuretics, including Moducren HCl, even in patients without evidence of diabetic nephropathy. Therefore, Moducren (Amiloride Hydrochloride) and hydrochlorothiazide should be avoided, if possible, in diabetic patients and, if it is used, serum electrolytes and renal function must be monitored frequently.

Moducren (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued at least three days before glucose tolerance testing.

Metabolic or Respiratory Acidosis

Antikaliuretic therapy should be instituted only with caution in severely ill patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or poorly controlled diabetes. If Moducren (Amiloride Hydrochloride) and hydrochlorothiazide is given to these patients, frequent monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.

PRECAUTIONS

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 electrolytes 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 Moducren HCl component of this product. 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 Moducren (Amiloride Hydrochloride) hydrochloride component of this combination drug product.

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. Moducren (Amiloride Hydrochloride) hydrochloride, a component of this combination product, 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 Moducren (Amiloride Hydrochloride) hydrochloride 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 Moducren (Amiloride Hydrochloride) and hydrochlorothiazide 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 Moducren (Amiloride Hydrochloride) HCl and hydrochlorothiazide.

In patients with renal disease, diuretics may precipitate azotemia. Cumulative effects of the components of Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide may develop in patients with impaired renal function. If renal impairment becomes evident, Moducren (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued.

Drug Interactions

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 Moducren (Amiloride Hydrochloride) and hydrochlorothiazide plus 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 this product, 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.

Moducren HCl

When Moducren (Amiloride Hydrochloride) HCl is administered concomitantly with an angiotensin-converting enzyme inhibitor, 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.

Hydrochlorothiazide

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, Barbiturates, or Narcotics

Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs

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 cholestyramine and 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

Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, Nondepolarizing

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 this combination product.

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, Moducren and hydrochlorothiazide 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.

Carcinogenesis, Mutagenicity, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the effects upon fertility, mutagenicity or carcinogenic potential of Moducren hydrochloride and hydrochlorothiazide.

Moducren (Amiloride Hydrochloride) HCl

There was no evidence of a tumorigenic effect when Moducren (Amiloride Hydrochloride) hydrochloride was administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the maximum daily human dose). Moducren (Amiloride Hydrochloride) hydrochloride has also been administered for 104 weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times the maximum daily dose for humans, respectively) and showed no evidence of carcinogenicity.

Moducren (Amiloride Hydrochloride) hydrochloride was devoid of mutagenic activity in various strains of Salmonella typhimurium with or without a mammalian liver microsomal activation system (Ames test).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese Hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Teratogenicity studies have been performed with combinations of Moducren hydrochloride and hydrochlorothiazide in rabbits and mice at doses up to 25 times the expected maximum daily dose for humans and have revealed no evidence of harm to the fetus. No evidence of impaired fertility in rats was apparent at dosage levels up to 25 times the expected maximum human daily dose. A perinatal and postnatal study in rats showed a reduction in maternal body weight gain during and after gestation at a daily dose of 25 times the expected maximum daily dose for humans. The body weights of alive pups at birth and at weaning were also reduced at this dose level. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, and because of the data listed below with the individual components, this drug should be used during pregnancy only if clearly needed.

Moducren (Amiloride Hydrochloride) Hydrochloride

Teratogenicity studies with Moducren (Amiloride Hydrochloride) hydrochloride in rabbits and mice given 20 and 25 times the maximum human dose, respectively, revealed no evidence of harm to the fetus, although studies showed that the drug crossed the placenta in modest amounts. Reproduction studies in rats at 20 times the expected maximum daily dose for humans showed no evidence of impaired fertility. At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred.

Hydrochlorothiazide

Teratogenic Effects

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing Mothers

Studies in rats have shown that Moducren is excreted in milk in concentrations higher than those found in blood, but it is not known whether Moducren (Amiloride Hydrochloride) 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and the comitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

ADVERSE REACTIONS

Moducren hydrochloride and hydrochlorothiazide is usually well tolerated and significant clinical adverse effects have been reported infrequently. The risk of hyperkalemia (serum potassium levels greater than 5.5 mEq per liter) with Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide is about 1 to 2 percent in patients without renal impairment or diabetes mellitus. Minor adverse reactions to Moducren (Amiloride Hydrochloride) hydrochloride have been reported relatively frequently (about 20%) but the relationship of many of the reports to Moducren (Amiloride Hydrochloride) HCl is uncertain and the overall frequency was similar to hydrochlorothiazide treated groups. Nausea/anorexia, abdominal pain, flatulence, and mild skin rash have been reported and probably are related to Moducren (Amiloride Hydrochloride). Other adverse experiences that have been reported with Moducren (Amiloride Hydrochloride) and hydrochlorothiazide are generally those known to be associated with diuresis, thiazide therapy, or with the underlying disease being treated. Clinical trials have not demonstrated that combining Moducren (Amiloride Hydrochloride) and hydrochlorothiazide increases the risk of adverse reactions over those seen with the individual components.

The adverse reactions for Moducren (Amiloride Hydrochloride) and hydrochlorothiazide listed in the following table have been arranged into two groups: (1) incidence greater than one percent; and (2) incidence one percent or less. The incidence for group (1) was determined from clinical studies conducted in the United States (607 patients treated with Moducren (Amiloride Hydrochloride) and hydrochlorothiazide). The adverse effects listed in group (2) include reports from the same clinical studies and voluntary reports since marketing. The probability of a causal relationship exists between Moducren (Amiloride Hydrochloride) and hydrochlorothiazide and these adverse reactions, some of which have been reported only rarely.

Other adverse reactions that have been reported with the individual components and within each category are listed in order of decreasing severity:

Moducren (Amiloride Hydrochloride)

Body as a Whole: Painful extremities, neck/shoulder ache, fatigability.

Cardiovascular: Palpitation.

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

Hematologic: Aplastic anemia, neutropenia.

Integumentary: Alopecia, itching, dry mouth.

Nervous System/Psychiatric: Encephalopathy, tremors, decreased libido.

Respiratory: Shortness of breath, cough.

Special Senses: Increased intraocular pressure, tinnitus.

Urogenital: Bladder spasms, polyuria, urinary frequency.

Hydrochlorothiazide

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

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, purpura.

Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, hyperuricemia.

Nervous System/Psychiatric: Restlessness.

Special Senses: Transient blurred vision, xanthopsia.

Urogenital: Interstitial nephritis.

OVERDOSAGE

No data are available in regard to overdosage in humans. The oral LD₅₀ of the combination drug is 189 and 422 mg/kg for female mice and female rats, respectively.

It is not known whether the drug is dialyzable.

No specific information is available on the treatment of overdosage with Moducren and hydrochlorothiazide and no specific antidote is available. Treatment is symptomatic and supportive. Therapy with Moducren (Amiloride Hydrochloride) and hydrochlorothiazide should be discontinued and the patient observed closely. Suggested measures include the induction of emesis and/or gastric lavage.

Moducren (Amiloride Hydrochloride) Hydrochloride

No data are available in regard to overdosage in humans.

The oral LD₅₀ of Moducren (Amiloride Hydrochloride) hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain.

The most common signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. If hyperkalemia occurs, active measures should be taken to reduce the serum potassium levels.

Hydrochlorothiazide

The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

DOSAGE AND ADMINISTRATION

Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide tablets should be administered with food.

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 Moducren (Amiloride Hydrochloride) hydrochloride and hydrochlorothiazide 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.

HOW SUPPLIED

Moducren (Amiloride Hydrochloride) Hydrochloride and Hydrochlorothiazide Tablets USP are available as:

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. A 3/2016

NDC 0555-0483-02

Moducren (Amiloride Hydrochloride)

Hydrochloride and

Hydrochlorothiazide

Tablets USP

5 mg/50 mg

Rx only

100 TABLETS

TEVA

Hydrochlorothiazide:

• Moducren information
• Moducren indications
• Moducren warnings
• Moducren intake guidelines
• Moducren dosage
• Moducren overdose
• Moducren missed dose
• Moducren side effects
• Moducren drug reactions
• Moducren (Hydrochlorothiazide) reviews

Moducren information

Moducren (Hydrochlorothiazide) is an antihypertensive, diuretic drug that acts on the electrolyte reabsorption in the renal tubular mechanism increasing the excretion of chloride and sodium in equivalent amounts. The exact mechanism of its antihypertensive action is not known at this time.

Moducren indications

Moducren (Hydrochlorothiazide) is typically employed for the treatment of patients suffering from hypertension, either as monotherapy or in combination with other antihypertensive medication. It is also employed in some cases as a diuretic agent. Moducren (Hydrochlorothiazide) therapy may also be prescribed for the treatment of hepatic cirrhosis, edema (in patients suffering from congestive heart failure), nephrotic syndrome, drug induced edema, chronic renal failure or acute glomerulonephritis. Health care professionals may prescribe this drug in order to treat other medical conditions as well; if you would like to know more about the reasons you have been prescribed this drug, it is advised to ask your personal physician.

Moducren warnings

Moducren (Hydrochlorothiazide) may not be used in the treatment of patients who are allergic to this drug, any of its components or other sulfonamide-derived medication. Also, this drug may not be suitable for use in patients that are suffering from anuria, azotemia or impaired renal functions. Caution should be employed if the patient is suffering from hepatic disease. Other medical conditions may also influence the examining health care provider's decision of prescribing Moducren (Hydrochlorothiazide); it is strongly recommended to make sure that the health care professional is fully aware of your health condition and medical history before starting a treatment with this drug.

Use of Moducren (Hydrochlorothiazide) during pregnancy or breast-feeding is also not recommended. This medicine may affect an unborn baby and it also passes into breast milk. As such, use of this drug in pregnant women or breast-feeding mothers should not be employed.

Moducren intake guidelines

You should always take Moducren (Hydrochlorothiazide) as you have been directed by the prescribing health care specialist. While in some cases daily administration of the drug is recommended, other patients may be prescribed an intermittent therapy. Also, the number of daily doses may vary. As such, it is best that you do not follow another patient's intake schedule. If you have difficulties understanding the intake guidelines that your prescribing health care professional has provided, you should ask for further explanations from an authorized health care specialist - such as a pharmacist, a doctor or a nurse.

Moducren dosage

The exact Moducren (Hydrochlorothiazide) dosage may vary greatly from one case to another, depending on the condition being treated, on the patient's medical history and general health condition, on his or her age as well as on a number of other factors. As such you are advised to use the exact Moducren (Hydrochlorothiazide) dosage that has been prescribed to you and never use the dosage prescribed to another patient or a dosage that you have been prescribed in the past. Taking a different Moducren (Hydrochlorothiazide) dose may cause the treatment to not have the desired effect, and if you take this drug in larger doses you may have a higher risk of developing side effects, or you may suffer from an overdose.

Moducren overdose

You should never exceed the Moducren (Hydrochlorothiazide) prescribed dosage, in order to avoid an overdose with this medication. However, if you consider that you are affected by an overdose with this drug it is advised to immediately consult your personal health care provider, the local poisons center or to go to the nearest medical facility to seek emergency medical attention. The common symptoms of an overdose with Moducren (Hydrochlorothiazide) are dehydration and cardiac arrhythmia. The patient may also suffer from electrolyte depletion and thus may present the relevant signs and symptoms.

Moducren missed dose

In case you have missed a dose of Moducren (Hydrochlorothiazide), it is advised that you take the dose as soon as you remember. If the moment when you remember is too close to another intake of the medication, you should completely skip the missed Moducren (Hydrochlorothiazide) dose and take the next scheduled dose on time. You should never take a larger dose of the drug in order to make up for a missed dose, unless your prescribing health care provider directs you to do so.

Moducren side effects

In some patients Moducren (Hydrochlorothiazide) may cause side effects. While they are not very common, it is recommended to let your personal health care provider know if you begin experiencing any side effects. Several types of symptoms are possible: dizziness, headache, paresthesias, gastric irritation, anorexia, nausea and vomiting, diarrhea or constipation, pancreatitis, jaundice, hypotension. Metabolic side effects may include glycosuria, hyperglycemia, hyperuricemia, hypokalemia or hyponatremia. Renal failure or dysfunction may develop, as well as interstitial nephritis. Some patients reported experiencing muscle spasms, restlessness, unusual weakness and blurred vision. In some cases photosensitivity, anaphylactic reactions, respiratory distress, fever, rashes, vasculitis or toxic epidermal necrolysis have occurred.

Moducren drug reactions

Moducren (Hydrochlorothiazide) may interact with barbiturates and narcotics, as well as with alcohol. If you are also following a treatment course with antidiabetic drugs, their dosage may need to be adjusted before starting to take Moducren (Hydrochlorothiazide). This drug may have an additive effect with other antihypertensive medication. ACE inhibitors, ACTH, corticosteroids and skeletal muscle relaxants may also interact with this drug causing unwanted effects. This drug may not be properly absorbed if the patient is also taking Colestipol resins or Cholestyramine. NSAIDs, lithium and Pressor amines may affect or be affected by Moducren (Hydrochlorothiazide), and as such it is strongly recommended to let the prescribing health care provider know if you are taking these or any other drugs before starting a therapy course with this medicine. Other drug interactions that are not listed here are also possible.

Timolol Maleate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Moducren (Timolol Maleate) reviews

DESCRIPTION

Moducren (Timolol Maleate)^® (timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist for ophthalmic use. The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-[(4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol. Moducren (Timolol Maleate) hemihydrate is the levo isomer. Specific rotation is [α]²⁵ _405nm=-16° (C=10% as the hemihydrate form in 1N HCl).

The molecular formula of Moducren (Timolol Maleate) is Formula C₁₃H₂₄N₄O₃S and its structural formula is:

Moducren (Timolol Maleate) (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water and freely soluble in ethanol. Moducren (Timolol Maleate) hemihydrate is stable at room temperature.

Moducren (Timolol Maleate)^® is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered aqueous solution.

It is supplied in two dosage strengths, 0.25% and 0.5%.

Each mL of Moducren (Timolol Maleate)^® 0.25% contains 2.56 mg of Moducren (Timolol Maleate) hemihydrate equivalent to 2.5 mg Moducren (Timolol Maleate).

Each mL of Moducren (Timolol Maleate)^® 0.5% contains 5.12 mg of Moducren (Timolol Maleate) hemihydrate equivalent to 5.0 mg Moducren (Timolol Maleate).

Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 - 7.5) and water for injection, benzalkonium chloride 0.01% added as preservative.

The osmolality of Moducren (Timolol Maleate)^® is 260 to 320 mOsmol/kg.

Chemical Structure

CLINICAL PHARMACOLOGY

Moducren is a non-selective beta-adrenergic antagonist.

It blocks both beta₁-and beta₂-adrenergic receptors. Moducren (Timolol Maleate) does not have significant intrinsic sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant activity.

Moducren (Timolol Maleate), when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous humor production.

In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway resistance because of unopposed parasympathetic activity.

Pharmacokinetics

When given orally, Moducren (Timolol Maleate) is well absorbed and undergoes considerable first pass metabolism. Moducren (Timolol Maleate) and its metabolites are primarily excreted in the urine. The half-life of Moducren (Timolol Maleate) in plasma is approximately 4 hours.

Clinical Studies

In two controlled multicenter studies in the U.S., Moducren (Timolol Maleate)^® 0.25% and 0.5% were compared with respective Moducren (Timolol Maleate) maleate eyedrops. In these studies, the efficacy and safety profile of Moducren (Timolol Maleate)^® was similar to that of Moducren (Timolol Maleate) maleate.

INDICATIONS AND USAGE

Moducren (Timolol Maleate)^® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

CONTRAINDICATIONS

Moducren (Timolol Maleate)^® is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia, second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.

WARNINGS

As with other topically applied ophthalmic drugs, Moducren ^® is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure have been reported following systemic or topical administration of beta-adrenergic blocking agents.

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe cardiac failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. Moducren (Timolol Maleate)^® should be discontinued at the first sign or symptom of cardiac failure.

Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma which are contraindications) should in general not receive beta-blocking agents.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents is recommended. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-adrenergic agonists.

Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.

PRECAUTIONS

General

Because of the potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Moducren ^®, alternative therapy should be considered.

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. dipIopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting the pupil. Moducren (Timolol Maleate)^® has no effect on the pupil. Therefore, if Moducren (Timolol Maleate) is used in angle-closure glaucoma, it should always be combined with a miotic and not used alone.

Anaphylaxis

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft contact lenses should wait 5 minutes after instilling Moducren ^® before they insert their lenses.

Information for Patients

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product

Drug Interactions

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Moducren ^® should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade.

Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently.

Catecholamine-depleting drugs

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Calcium antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

Digitalis and calcium antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

Injectable Epinephrine

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity of Moducren (Timolol Maleate) (as the maleate) has been studied in mice and rats. In a two-year study orally administrated Moducren (Timolol Maleate) maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose) in male rats caused a significant increase in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not cause any changes.

In a life span study in mice the overall incidence of neoplasms was significantly increased in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Furthermore, significant increases were observed in the incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). For comparison, the maximum recommended human oral dose of Moducren (Timolol Maleate) maleate is 1 mg/kg/day.

Mutagenic potential of Moducren (Timolol Maleate) was evaluated in vivo in the micronucleus test and cytogenetic assay and in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames test) high concentrations of Moducren (Timolol Maleate) maleate (5000 and 10,000 g/plate) statistically significantly increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains tested. However, no consistent dose-response was observed nor did the number of revertants reach the double of the control value, which is regarded as one of the criteria for a positive result in the Ames test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL, respectively.

No adverse effects on male and female fertility were reported in rats at Moducren (Timolol Maleate) oral doses of up to 150 mg/kg/day (21,000 times the systemic exposure following the maximum recommended human ophthalmic dose).

Pregnancy Teratogenic effects

Category C

Teratogenicity of Moducren (as the maleate) after oral administration was studied in mice and rabbits. No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Moducren (Timolol Maleate)^® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Because of the potential for serious adverse reactions in nursing infants from Moducren (Timolol Maleate), 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.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Moducren (Timolol Maleate)^® and Moducren (Timolol Maleate) maleate (approximately one in eight patients).

The following adverse events were associated with use of Moducren (Timolol Maleate)^® in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Moducren (Timolol Maleate)^®:

OCULAR:

Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection, and headache.

BODY AS A WHOLE:

Headache.

The following side effects were reported in frequencies of 1 to 5%:

OCULAR:

Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis, blepharitis and cataract.

BODY AS A WHOLE:

Allergic reaction, asthenia, common cold and pain in extremities.

CARDIOVASCULAR:

Hypertension.

DIGESTIVE:

Nausea.

METABOLlC/NUTRITIONAL:

Peripheral edema.

NERVOUS SYSTEM/PSYCHIATRY:

Dizziness and dry mouth.

RESPIRATORY:

Respiratory infection and sinusitis.

In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:

OCULAR:

Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes, diplopia and retinal vascular disorder.

BODY AS A WHOLE:

Chest pain.

CARDIOVASCULAR:

Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure and cardiac arrest.

DIGESTIVE:

Diarrhea.

ENDOCRINE:

Masked symptoms of hypoglycemia in insulin dependent diabetics.

NERVOUS SYSTEM/PSYCHIATRY:

Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.

RESPIRATORY:

Dyspnea, bronchospasm, respiratory failure and nasal congestion.

SKIN:

AIOPecia, hypersensitivity including localized and generalized rash, urticaria.

OVERDOSAGE

No information is available on overdosage with Moducren (Timolol Maleate)^®. Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.

DOSAGE AND ADMINISTRATION

Moducren (Timolol Maleate)^® Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Moducren (Timolol Maleate)^® in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Since in some patients the pressure-lowering response to Moducren (Timolol Maleate)^® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Moducren (Timolol Maleate)^®.

Dosages above one drop of 0.5 percent Moducren (Timolol Maleate)^® twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.

HOW SUPPLIED

Moducren ^® (timolol ophthalmic solution) is a clear, colorless solution.

Moducren (Timolol Maleate)^® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Moducren (Timolol Maleate)^® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Rx Only

STORAGE

Store between 15-25°C (59-77°F). Do not freeze. Protect from light.

MARKETED BY:

VISTAKON^® Pharmaceuticals, LLC

Jacksonville, FL 32256 USA

MANUFACTURED BY:

Santen Oy, P.O. Box 33

FIN-33721 Tampere, Finland

November 2006 Version

3220660/5