Cartia XT

The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.

The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.

There have been reports of diltiazem overdose in amounts ranging from < 1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.

The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases, intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:

Bradycardia: Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

High-degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

Hypotension: Vasopressors (e.g., dopamine or norepinephrine).

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

Diltiazem is a calcium channel blocker. It works by relaxing the muscles of your heart and blood vessels.

Diltiazem is used to treat hypertension (high blood pressure), angina (chest pain), and certain heart rhythm disorders.

Diltiazem may also be used for purposes not listed in this medication guide.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole.

To make swallowing easier, ask your doctor or pharmacist if you can open a diltiazem capsule and sprinkle the medicine into a spoonful of applesauce. Swallow right away without chewing. Do not save the mixture for later use.

Use diltiazem regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

You should not stop using diltiazem suddenly. Stopping suddenly may make your condition worse.

If you are being treated for high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Your blood pressure will need to be checked often. You may also need frequent blood tests.

Store at room temperature away from moisture and heat.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of diltiazem in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of diltiazem in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving diltiazem.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Cisapride
• Colchicine
• Flibanserin
• Lomitapide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Afatinib
• Alprenolol
• Amiodarone
• Apixaban
• Aprepitant
• Atazanavir
• Atenolol
• Atorvastatin
• Betaxolol
• Bevantolol
• Bisoprolol
• Bosutinib
• Brexpiprazole
• Bucindolol
• Carbamazepine
• Carteolol
• Carvedilol
• Celiprolol
• Ceritinib
• Cilostazol
• Clarithromycin
• Clonidine
• Clopidogrel
• Cobimetinib
• Conivaptan
• Crizotinib
• Cyclosporine
• Dantrolene
• Deflazacort
• Digoxin
• Dilevalol
• Domperidone
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Droperidol
• Eliglustat
• Eplerenone
• Erythromycin
• Esmolol
• Fingolimod
• Fosaprepitant
• Hydrocodone
• Ibrutinib
• Idelalisib
• Ifosfamide
• Ivabradine
• Ivacaftor
• Labetalol
• Lacosamide
• Levobunolol
• Lovastatin
• Lurasidone
• Mepindolol
• Metipranolol
• Metoprolol
• Morphine
• Morphine Sulfate Liposome
• Nadolol
• Naloxegol
• Nebivolol
• Netupitant
• Nilotinib
• Olaparib
• Oxprenolol
• Penbutolol
• Pindolol
• Piperaquine
• Pixantrone
• Propranolol
• Ranolazine
• Simeprevir
• Simvastatin
• Sonidegib
• Sotalol
• St John's Wort
• Tacrolimus
• Talinolol
• Tertatolol
• Timolol
• Tolvaptan
• Topotecan
• Venetoclax
• Vincristine
• Vincristine Sulfate Liposome

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfentanil
• Alfuzosin
• Buspirone
• Cimetidine
• Colestipol
• Dalfopristin
• Digitoxin
• Dutasteride
• Efavirenz
• Enflurane
• Fosphenytoin
• Guggul
• Indinavir
• Lithium
• Methylprednisolone
• Midazolam
• Moricizine
• Nevirapine
• Phenytoin
• Quinupristin
• Rifampin
• Sirolimus
• Suvorexant
• Triazolam

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bowel blockage, severe or
• Congestive heart failure—Use with caution. May make these conditions worse.

• Heart attack or
• Heart block (type of abnormal heart rhythm, can use if have a pacemaker that works properly) or
• Hypotension (low blood pressure), severe or
• Lung problem (eg, pulmonary congestion) or
• Sick sinus syndrome (type of abnormal heart rhythm, can use if have a pacemaker that works properly)—Should not be used in patients with these conditions.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Hypotension (low blood pressure) may occur while taking this medicine. Check with your doctor right away if you have the following symptoms: blurred vision, confusion, severe dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly, sweating, or unusual tiredness or weakness. .

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have any of the following symptoms while taking this medicine: blistering, peeling, or loose skin, chills, cough, diarrhea, itching, joint or muscle pain, red skin lesions, often with a purple center, skin rash, sore throat, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to treat high blood pressure.
• It is used to treat chest pain or pressure.
• It may be given to you for other reasons. Talk with the doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Diltiazem is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

General

Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

Drug Interactions

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction (see WARNINGS). Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (see WARNINGS).

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem 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 diltiazem. 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 diltiazem 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 diltiazem 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 diltiazem.  These pharmacokinetic effects seen during diltiazem 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 diltiazem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of diltiazem hydrochloride 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 diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).

Buspirone

In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.

Carbamazepine

Concomitant administration of diltiazem 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 diltiazem 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 diltiazem 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 diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem 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 diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15% to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.

The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Digitalis

Administration of diltiazem 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 diltiazem therapy to avoid possible over- or under-digitalization (see WARNINGS).

Quinidine

Diltiazem significantly increases the AUC(0 →∞) of quinidine by 51%, T1/2 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 diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.

Statins

Diltiazem 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 diltiazem. When possible, use a non CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem 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), coadministration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.

In a ten-subject randomized, open label, 4-way cross-over study, coadministration of diltiazem (120 mg BID diltiazem 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 diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21-month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

Pregnancy

Category C. Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond 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 of concomitant disease or other drug therapy.

NDC 62037-599-90
Cartia XT®
(Diltiazem HCI Extended-
Release Capsules, USP)
ONCE-A-DAY DOSAGE
240 mg
Actavis 90 Capsules Rx only