Ismelin

In addition to the use of the medicine your doctor has prescribed, treatment for your high blood pressure may include weight control and care in the types of foods you eat, especially foods high in sodium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that guanethidine will not cure your high blood pressure but it does help control it. Therefore, you must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life . If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

To help you remember to take your medicine, try to get into the habit of taking it at the same time each day.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For high blood pressure:
    • Adults—At first, 10 or 12.5 milligrams (mg) once a day. Then, your doctor may increase your dose to 25 to 50 mg once a day.
    • Children—The dose is based on body weight and must be determined by your doctor. The usual dose is 200 micrograms (mcg) per kilogram (kg) (90.9 mcg per pound) of body weight a day. Then, your doctor may increase your dose as needed.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. This is more likely to occur in the morning. Getting up slowly may help. When you get up from lying down, sit on the edge of the bed with your feet dangling for 1 or 2 minutes. Then stand up slowly. If the problem continues or gets worse, check with your doctor.

The dizziness, lightheadedness, or fainting is also more likely to occur if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot. While you are taking this medicine, be careful in the amount of alcohol you drink. Also, use extra care during exercise or hot weather or if you must stand for long periods of time.

Do not take other medicines unless they have been discussed with your doctor. This especially includes over-the-counter (nonprescription) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, since they may tend to increase your blood pressure.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.

Tell your doctor if you get a fever since that may change the amount of medicine you have to take.

Male patients: This medicine may interfere with ejaculation.

Ismelin, guanethidine monosulfate USP, is an antihypertensive, available as tablets of 10 mg and 25 mg for oral administration. Each 10-mg and 25-mg tablet contains guanethidine monosulfate USP equivalent to 10 mg and 25 mg of guanethidine sulfate USP. Its chemical name is [2-(hexahydro-1(2H)-azocinyl)ethyl]guanidine sulfate 1:1, and its structural formula is

Guanethidine monosulfate USP is a white to off-white crystalline powder with a molecular weight of 296.38. It is very soluble in water, sparingly soluble in alcohol, and practically insoluble in chloroform.

Inactive Ingredients. Calcium stearate, colloidal silicon dioxide, D&C Yellow No. 10 (10-mg tablets), lactose, starch, stearic acid, and sucrose.

Ismelin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of the chemical mediator (presumably the catecholamine norepinephrine), rather than acting at the effector cell by inhibiting the association of the transmitter with its receptors. In contrast to ganglionic blocking agents, Ismelin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Ismelin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more. The inhibition of sympathetic venoconstrictive mechanisms results in venous pooling of blood. Therefore, the effect of Ismelin is especially pronounced when the patient is standing. Both the systolic and diastolic pressures are reduced.

Other actions at the sympathetic nerve terminal include depletion of norepinephrine. Once it gains access to the neuron, Ismelin accumulates within the intraneuronal storage vesicles and causes depletion of norepinephrine stores within the nerve terminal. Prolonged oral administration of Ismelin produces a denervation sensitivity of the neuroeffector junction, probably resulting from the chronic reduction in norepinephrine released by the sympathetic nerve endings. Systemic responses to catecholamines released from the adrenal medulla are not prevented and may even be augmented as a result of this denervation sensitivity. A paradoxical hypertensive crisis may occur if Ismelin is given to patients with pheochromocytoma or if norepinephrine is given to a patient receiving the drug.

Due to its poor lipid solubility, Ismelin does not readily cross the blood-brain barrier. In contrast to most neural blocking agents, Ismelin does not appear to suppress plasma renin activity in many patients.

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.

Tablets 10 mg – round, pale yellow, scored (imprinted CIBA 49)

Bottles of 100..................................................................................NDC 0083-0049-30

Tablets 25 mg – round, white, scored (imprinted CIBA 103)

Bottles of 100..................................................................................NDC 0083-0103-30

Do not store above 86°F (30°C).

Dispense in tight container (USP).

C96-14(Rev.3/96)

C I B A

Ciba-Geigy Corporation

Pharmaceuticals Division

Summit, New Jersey 07901

Applies to guanethidine: oral tablet

Cardiovascular

The risk of orthostatic hypotension, sometimes followed by syncope, is greatest within the first 10 minutes after dosing, early in the morning, and in hypovolemic patients. It is accentuated by alcohol, hot weather, or exercise--all of which are associated with peripheral vasodilation. The manufacturer recommends that guanethidine (the active ingredient contained in Ismelin) be gradually withdrawn over at least two weeks prior to administration of general anesthetics to avoid cardiovascular collapse during induction.[Ref]

Cardiovascular side effects can result from excessive sympathetic blockade or a relative increase in parasympathetic tone. Orthostatic hypotension is reported in approximately 15% of patients, some of whom experience syncope.

Unopposed or excessive parasympathetic tone can cause excessive bradycardia in rare cases. This may cause serious problems in patients with underlying sinus node dysfunction.

Guanethidine can cause generalized edema in 10% to 15% of patients. Some patients with preexisting congestive heart failure do not tolerate this, and require concomitant diuretic therapy.[Ref]

Gastrointestinal

Gastrointestinal side effects are also related to increased parasympathetic tone. Diarrhea is reported in 11% of patients, some of whom discontinued therapy because of it. Dry mouth or parotid tenderness are reported in approximately 5% of patients.[Ref]

Genitourinary

There is evidence that guanethidine (the active ingredient contained in Ismelin) may interfere with ejaculation by inhibiting contraction of the seminal vesicle, ampula and ductus deferens.[Ref]

Large studies report sexual impotence as a relatively uncommon genitourinary complaint, occurring in only approximately 2% of male patients. Smaller studies, where specific questions were asked of male patients reveal an incidence of impotence as high as 60%. Delayed or retrograde ejaculation and decreased sperm counts are reported. Impotence appears to be reversible upon discontinuation of therapy or reduction in dosage.[Ref]

Respiratory

A relatively common respiratory system complaint, nasal stuffiness in up to 30% of patients, is related to increased parasympathetic tone. Rare reports of dyspnea or exertion unaccompanied by other signs or symptoms of congestive heart failure are associated with guanethidine (the active ingredient contained in Ismelin) [Ref]

Renal

In one study, 58% of patients with or without preexisting elevated BUN developed an increase in the BUN during guanethidine (the active ingredient contained in Ismelin) therapy. The study did not, however, quantify the rise in BUN, attempt to make an association with the degree of blood pressure control, or attempt to measure other parameters of renal function.[Ref]

Nervous system

Because guanethidine (the active ingredient contained in Ismelin) does not affect the central nervous system, neurologic side effects are notably either absent or infrequent. Insomnia and weakness are occasionally reported more often with guanethidine than with placebo.[Ref]

Hypersensitivity

Hypersensitivity reactions are not associated with guanethidine (the active ingredient contained in Ismelin) [Ref]

Some side effects of Ismelin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.