Diltan

Hypertension

Diltan is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Diltan may be used alone or in combination with other antihypertensive medications.

Angina

Diltan is indicated to improve exercise tolerance in patients with chronic stable angina.

DOSAGE AND ADMINISTRATION

Take Diltan once a day at approximately the same time. Do not chew or crush the tablet.

Hypertension

Initiate dosing at 180 to 240 mg once daily, although some patients may respond to lower doses. Titrate according to blood pressure to a maximum of 540 mg daily. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy.

Angina

Initiate dosing at 180 mg once daily and increase dose at intervals of 7 to 14 days if adequate response is not obtained, to a maximum of 360 mg.

Switching To Diltan Tablets

Patients controlled on Diltan alone or in combination with other medications may be switched to Diltan once-a-day at the nearest equivalent total daily dose. Higher doses of Diltan may be needed in some patients based on clinical response.

Diltan is used alone or together with other medicines to treat angina (severe chest pain) or hypertension (high blood pressure). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.

Diltan is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, Diltan relaxes the blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload.

Diltan is available only with your doctor's prescription.

Patients controlled on Diltan alone or in combination with other medications may be switched to Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) at the nearest equivalent total daily dose. Higher doses of Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) may be needed in some patients. Patients should be closely monitored. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. There is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been studied in clinical trials. The incidence of side effects increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.

Hypertension

Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily.

Angina

Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.

Concomitant Use With Other Cardiovascular Agents

May be taken as required to abort acute anginal attacks during Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) therapy.

2. Prophylactic Nitrate Therapy

Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) may be safely coadministered with short- and long-acting nitrates.

3. Beta-blockers

4. Antihypertensives

Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltan (Diltan Extended-Release Capsules, USP) (Once-a-day dosage) or the concomitant antihypertensives may need to be adjusted when adding one to the other.

See also:
What is the most important information I should know about Diltan?

Do not use this medication if you have certain heart conditions such as "sick sinus syndrome" or "AV block" (unless you have a pacemaker), low blood pressure, or if you have recently had a heart attack.

Before taking Diltan, tell your doctor if you have kidney disease, liver disease, or congestive heart failure.

Diltan may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Do not stop taking this medication without first talking to your doctor. If you stop taking Diltan suddenly, your condition may become worse.

Diltan may be only part of a complete program of treatment that also includes diet, exercise, and other medications. Follow your diet, medication, and exercise routines very closely.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms.

Use Diltan 12-hour sustained-release capsules as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Diltan 12-hour sustained-release capsules by mouth with or without food. It is important to take it consistently with regard to meals. If you take it with food, try to always take it with food. If you prefer to take it on an empty stomach, then always try to take it on an empty stomach.
• Swallow Diltan 12-hour sustained-release capsules whole. Do not break, crush, or chew before swallowing.
• Take Diltan 12-hour sustained-release capsules on a regular schedule to get the most benefit from it.
• Taking Diltan 12-hour sustained-release capsules at the same time each day will help you remember to take it.
• Continue to take Diltan 12-hour sustained-release capsules even if you feel well. Do not miss any doses.
• If you miss a dose of Diltan 12-hour sustained-release capsules, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Diltan 12-hour sustained-release capsules.

Diltan 12-hour sustained-action capsules are used to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Diltan is called a calcium channel blocker. It works by relaxing blood vessels in the body and heart so blood can flow more easily. This effect lowers blood pressure. Diltan may also lower your heart rate.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Diltan is also used to prevent chest pain (angina). When used regularly, Diltan can decrease the number and severity of episodes of chest pain from angina. Diltan may also be used to control your heart rate if you have a fast/irregular heartbeat (such as atrial fibrillation).

How to use Diltan SR

Take this medication by mouth with or without food, usually twice daily or as directed by your doctor. Swallow the capsules whole. Do not crush or chew the capsules. Doing so can release all of the drug at once and may increase your risk of side effects.

Your doctor may gradually increase your dose. Follow your doctor's instructions carefully. The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Use this medication regularly to get the most benefit from it. To help you remember, use it at the same times each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick.

If this medication is used for angina, this medication must be taken regularly to be effective. It should not be used to treat angina when it occurs. Use other medications (such as nitroglycerin placed under the tongue) to relieve an angina attack as directed by your doctor. Consult your doctor or pharmacist for details.

It may take up to 2 weeks before you get the full benefit of this drug. Tell your doctor if your condition persists or worsens (for example, your routine blood pressure readings remain high or increase).

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What other drugs will affect Diltan?

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Diltan concomitantly with any agents known to affect cardiac contractility and/or conduction.

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Diltan.

As with all drugs, care should be exercised when treating patients with multiple medications. Diltan is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of Diltan. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered Diltan in order to maintain optimum therapeutic blood levels.

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity, as well as the vascular dilation associated with anesthetics, may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Benzodiazepines

Studies showed that Diltan increased the AUC of midazolam and triazolam by 3-to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5-to 2.5-fold) during coadministration with Diltan. These pharmacokinetic effects seen during Diltan coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.

Beta-blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of Diltan and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of Diltan (Diltan) concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by Diltan. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted.

Buspirone

In nine healthy subjects, Diltan significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T½ and Tmax of buspirone were not significantly affected by Diltan. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with Diltan. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.

Carbamazepine

Concomitant administration of Diltan with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase) resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cimetidine

A study in six healthy volunteers has shown a significant increase in peak Diltan plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of Diltan 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of Diltan. Patients currently receiving Diltan therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the Diltan dose may be warranted.

Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with Diltan. Monitor heart rate in patients receiving concomitant Diltan and clonidine.

Cyclosporine

A pharmacokinetic interaction between Diltan and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine trough dose ranging from 15% to 48% was necessary to maintain concentrations similar to those seen prior to the addition of Diltan. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when Diltan therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on Diltan plasma concentrations has not been evaluated.

Digitalis

Administration of Diltan with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Diltan therapy to avoid possible over-or under-digitalization.

Quinidine

Diltan significantly increases the AUC (0→infin;) of quinidine by 51%, T½ by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

Rifampin

Coadministration of rifampin with Diltan lowered the Diltan plasma concentrations to undetectable levels. Coadministration of Diltan with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.

Statins

Diltan is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of Diltan. When possible, use a non-CYP3A4-metabolized statin together with Diltan; otherwise, dose adjustments for both Diltan and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.

In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID Diltan SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of Diltan showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of Diltan, an 8-to 9-fold mean increase in simvastatin AUC can be expected. If co-administration of simvastatin with Diltan is required, limit the daily doses of simvastatin to 10 mg and Diltan to 240 mg.

In a ten-subject randomized, open label, 4-way cross-over study, co-administration of Diltan (120 mg BID Diltan SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3-to 4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during Diltan coadministration. Diltan plasma levels were not significantly affected by lovastatin or pravastatin.

See also:
What are the possible side effects of Diltan?

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.

In the hypertension study, the following table presents adverse reactions more common on Diltan than on placebo (but excluding events with no plausible relationship to treatment), as reported in placebo-controlled hypertension trials in patients receiving a Diltan extended-release formulation (once-a-day dosing) up to 540 mg.

In the angina study, the adverse event profile of Diltan extended-release tablets was consistent with what has been previously described for Diltan extended-release tablets and other formulations of Diltan HCl. The most frequent adverse effects experienced by Diltan extended-release tablets-treated patients were edema lower-limb (6.8%), dizziness (6.4%), fatigue (4.8%), bradycardia (3.6%), first-degree atrioventricular block (3.2%), and cough (2%).

In clinical trials of other Diltan formulations involving over 3200 patients, the most common events (i.e. greater than 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%), bradycardia (1.7%), flushing (1.4%), nausea (1.4%), and rash (1.2%).

In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials:

Cardiovascular: Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal: Anorexia, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, mild elevations of SGOT, SGPT, LDH, and alkaline phosphatase, thirst, vomiting, weight increase.

Dermatological: Petechiae, photosensitivity, pruritus, urticaria.

Other: Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties.

The following postmarketing events have been reported infrequently in patients receiving Diltan: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. In addition, events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients. A number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and Diltan therapy is yet to be established.

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Diltan is 1,5-benzothiazepin-4(5H)one,3-(acetyloxy)-5[2-(dimethylamino)-ethyl]-2-3-dihydro-2-(4-methoxyphenyl),-monohydrochloride,(+)-cis-. It has an empirical formula of C₂₂H₂₆N₂O₄S·HCl and a molecular weight of 450.98.

Diltan is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol and chloroform.