CLORPRES^®
(Clonidine Hydrochloride
and
Chlorthalidone)
TABLETS, USP

CLORPRES^® is a combination of clonidine hydrochloride (a centrally acting antihypertensive agent) and chlorthalidone (a diuretic). CLORPRES^® is available as tablets for oral administration in three dosage strengths: 0.1 mg/15 mg, 0.2 mg/15 mg and 0.3 mg/15 mg of clonidine hydrochloride/ chlorthalidone, respectively.

The inactive ingredients are ammonium chloride, colloidal silicon dioxide, croscarmellose sodium (Type A), magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, D&C yellow #10.

Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-[(2,6-dichlorophenyl)imino]imidazoline monohydrochloride. The following are the structural formula, molecular formula and molecular weight:

Clonidine hydrochloride is an odorless, bitter, white crystalline substance soluble in water and alcohol.

Chlorthalidone is a monosulfamyl diuretic that differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is 2-chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide with the following structural formula, molecular formula and molecular weight:

Chlorthalidone is practically insoluble in water, in ether and in chloroform; soluble in methanol; slightly soluble in alcohol.

Clorpres produces a more pronounced antihypertensive response than occurs after either clonidine hydrochloride or chlorthalidone alone in equivalent doses.

Clonidine hydrochloride acts relatively rapidly. The patient's blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. The plasma level of clonidine hydrochloride peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.

Clonidine stimulates alpha-adrenoreceptors in the brain stem, resulting in reduced sympathetic outflow from the central nervous system and a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent.

Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15 to 20%) of cardiac output in the supine position with no change in the peripheral resistance; at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine but the drug does not alter normal hemodynamic response to exercise.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines, but the exact relationship of these pharmacologic actions to the antihypertensive effect has not been fully elucidated.

Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.

Tolerance may develop in some patients, necessitating a reevaluation of therapy.

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity. Its diuretic action commences a mean of 2.6 hours after dosing and continues for up to 72 hours. The drug produces diuresis with increased excretion of sodium and chloride. The diuretic effects of chlorthalidone and the benzothiadiazine (thiazide) diuretics appear to arise from similar mechanisms and the maximal effect of chlorthalidone and the thiazides appears to be similar. The site of action appears to be the distal convoluted tubule of the nephron. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate, and renal plasma flow. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect. Like the thiazide diuretics, chlorthalidone produces dose-related reductions in serum potassium levels, elevations in serum uric acid and blood glucose, and it can lead to decreased sodium and chloride levels.

The mean plasma half-life of chlorthalidone is about 40 to 60 hours. It is eliminated primarily as unchanged drug in the urine. Non-renal routes of elimination have yet to be clarified. In the blood, approximately 75% of the drug is bound to plasma proteins.

CLORPRES^® (clonidine hydrochloride USP/chlorthalidone USP) is indicated in the treatment of hypertension. This fixed combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management. The treatment of hypertension is not static, but must be reevaluated as conditions in each patient warrant.

CLORPRES^® is contraindicated in patients with known hypersensitivity to chlorthalidone or other sulfonamide-derived drugs.

Chlorthalidone should be used with caution in severe renal disease. In patients with renal disease, chlorthalidone or related drugs may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Chlorthalidone should be used with caution in patients with impaired hepatic function or progressive liver disease, because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics which are structurally related to chlorthalidone. However, systemic lupus erythematosus has not been reported following chlorthalidone administration.

CLORPRES^® is generally well tolerated. Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100.

In addition to the reactions uled above, certain less frequent adverse experiences, which are shown below, have also been reported in patients receiving the component drugs of CLORPRES^® but in many cases patients were receiving concomitant medication and a causal relationship has not been established:

Gastrointestinal: Nausea and vomiting, about 5 in 100 patients; anorexia and malaise, each about 1 in 100; mild transient abnormalities in liver function tests, about 1 in 100; rare reports of hepatitis; parotitis, rarely.

Metabolic: Weight gain, about 1 in 100 patients; gynecomastia, about 1 in 1000, transient elevation of blood glucose or serum creatine phosphokinase, rarely.

Central Nervous System: Nervousness and agitation, about 3 in 100 patients; mental depression, about 1 in 100; headache, about 1 in 100; insomnia, about 5 in 1000. Vivid dreams or nightmares, other behavioral changes, restlessness, anxiety, visual and auditory hallucinations and delirium have been reported.

Cardiovascular: Orthostatic symptoms, about 3 in 100 patients; palpitations and tachycardia, and bradycardia, each about 5 in 1000. Raynaud's phenomenon, congestive heart failure, and electrocardiographic abnormalities, i.e., conduction disturbances and arrhythmias, have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Dermatological: Rash, about 1 in 100 patients; pruritus, about 7 in 1000; hives, angioneurotic edema and urticaria, about 5 in 1000, alopecia, about 2 in 1000.

Genitourinary: Decreased sexual activity, impotence and loss of libido, about 3 in 100 patients; nocturia, about 1 in 100; difficulty in micturition, about 2 in 1000; urinary retention, about 1 in 1000.

Other: Weakness, about 10 in 100 patients; fatigue, about 4 in 100; discontinuation syndrome, about 1 in 100; muscle or joint pain, about 6 in 1000 and cramps of the lower limbs, about 3 in 1000. Dryness, burning of the eyes, blurred vision, dryness of the nasal mucosa, pallor, weakly positive Coombs' test, increased sensitivity to alcohol and fever have been reported.

Gastrointestinal: Anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.

Central Nervous System: Dizziness, vertigo, paresthesias, headache, xanthopsia.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.

Dermatologic-Hypersensitivity: Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis).

Cardiovascular: Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.

Other Adverse Reactions: Hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence.

Whenever adverse reactions are moderate or severe, chlorthalidone dosage should be reduced or therapy withdrawn.

The signs and symptoms of clonidine hydrochloride overdosage include hypotension, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, miosis, vomiting and hypoventilation. With large overdoses, reversible cardiac conduction defects or arrhythmias, apnea, seizures and transient hypertension have been reported. The oral LD₅₀ of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.

The general treatment of clonidine hydrochloride overdosage may include intravenous fluids as indicated. Bradycardia can be treated with intravenous atropine sulfate and hypotension with dopamine infusion in addition to intravenous fluids. Hypertension, associated with overdosage, has been treated with intravenous furosemide or diazoxide or alpha-blocking agents such as phentolamine. Tolazoline, an alpha-blocker, in intravenous doses of 10 mg at 30-minute intervals, may reverse clonidine's effects if other efforts fail. Routine hemodialysis is of limited benefit, since a maximum of 5% of circulating clonidine is removed.

In a patient who ingested 100 mg clonidine hydrochloride, plasma clonidine levels were 60 ng/mL (one hour), 190 ng/mL (1.5 hours), 370 ng/mL (two hours) and 120 ng/mL (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.

Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD₅₀ of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

The dosage must be determined by individual titration. (See INDICATIONS AND USAGE.)

Chlorthalidone is usually initiated at a dose of 25 mg once daily and may be increased to 50 mg if the response is insufficient after a suitable trial.

Clonidine hydrochloride is usually initiated at a dose of 0.1 mg twice daily. Elderly patients may benefit from a lower initial dose. Further increments of 0.1 mg/day may be made if necessary until the desired response is achieved. The therapeutic doses most commonly employed have ranged from 0.2 to 0.6 mg per day in divided doses.

One CLORPRES^® (clonidine hydrochloride/chlorthalidone) Tablet administered once or twice daily can be used to administer a minimum of 0.1 mg clonidine hydrochloride and 15 mg chlorthalidone to a maximum of 0.6 mg clonidine hydrochloride and 30 mg chlorthalidone.

CLORPRES^® (clonidine hydrochloride and chlorthalidone) Tablets, USP are available containing:

0.1 mg clonidine hydrochloride, USP and 15 mg chlorthalidone, USP
or
0.2 mg clonidine hydrochloride, USP and 15 mg chlorthalidone, USP
or
0.3 mg clonidine hydrochloride, USP and 15 mg chlorthalidone, USP

The 0.1 mg/15 mg product is a yellow, round, scored tablet debossed with M1. They are available as follows:

NDC 62794-001-01
bottles of 100 tablets

The 0.2 mg/15 mg product is a yellow, round, scored tablet debossed with M27. They are available as follows:

NDC 62794-027-01
bottles of 100 tablets

The 0.3 mg/15 mg product is a yellow, round, scored tablet debossed with M72. They are available as follows:

NDC 62794-072-01
bottles of 100 tablets