Pregnancy & Lactation : הריון/הנקה

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.