Pharmacokinetics

The pharmacokinetics of Ismelin are complex. The amount of drug in plasma and in urine is linearly related to dose, although large differences occur between individuals because of variation in absorption and metabolism. Adrenergic blockade occurs with a minimum concentration in plasma of 8 ng/ml; this concentration is achieved in different individuals with dosages of 10-50 mg/day at steady state. Ismelin is eliminated slowly because of extensive tissue binding. After chronic oral administration, the initial phase of elimination with a half-life of 1.5 days is followed by a second phase of elimination with a half-life of 4-8 days. The renal clearance of Ismelin is 56 ml/min. Ismelin is converted by the liver to three metabolites, which are excreted in the urine. The metabolites are pharmacologically less active than Ismelin.

General

Dosage requirements may be reduced in the presence of fever.

Special care should be exercised when treating patients with a history of bronchial asthma; asthmatic patients are more apt to be hypersensitive to catecholamine depletion, and their condition may be aggravated.

The effects of Ismelin are cumulative over long periods; initial doses should be small and increased gradually in small increments.

Ismelin should be used very cautiously in hypertensive patients with: renal disease and nitrogen retention or rising BUN levels, since decreased blood pressure may further compromise renal function; coronary insufficiency or recent myocardial infarction; and cerebrovascular disease, especially with encephalopathy.

Ismelin should not be given to patients with severe cardiac failure except with extreme caution, since Ismelin may interfere with the compensatory role of the adrenergic system in producing circulatory adjustment in patients with congestive heart failure.

Patients with incipient cardiac decompensation should be watched for weight gain or edema, which may be averted by the concomitant administration of a thiazide.

Ismelin should be used cautiously in patients with a history of peptic ulcer or other chronic disorders that may be aggravated by a relative increase in parasympathetic tone.

Information for Patients

The patient should be advised to take Ismelin exactly as directed. If the patient misses a dose, he or she should be told to take only the next scheduled dose (without doubling it).

The patient should be advised to avoid sudden or prolonged standing or exercise and to arise slowly, especially in the morning, to reduce the orthostatic hypotensive effects of dizziness, lightheadedness, or fainting.

The patient should be cautioned about ingesting alcohol, since it aggravates the orthostatic hypotensive effects of Ismelin.

Male patients should be advised that guanethidine may interfere with ejaculation.

Drug Interactions

Concurrent use of Ismelin and rauwolfia derivatives may cause excessive postural hypotension, bradycardia, and mental depression.

Both digitalis and Ismelin slow the heart rate.

Thiazide diuretics enhance the antihypertensive action of Ismelin (see DOSAGE AND ADMINISTRATION).

Amphetamine-like compounds, stimulants (e. g., ephedrine, methylphenidate), tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine) and other psychopharmacologic agents (e.g., phenothiazines and related compounds), as well as oral contraceptives, may reduce the hypotensive effect of Ismelin.

MAO inhibitors should be discontinued for at least 1 week before starting therapy with Ismelin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with Ismelin.

While inhibition of sperm passage and accumulation of sperm debris have been reported in rats and rabbits after several weeks of administration of Ismelin, 5 or 10 mg/kg per day, subcutaneously or intraperitoneally, recovery of ejaculatory function and fertility has been demonstrated in rats given Ismelin intramuscularly, 25 mg/kg per day, for 8 weeks. Inhibition of ejaculation has also been reported in men (see WARNINGS and ADVERSE REACTIONS). This effect, which is attributable to the sympathetic blockade caused by the drug, is reversible several weeks after discontinuance of the drug.

Pregnancy Category C

Animal reproduction studies have not been conducted with Ismelin. It is also not known whether Ismelin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ismelin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Ismelin is excreted in breast milk in very small quantity. Caution should be exercised when Ismelin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Acute Toxicity

No deaths due to acute poisoning have been reported.

Oral LD50 in rats: 1262 mg/kg.

Signs and Symptoms

Postural hypotension (with dizziness, blurred vision, and possibly syncope when standing), shock, and bradycardia are most likely to occur; diarrhea (possibly severe), nausea, and vomiting may also occur. Unconsciousness is unlikely if adequate blood pressure and cerebral perfusion can be maintained by placing the patient in the supine position and by administering other treatment as required.

Treatment

There is no specific antidote.

Treatment should consist of gastric lavage. An activated charcoal slurry should be instilled and laxatives given, if conditions permit.

In sinus bradycardia, atropine should be administered.

In previously normotensive patients, treatment has consisted essentially of restoring blood pressure and heart rate to normal by keeping the patient in the supine position. Normal homeostatic control usually returns gradually over a 72-hour period in these patients.

In previously hypertensive patients, particularly those with impaired cardiac reserve or other cardiovascular- renal disease, intensive treatment may be required to support vital functions and to control cardiac irregularities that might be present. The supine position must be maintained; if vasopressors are required, they must be used with extreme caution, since Ismelin may increase responsiveness, causing a rise in blood pressure and development of cardiac arrhythmias.

Diarrhea, if severe or persistent, should be treated with anticholinergic agents to reduce intestinal hypermotility; hydration and electrolyte balance should be maintained.

Since Ismelin is excreted slowly, cardiovascular and renal function should be monitored for a few days.

Ambulatory Patients

Initial doses should be small (10 mg) and increased gradually, depending upon the patient's response. Ismelin has a long duration of action; therefore, dosage increases should not be made more often than every 5-7 days, unless the patient is hospitalized.

Blood pressure should be measured in the supine position, after standing for 10 minutes, and immediately after exercise if feasible. Dosage may be increased only if there has been no decrease in the standing blood pressure from previous levels. The average daily dose is 25-50 mg; only one dose a day is usually required.

Dosage Chart for Ambulatory Patients

Visits (intervals of 5 - 7 Days)                                    Daily Dose

Visit 1 (Patient may be started on 10-mg tablets)............................................................ 10 mg

Visit 2 ...............................................................................................................................20 mg

Visit 3 (Patient may be changed to 25-mg tablets whenever convenient)....................... 30 mg (three 10-mg tablets) or 37.5 mg (one and one-half 25-mg tablets)

Visit 4 .............................................................................................................................. 50 mg

Visit 5 and subsequent........................... Dosage may be increased by 12.5 mg or 25 mg if necessary.

The dosage should be reduced in any of the following situations: (1) normal supine pressure: (2) excessive orthostatic fall in pressure; (3) severe diarrhea.

Hospitalized Patients

Initial oral dose is 25-50 mg, increased by 25 mg or 50 mg daily or every other day, as indicated. This higher dosage is possible because hospitalized patients can be watched carefully. Unless absolutely impossible, the standing blood pressure should be measured regularly. Patients should not be discharged from the hospital until the effect of the drug on the standing blood pressure is known. Patients should be told about the possibility of orthostatic hypotension and warned not to get out of bed without help during the period of dosage adjustment.

Combination Therapy

Ismelin may be added gradually to thiazides and/or hydralazine. Thiazide diuretics enhance the effectiveness of Ismelin and may reduce the incidence of edema. When thiazide diuretics are added to the regimen in patients taking Ismelin, it is usually necessary to reduce the dosage of Ismelin. After control is established, the dosage of all drugs should be reduced to the lowest effective level.

Note: When Ismelin is replacing MAO inhibitors, at least 1 week should elapse before commencing treatment with Ismelin (see CONTRAINDICATIONS). If ganglionic blockers have not been discontinued before Ismelin is started, they should be gradually withdrawn to prevent a spiking blood pressure response during the transfer period.