Thalitone

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 appear to be similar. The site of the 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.

Thalitone® (chlorthalidone USP) has been formulated with PVP (povidone polyvinylpyrrolidone), a bioavailability enhancer that provides 104% to 116% bioavailability relative to an oral solution of chlorthalidone. Thalitone® (chlorthalidone) cannot be substituted for other formulations of chlorthalidone and likewise, other formulations of chlorthalidone cannot be substituted for Thalitone® (chlorthalidone) .

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• other medications for high blood pressure
• nonsteroidal anti-inflammatory medications such as ibuprofen (Motrin) or naproxen (Aleve) and salicylates
• corticosteroids such as prednisone, hydrocortisone (Cortef), and dexamethasone (Decadron, Dexone, Hexadrol)
• lithium (Eskalith, Lithobid)
• medications for diabetes
• probenecid (Benemid)
• alcohol
• narcotics
• barbiturates such as amobarbital (Amytal), butalbital (Fioricet, Fiorinal), phenobarbital (Luminal) and others
• digoxin (Digitek, Lanoxin)
• cholestyramine (Prevalite, Questran, Questran Light)
• colestipol (Colestid)

This is not a complete list of Thalitone drug interactions. Ask your doctor or pharmacist for more information.

If you take too much Thalitone call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Thalitone is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Drinking alcohol with this medicine can cause side effects.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

General

BP Monitoring and Treatment Goals

• Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

• When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

• If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

• Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

• Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Administer orally.a

Dosage

Individualize according to requirements and response.a

If added to potent hypotensive agent regimen, initially reduce hypotensive dosage to avoid the possibility of severe hypotension.a

Thalitone tablets are formulated with povidone to enhance oral bioavailability of chlorthalidone; because of the enhanced bioavailability of this formulation, Thalitone tablets are not bioequivalent with other formulations of the drug, and the tablets cannot be substituted for other preparations or vice versa on a mg-for-mg basis.103

For the management of fluid retention associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

Pediatric Patients

Initially, 0.3 mg/kg once daily.113 Increase dosage as necessary up to a maximum of 2 mg/kg (up to 50 mg) once daily.113

Adults

JNC 8 expert panel recommends initial dosage of 12.5 mg once daily and target dosage of 12.5–25 mg once daily based on dosages used in randomized controlled studies.501 Other experts have recommended initial dosage of 12.5–25 mg daily and usual maximum dosage of 25 mg daily.101 102 109

Dosages >100 mg daily usually do not increase efficacy.600

If adequate response is not achieved with monotherapy, add another antihypertensive agent.501

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Initially, 15 mg once daily.103

May increase dosage to 30 mg once daily and, if necessary, to 45–50 mg daily if response is inadequate after a sufficient trial.103

If BP control still is inadequate at the upper dosage, a second antihypertensive drug should be added rather than increasing the dosage of Thalitone further.103

Initially, administer each drug separately to adjust dosage; may use fixed combination if optimum maintenance dosage corresponds to drug ratio in combination preparation.a

Manufacturers state that fixed-combination preparations containing chlorthalidone and atenolol or clonidine should not be used for initial antihypertensive therapy.601 602

Combination preparations do not contain chlorthalidone in enhanced bioavailability formulations; therefore, combination dosing does not apply to dosages attained with Thalitone.

Usually, 50–100 mg daily in a single dose after breakfast.a

Alternatively, initiate 100 mg every other day or 3 times a week; some patients require dosages of 150–200 mg daily or every other day.a

Dosages >200 mg daily do not produce a greater response.a

Maintenance: Reduction of dosage to a lower level may be possible after several days or when nonedematous weight is attained.a

For management of fluid retention associated with heart failure, some experts recommend initiating chlorthalidone at a low dosage (e.g., 12.5–25 mg once daily) and increasing dosage until urine output increases and weight decreases, generally by 0.5–1 kg daily.524

Usual initial dosage: 30–60 mg daily or 60 mg on alternate days.103

Adjust dosage as necessary to 90–120 mg on alternate days or daily.103

Dosages >120 mg daily usually do not produce a greater response.103

Maintenance: May be lower than initial dosages and therefore should be adjusted according to individual response.103

Prescribing Limits

Pediatric Patients

Maximum 2 mg/kg (up to 50 mg) once daily.113

Adults

Usual maximum is 25 mg daily.101 102 500 Higher dosages (up to 100 mg daily)a previously used but no longer recommended.101

Maximum before switching/adding alternative drug is 50 mg daily.103

Dosages >200 mg daily do not produce a greater response.a

Management of fluid retention in heart failure: 100 mg maximum daily dose recommended by ACCF/AHA.524

Dosages >120 mg daily usually do not produce a greater response.103

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution because of risk of precipitating hepatic coma.a y

Renal Impairment

No specific dosage recommendations for renal impairment; caution because of risk of precipitating azotemia.a y

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.103

• Exact mechanism of diuretic action is unclear; may act by altering metabolism of the tubular cells.b

• Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.b

• Primary site of diuretic action appears to be the cortical diluting segment of the nephron.b

• GFR decreases, but unclear whether secondary to a direct effect on renal vasculature or to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption.b The fall in GFR is not important in the mechanism of action.b

• Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.b

• Increases urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy is not affected by the acid-base balance of the patient.b

• Hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, slight or intermittent elevations in serum calcium concentration.b

• Rate of uric acid excretion is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.b

• Hypotensive activity in hypertensive patients; also augments the action of other hypotensive agents.b Precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation.b

Prescribing Information

Thalitone® (chlorthalidone USP) 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.

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.

Applies to chlorthalidone: oral tablet

Along with its needed effects, chlorthalidone (the active ingredient contained in Thalitone) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking chlorthalidone:

• Abdominal or stomach pain
• black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of skin
• bloating
• blood in urine or stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• chills
• clay-colored stools
• cold sweats
• confusion
• constipation
• cough or hoarseness
• coughing up blood
• darkened urine
• diarrhea
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
• dry mouth
• fast heartbeat
• fatigue
• fever
• flushed, dry skin
• fruit-like breath odor
• general feeling of tiredness or weakness
• headache
• increased hunger
• increased thirst
• increased urination
• indigestion
• itching
• joint pain, stiffness, or swelling
• loss of appetite
• lower back or side pain
• nausea
• pain in joints or muscles
• painful or difficult urination
• pains in stomach, side, or abdomen, possibly radiating to the back
• pinpoint red spots on skin
• red irritated eyes
• red skin lesions, often with a purple center
• redness, soreness or itching skin
• shortness of breath
• skin rash
• sore throat
• sores, ulcers, or white spots on lips or in mouth
• sores, welting, or blisters
• sugar in the urine
• sweating
• swelling of feet or lower legs
• swollen glands
• tightness in chest
• troubled breathing
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight loss
• vomiting
• vomiting of blood
• weight loss
• wheezing
• yellow eyes or skin

Some side effects of chlorthalidone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Cramping
• decreased interest in sexual intercourse
• difficulty having a bowel movement (stool)
• feeling of constant movement of self or surroundings
• hives
• inability to have or keep an erection
• increased sensitivity of skin to sunlight
• loss in sexual ability, desire, drive, or performance
• muscle spasm
• redness or other discoloration of skin
• restlessness
• sensation of spinning
• severe sunburn
• weakness