Source: Health Products and Food Branch (CA) Revision Year: 2014
NOVAMILOR (amiloride hydrochloride and hydrochlorothiazide) is contraindicated in patients with serum potassium levels greater than 5.5 mEq/L (see WARNINGS).
Other antikaliuretic agents and potassium supplements are contraindicated in patients taking NOVAMILOR. This type of combination therapy may cause rapid increases in plasma potassium levels. If potassium supplements are deemed necessary, careful monitoring of serum potassium levels is required.
NOVAMILOR should not be administered to patients with anuria, acute renal failure, severe or progressive renal disease or diabetic nephropathy.
NOVAMILOR is contraindicated in patients who are hypersensitive to either component or to other sulfonamide-derived drugs.
Paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and electrocardiographic (ECG) abnormalities are warning signs and symptoms of hyperkalemia.
Some patients receiving amiloride hydrochloride, with or without diuretics, may develop hyperkalemia (serum potassium levels over 5.5 mEq/litre). Elderly patients, diabetic patients, hospitalized patients with hepatic cirrhosis or cardiac edema, patients with known renal impairment, seriously ill patients, and those receiving vigorous diuretic therapy are the most susceptible to hyperkalemia. Since fatalities have occurred in such patients, they should be monitored carefully for clinical, laboratory and ECG evidence of hyperkalemia and for acidosis. Hyperkalemia is not always associated with abnormal ECG; therefore, it is also necessary to monitor serum potassium levels.
The primary characteristic of the abnormal ECG when associated with hyperkalemia is tall peaked T-waves or elevations from previous tracings. Other changes that may also occur include lowering of the R-wave and increased depth of the S-wave, widening and even the disappearance of the P-wave, progressive widening of the QRS complex, prolongation of the PR interval and ST depression.
NOVAMILOR (amiloride hydrochloride and hydrochlorothiazide) treatment should be discontinued immediately if hyperkalemia develops. Active measures, such as intravenous administration of sodium bicarbonate solution or oral parenteral glucose with a rapid acting insulin preparation should be taken to reduce serum potassium levels if they exceed 6.5 mEq/litre. A cation exchange resin, such as sodium polystyrene sulfonate, can be given orally or by enema if necessary. Dialysis may be required if hyperkalemia persists.
If amiloride hydrochloride therapy is considered essential for diabetic or suspected diabetic patients, the drug should be used with extreme caution and only after the status of renal function has been determined. Hyperkalemia is commonly associated with the use of amiloride hydrochloride in diabetic patients, particularly if they have chronic renal disease or prerenal azotemia. Such deaths have been reported in diabetic patients with prerenal azotemia being treated with amiloride hydrochloride.
Insulin requirements for diabetic patients may increase, decrease or remain unchanged due to the hydrochlorothiazide component. Latent diabetes mellitus may become manifest during administration of thiazide diuretics.
Amiloride hydrochloride should be discontinued at least 3 days before glucose tolerance testing. One patient with poorly controlled diabetes mellitus became severely hyperkalemic while on amiloride hydrochloride. This patient died following 2 repeated intravenous glucose tolerance tests.
Serum potassium levels must be carefully monitored throughout therapy.
Frequent monitoring of acid-base balance is necessary in patients in whom respiratory or metabolic acidosis may occur, such as those patients with cardiopulmonary disease or diabetes. Antikaliuretic therapy should be instituted with caution in these patients. Changes in the acidbase balance disrupts the ratio of extracellular/intracellular potassium, and acidosis may develop in association with rapid increases in serum potassium levels.
Renal impairment may accentuate the potassium retention associated with the use of NOVAMILOR which may result in the rapid development of hyperkalemia. Those patients with impaired renal function other than those listed under CONTRAINDICATIONS and who have BUN levels over 30 mg/100 mL, serum creatinine levels over 1.5 mg/l00 mL or blood urea levels over 60 mg/l00 mL should not receive NOVAMILOR unless frequent, careful monitoring of serum electrolytes, creatinine and BUN levels is maintained. Renal impairment may also prolong the excretion of amiloride hydrochloride.
Use of NOVAMILOR (amiloride hydrochloride and hydrochlorothiazide) can result in the development of hyponatremia, hypochloremia, and hypokalemia (to a lesser degree than with thiazides alone). In seriously ill patients, such as those with hepatic cirrhosis with ascites and metabolic alkalosis or those with resistant edema, increases in BUN levels are usually accompanied by vigorous fluid elimination. Chloride deficiencies are usually mild and may be prevented by near normal salt intake and corrected with ammonium chloride treatment in patients not suffering from hepatic disease. When using NOVAMILOR, careful monitoring of serum electrolytes and BUN levels is important.
Hydrochlorothiazide treatment may precipitate or increase azotemia in patients with impaired renal function. It is therefore necessary to monitor these patients carefully. NOVAMILOR should be discontinued if increasing azotemia and oliguria occur during treatment.
Acute shifts in electrolyte balance cannot be tolerated by patients with hepatic cirrhosis and ascites. Pre-existing hypokalemia may also be present in these patients as a result of secondary hyperaldosteronism. Therefore, it is necessary to ensure that diuresis is gradual and that these patients are carefully monitored for shifts in electrolyte imbalances.
Hepatic encephalopathy which is manifested by tremors, confusion and coma has been reported in association with amiloride hydrochloride treatment.
When treated with amiloride hydrochloride alone, some cirrhotic patients have experienced a deepening of the jaundice associated with the underlying disease process; however, the relationship between this and the drug is not known.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Hydrochlorothiazide causes a decrease in urinary calcium excretion and an increase in urinary magnesium excretion.
In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed. However, complications commonly associated with hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been observed. It is advisable to discontinue thiazide treatment before performing parathyroid function tests.
Hyperuricemia may occur or gout may be precipitated in certain patients receiving thiazide therapy.
Patients should be monitored for signs of liver dysfunction, idiosyncratic reactions or blood dyscrasias.
Patients with or without a history of allergy or bronchial asthma may experience sensitivity reactions to thiazides.
Systemic lupus erythematosus may be exacerbated or activated by thiazide therapy.
NOVAMILOR is not recommended for use during pregnancy due to limited clinical experience.
No evidence of impaired fertility has been demonstrated in reproduction studies in rats. Teratologic studies with rabbits and mice have failed to produce evidence that amiloride hydrochloride harms the fetus. Some toxicity was seen in adult rats and rabbits and a decrease in rat pup survival and growth was observed when the animals were given a dose of 8 mg/kg/day. A trace amount of the drug has been shown to cross the placental barrier in rats.
Thiazides cross the placental barrier and occur in cord blood.
Use of NOVAMILOR during pregnancy or suspected pregnancy requires that the benefits be weighed against the potential hazards to the fetus. Some potential hazards include fetal or neonatal jaundice, thrombocytopenia and the possibility of other side effects that have occurred in adults.
Amiloride hydrochloride is excreted in rat’s milk, but it is not known if it is present in human breast milk. Thiazides are known to be excreted in human milk. If use of NOVAMILOR is deemed essential, the patient should stop nursing due to the potential for serious adverse reactions in nursing infants.
NOVAMILOR is not recommended for pediatric patients since the safety of amiloride hydrochloride alone or in combination with hydrochlorothiazide has not been determined for this age group.
The actions of other antihypertensive drugs are potentiated by hydrochlorothiazide. It may therefore be necessary to reduce the dosage of other antihypertensive agents, especially ganglion blockers when NOVAMILOR is added to the regimen.
Diuretic drugs increase the risk of lithium toxicity; therefore, patients receiving diuretics generally should not receive lithium.
Responsiveness to tubocurarine may be increased by thiazide drugs. Post-sympathectomy enhances the drug’s antihypertensive effect.
Arterial responsiveness to norepinephrine may be decreased by hydrochlorothiazide; however, this decrease is not sufficient to preclude the effectiveness of the pressor agent for therapeutic use.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.
Although rare, the most severe adverse effect associated with the use of NOVAMILOR (amiloride hydrochloride and hydrochlorothiazide) is symptomatic hyperkalemia. Other metabolic changes that occur are asymptomatic hyperkalemia, hypokalemia and hypochloremia.
The following adverse reactions with the approximate incidences were reported:
Gastrointestinal: Adverse reactions were reported in 6% of the patients. Nausea/anorexia (4%), diarrhea (2%), gastrointestinal pain (2%), abdominal pain (1-3%), constipation, GI bleeding, GI disturbance, appetite changes (1-3%), abdominal fullness, hiccups, thirst (≤1%), vomiting (0.5%), flatulence and bad taste (≤1%).
Nervous System: Adverse reactions were reported in 4% of the patients. Headaches (8%). dizziness (3%), weakness (3%), paresthesia/numbness (0.5%), stupor, vertigo, insomnia, nervousness, depression, sleepiness (0.5%), mental confusion and visual disturbance (≤l%).
Dermatologic: Adverse reactions were reported in 5% of the patients. Rashes (3%), pruritus (2%) and flushing.
Cardiovascular: Adverse reactions were reported in 4% of the patients. Arrhythmia (2%), tachycardia, digitalis toxicity, orthostatic hypotension (≤1%) and angina pectoris (≤1%).
Musculoskeletal: Leg aches, muscle cramps/spasm (1-3%), joint pain, chest pain and back pain.
Respiratory: Adverse reactions were reported in 2% of the patients. Dyspnea (2%) and nasal congestion.
Urogenital: Adverse reactions were reported in 3% of the patients. Impotence, nocturla (0.5%), dysuria (0.5%), and incontinence (0.5%).
Endocrine: Gout and dehydration (1%).
Other: Fatigue/tiredness (3%), malaise (0.5%).
Other reactions that have been reported with the individual components include:
Cardiovascular: Necrotizing angiitis (vasculitis, cutaneous vasculitis).
Gastrointestinal: Abnormal liver function, activation of pre-existing peptic ulcer, cramping, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, dry mouth and sialadenitis.
Endocrine: Glycosuria, hyperglycemia, hyperuricemia.
Hypersensitivity: Urticaria and anaphylactic reactions.
Respiratory: Respiratory distress including pneumonitis.
Special Senses: Photosensitivity, transient blurred vision and xanthopsia.
Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia and neutropenia.
Others: Restlessness and fever.
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