Special Warning : אזהרת שימוש

Warnings
Hypotension
Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

Congestive Heart Failure
Although diltiazem has a negative inotropic effect in vitro, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index or consistent negative effects on contractility.
Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem in combination with β-blockers in patients with impaired ventricular function is limited.
Caution should be exercised when using this combination.

Cardiac Conduction
Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a first degree AV block detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).

Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome), or second or third degree AV block (0.4%). A patient with Prinzmetal's angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg diltiazem. Concomitant use of diltiazem with β-blockers or digitalis may result in additive effects on cardiac conduction.

Acute Hepatic Injury
In rare instances, symptoms consistent with acute hepatic injury including significant elevations in enzymes such as alkaline phosphatase, creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), have occurred with diltiazem. These were reversible on drug discontinuation. Drug relationship was uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however cholestasis, with or without jaundice, has been reported. Rare instances of allergic hepatitis have been reported.


General Anesthesia
In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Psychic Effects
Treatment with diltiazem may be associated with mood changes, including depression. Early recognition of relevant symptoms is important, especially in predisposed patients. In such cases, drug discontinuation should be considered.

Gastrointestinal Effects
Diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing an intestinal obstruction.

Diabetes Mellitus
Careful monitoring is necessary in patients with latent or manifest diabetes mellitus due to a possible increase in blood glucose.

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 100mg/kg/day.

Use in Pregnancy
Reproduction studies have been conducted in mice, rats and rabbits.
Administration of doses ranging from 5-10 times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. In some studies, these doses have been reported to cause skeletal abnormalities. In peri- and post-natal studies, there was some reduction in early pup weights and survival rates. There was an increased incidence of stillbirth at doses of 20 times the human dose or greater.

There are very limited data from the use of diltiazem in pregnant patients. Therefore, diltiazem is not recommended during pregnancy or in women of childbearing potential not using effective contraception.
Use diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Use in Breastfeeding
(see Contraindications)
Diltiazem is excreted in breast milk. Diltiazem levels were measured in both serum and milk in lactating women. One report suggests that concentrations in breast milk may approximate serum levels.

These data show that diltiazem is freely diffusible in milk but it is not known whether it is harmful to the newborn. Therefore, breastfeeding while taking this drug is contraindicated.

Use in Pediatrics
Safety and efficacy of the use of diltiazem in children have not been established.



Use in the Elderly
The half-life of calcium channel blockers may be increased in the elderly as a result of decreased clearance.Therefore caution should be exercised in this patient group.
Increase in plasma concentrations may be associated with increase in incidence of adverse reactions (approximately 13% higher in this group). Those adverse reactions which occur more frequently include: peripheral oedema, bradycardia, palpitation, dizziness, rash and polyuria

Impaired Renal Function
Although the pharmacokinetic profile of diltiazem in patients with impaired renal function is similar to that in patients with normal renal function, caution is still advised.
Increase of plasma concentrations of diltiazem may be observed in the elderly and patients with renal or hepatic Insufficiency . The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment

Impaired Hepatic Function
Since diltiazem is extensively metabolized by the liver, it should be used with caution in patients with impaired hepatic function or reduced hepatic blood flow.
Increase of plasma concentrations of diltiazem may be observed in the elderly and patients with renal or hepatic Insufficiency . The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment
Dosing reduction may be necessary.

Adverse Reactions
Adverse reactions are generally not serious and rarely require discontinuation of therapy or dosage adjustment. In clinical trials of diltiazem and diltiazem SR formulations involving over 3200 patients, the most common events (i.e, greater than 1%) were edema (4.6%), headache (4.9% ), dizziness (3.5%), asthenia (2.7%), first degree AV block (2.2%), bradycardia (1.6%), flushing (1.5%), nausea (1.4%), rash (1.3%), dyspepsia (1.2%), palpitations, lower limb oedema, constipation, gastric pain, malaise and erythema.
In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials.

Cardiovascular System
Peripheral edema, hypotension, palpitations, syncope, AV block (1st, 2nd or 3rd degree), bradycardia, congestive heart failure, arrhythmia (unspecified), pulmonary edema, angina, tachycardia, abnormal ECG, ventricular extrasystoles.

Central Nervous System
Dizziness, lightheadedness, nervousness, sleep disturbances, psychiatric disturbances (depression, amnesia, paranoia, psychosis, hallucinations, personality changes), headache, weakness, shakiness, jitteriness, paresthesia, somnolence, asthenia, insomnia, abnormal dreams, tinnitus, tremor/hand tremor.

Gastrointestinal
Anorexia, nausea, diarrhea, constipation, abdominal discomfort, abdominal cramps, dyspepsia, disgeusia, hepatic enzyme increase (AST, ALT, LDH, ALP), vomiting, dry mouth, thirst, weight increase..

Dermatological
Dermatitis, rash, pruritus, urticaria, hair loss, photosensitivity (including lichenoid keratosis at sun exposed skin areas),,erythema multiforme, Stevens-Johnson syndrome.

Hematopoietic
Leukopenia, petechiae, ecchymosis, purpura, bruising, hematoma.

Other
Flushing, nasal congestion, chest congestion, sinusitis, rhinitis, gingival hyperplasia, micturition disorders (e.g. polyuria, nocturia, dysuria), sexual difficulties, impotence, shortness of breath, dyspnea, wheezing, joint stiffness, pain, arthritis, gynecomastia, hyperglycemia, hyperuricemia, weight gain, vomiting epistaxis, anorexia, muscle cramps, CPK increase, osteoarticular pain.
In addition to the adverse effects listed above, the following have been reported: gait abnormality, tremor, amblyopia, eye irritation, bundle branch block, and amnesia.

The following postmarketing events have been reported infrequently in patients receiving diltiazem: mood changes (including deprerssion), sino-atrial block, congestive heart failure, photosensitivity, hepatitis, musculo-cutaneous reactions such as simple erythema or occasionally desquamative erythema with or without fever, angioneurotic edema, symptoms of vasodilation (such as flushing, lower limb edema, sweating), alopecia, erythema multiforme (including rare cases of Steven- Johnson's syndrome), exfoliative dermatitis, extrapyramidal symptoms, acute generalized exanthematous pustular dermatitis, orthostatic hypotension, malaise, gastric pain, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, purpura, retinopathy and thrombocytopenia. Very rare cases of toxic epidermal necrolysis have also been reported 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, characterized as leukocyloclastic vasculitis, have been reported.
However, a definitive cause and effect relationship between these events and diltiazem therapy is yet to be established.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffec tMedic@moh.gov.il

Precautions
Diltiazem 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.

Dermatological Events
Dermatological events 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.

Use in Diabetics
Diltiazem should be used with caution in patients suffering from diabetes. Like other calcium channel blockers, diltiazem influences insulin secretion and its peripheral 
action by inhibiting calcium influx into cells. In one study, increases in fasting and peak glucose levels were observed after 2 to 6 months of diltiazem administration.

Other Effects
Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression.
Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility. Therefore, it should be used with caution in patients at risk to develop an intestinal obstruction.

Abrupt Withdrawal
The sudden withdrawal of dilitazem has been associated with sever angina in anginal paqtients.

Effects on Ability to Drive and Use Machines
Diltiazem may cause adverse reactions such as dizziness, which may impair patients' ability to drive or operate machinery to a varying extent depending on the dosage and individual susceptibility. Therefore, patients should not drive or operate machinery if affected.

Effects on Driving