Yutopar (Ritodrine HCl)

YUTOPAR®

Bristol

Ritodrine HCl

Uterine Relaxing Agent

Action And Clinical Pharmacology: Ritodrine is a beta-receptor agonist, which has been shown by in vitro and vivo pharmacologic studies in animals to exert a preferential effect on the adrenergic receptors such as those in the uterine smooth muscle. Stimulation of the receptors inhibits contractility of the uterine smooth muscle. Beta-adrenergic stimulation in other body systems may lead to some cardiovascular or metabolic effects.

Indications And Clinical Uses: For management of preterm labor in suitable patients with more than 20 weeks of gestation who have intact amniotic membranes, cervical dilatation up to 4 cm, and less than 80% cervical effacement. In cases involving ruptured amniotic membranes or more advanced labor, inhibition of labor is less likely and the benefits of treatment must be carefully weighed against the potential risks; contraindications, warnings and precautions must be closely observed.

Contra-Indications: Before the 20th week of pregnancy. In those conditions of the mother or fetus in which continuation of pregnancy is hazardous; specific contraindications include: antepartum hemorrhage which demands immediate delivery; eclampsia and severe preeclampsia; intra-uterine fetal death; chorioamnionitis; maternal cardiac disease; pulmonary hypertension; maternal hyperthyroidism; uncontrolled maternal diabetes mellitus (see Precautions); pre-existing maternal medical conditions that would be seriously affected by the known pharmacologic properties of a betamimetic drug, such as: hypovolemia, cardiac arrhythmias associated with tachycardia or digitalis intoxication, uncontrolled hypertension, pheochromocytoma, bronchial asthma already treated by betamimetics and/or steroids; known hypersensitivity to any component of the product; parenteral ritodrine: history of hypersensitivity to sulfite; asthma patients may react with bronchospasm and anaphylactic shock.

Manufacturers’ Warnings In Clinical States: The occurrence of pulmonary edema in conjunction with the use of ritodrine has been reported, in several cases with a fatal result. The underlying cause was almost certainly multifactorial. Predisposing factors that have been identified include pre-existing cardiac disease, multiple pregnancy, pre-eclampsia and eclampsia, fluid overload, concomitant corticosteroid treatment, maternal infection, and prolonged tachycardia. Patients must be closely monitored in hospital. The patient’s state of hydration should be carefully monitored; fluid overload must be avoided (see Dosage). If pulmonary edema develops during administration, the drug should be discontinued. Edema should be managed by conventional means.

Parenteral administration should be supervised by persons having knowledge of the pharmacology of the drug and who are qualified to identify and manage complications of drug administration and pregnancy. Careful screening of patients with potential cardiac risk and cardiac abnormalities is recommended. These patients should not be treated with ritodrine unless the physician considers that the benefits clearly outweigh the risks. Because cardiovascular responses are common and more pronounced during parenteral administration, cardiovascular effects, including maternal pulse rate and blood pressure and fetal heart rate, should be closely monitored. Care should be exercised for maternal signs and symptoms of pulmonary edema. A persistent high tachycardia (over 140 beats/minute) may be one of the signs of impending pulmonary edema with drugs of this class. Occult cardiac disease may be unmasked with its use. If the patient complains of chest pain or tightness of chest, the drug should be temporarily discontinued and an ECG should be done as soon as possible.

Prolonged treatment with i.v. ritodrine (see Adverse Effects and Dosage, I.V. Therapy) is not recommended. I.V. treatment for 2 to 3 weeks or more may lead to leukopenia and/or agranulocytosis, with a complete recovery after discontinuation of treatment.

The drug should not be administered to patients with mild to moderate preeclampsia, hypertension, or diabetes unless the attending physician considers that the benefits clearly outweigh the risks.

The benefit of this product for management of preterm labor in patients with premature rupture of the fetal membranes has not been established. In such cases a delay of delivery is associated with high risks of infection and chorioamnionitis.

Precautions: Positive diagnosis of preterm labor is essential.

Among low birth weight infants, approximately 9% may be growth retarded for gestational age. Therefore, Intra-Uterine Growth Retardation (IUGR) should be considered in the differential diagnosis of preterm labor; this is especially important when the gestational age is in doubt. The decision to continue or re-initiate ritodrine administration will depend on an assessment of fetal maturity. In addition to clinical parameters, studies such as sonography or amniocentesis may be helpful in establishing the state of fetal maturity if it is in doubt.

Metabolic effects are generally adequately compensated in non-diabetic patients, although a case of acidosis in an apparently normal patient receiving ritodrine and hydrocortisone has been reported. In diabetic patients, however, compensatory mechanisms are impaired or absent; severe hyperglycemia and acidosis may ensue presenting risk for both mother and fetus. To prevent deterioration of diabetic control during Yutopar therapy, careful monitoring of blood glucose, potassium and acid-base status is essential. High doses of insulin, preferably administered by continuous infusion, potassium supplementation and, in some cases, dextrose have been recommended and may be necessary for optimal diabetic control during ritodrine infusion. The hyperglycemic effects of corticosteroids used to promote fetal lung maturity are probably additive and may significantly aggravate diabetic decompensation. If possible, diabetic patients should be treated in a unit specializing in the management of diabetic pregnancy.

Laboratory Tests: Because parenteral administration has been shown to elevate plasma insulin and glucose and to decrease plasma potassium and standard bicarbonate concentrations, monitoring of glucose, electrolytes and acid-base balance is recommended during protracted infusions of healthy patients. Special attention should be paid to biochemical variables when treating diabetic patients and those receiving concomitant corticosteroids or potassium-depleting diuretics. In diabetics, frequent monitoring of blood glucose, potassium, and acid-base balance is necessary; tests for glucosuria and ketonuria may be useful. Patients receiving concomitant corticosteroids should be monitored as for the diabetics, but with additional fluid balance monitoring. Serum electrolytes, particularly potassium, should be frequently assessed in patients receiving diuretics.

Liver function and serum glucose and electrolytes as well as blood count determinations should be performed during therapy. Patients should be closely observed during administration of ritodrine and for several days thereafter in order to quickly undertake corrective measures if abnormalities are detected.

Drug Interactions: Corticosteroids used concomitantly may lead to pulmonary edema (see Warnings). The effects of other sympathomimetic amines may be potentiated when concurrently administered and these effects may be additive. A sufficient time interval should elapse prior to administration of another sympathomimetic drug. With either oral or i.v. administration, 90% of the excretion of the drug is completed within 24 hours after the dose.

Beta-adrenergic blocking drugs inhibit its action; coadministration of these drugs should, therefore, be avoided.

With anesthetics used in surgery, the possibility that hypotensive effects may be potentiated should be considered.

Outcome of Pregnancy and Neonates: There are no adequate and well controlled studies of effects in pregnant women before 20 weeks gestation; therefore, this drug should not be used before the 20th week of pregnancy. Studies in pregnant women from the 20th week of gestation onwards have not shown increased risk of fetal abnormalities. Follow-up of selected variables in a small number of children for up to 2 years has not revealed harmful effects on growth, developmental or functional maturation. Nonetheless, although clinical studies did not indicate a risk of permanent adverse fetal effects from ritodrine, the possibility cannot be excluded; therefore, it should be used only when clearly indicated.

Some studies indicate that infants born before 36 weeks’ gestation make up less than 10% of all births but account for as many as 75% of perinatal deaths and one-half of all neurologically handicapped infants. There are data available indicating that infants born at any time prior to full-term may manifest a higher incidence of neurologic or other handicaps than occurs in the total population of infants born at or after full-term. In delaying or preventing preterm labor, the use of ritodrine results in an overall increase in neonatal survival. Handicapped infants who might not have otherwise survived may survive.

Experiments in animals have revealed no teratogenic properties of ritodrine hydrochloride even in high dosage throughout gestation.

Adverse Reactions: Unwanted effects are related to its betamimetic activity and usually are controlled by suitable dosage adjustment. Some sensitivity reactions may be observed during prolonged oral therapy.

Effects Associated with I.V. Administration: Usual Effects (80 to 100% of patients): I.V. infusion leads almost invariably to dose-related alterations in maternal and fetal heart rates and in maternal blood pressure. During clinical studies in which the maximum infusion rate was limited to 0.35 mg/min (one patient received 0.40 mg/min), the maximum maternal and fetal heart rates averaged, respectively, 130 (range 60 to 180) and 164 (range 130 to 200) beats/minute. The maximum maternal systolic blood pressures averaged 128 mm Hg (range 96 to 162 mm Hg), an average increase of 12 mm Hg from pretreatment levels. The minimum maternal diastolic blood pressures averaged 48 mm Hg (range 0 to 76 mm Hg), an average decrease of 23 mm Hg from pretreatment levels. While the more severe effects were usually managed effectively by dosage adjustments, in less than 1% of patients, persistent maternal tachycardia or decreased diastolic blood pressure required withdrawal of the drug. A persistent high tachycardia (over 140 beats per minute) may be one of the signs of impending pulmonary edema (see Warnings).

The infusion is associated with transient elevation of blood glucose and insulin, which decreased toward normal values after 48 to 72 hours despite continued infusion. Elevation of free fatty acids and c-AMP has been reported. Reduction of potassium levels should be expected; other biochemical effects have not been reported.

Frequent Effects (10 to 50% of patients): I.V. dosing, in about one-third of the patients, was associated with palpitations. Tremor, nausea, vomiting, headache, or erythema was observed in 10 to 15% of patients.

Occasional Effects (5 to 10% of patients): Nervousness, jitteriness, restlessness, emotional upset, or anxiety was reported in 5 to 6% of patients and malaise in similar numbers. Infrequent effects (1 to 3% of patients): Cardiac symptoms including chest pain or tightness (rarely associated with abnormalities of ECG) or arrhythmia were reported in 1 to 2% of patients. Other infrequently reported maternal effects included: anaphylactic shock, rash, heart murmur, epigastric distress, ileus, bloating, constipation, diarrhea, dyspnea, hyperventilation, hemolytic icterus, glycosuria, lactic acidosis, sweating, chills, drowsiness, and weakness. Impaired liver function (i.e., increased transaminase levels and hepatitis) have also been reported infrequently with the use of ritodrine and other beta-sympathicomimetics. Most of the adverse signs and symptoms are reversible, when ritodrine is discontinued. A few cases of leukopenia have been reported in patients receiving prolonged i.v. ritodrine treatment. The leukocyte counts returned to normal after discontinuation of treatment.

Neonatal Effects: Infrequently reported neonatal symptoms include hypoglycemia and ileus. In addition, hypocalcemia and hypotension have been reported in neonates whose mothers were treated with other betamimetic agents.

Effects Associated with Oral Administration: Frequent effects (10 to 50% of patients): Oral dosing in clinical studies was often associated with small increases in maternal heart rate, but little or no effect upon either maternal systolic or diastolic blood pressure or upon fetal heart rate was found.

Oral ritodrine in 10 to 15% of patients was associated with palpitations or tremor. Nausea and jitteriness were less frequent (5 to 8%), while rash was observed in some patients (3 to 4%), and arrhythmia was infrequent (about 1%).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The symptoms of overdosage are those of excessive beta-adrenergic stimulation including exaggeration of the known pharmacologic effects, the most prominent being tachycardia (maternal and fetal), palpitation, cardiac arrhythmia, hypotension, dyspnea, nervousness, tremor, nausea, and vomiting. If an excess of ritodrine tablets is ingested, gastric lavage or induction of emesis should be carried out followed by administration of activated charcoal. When symptoms of overdose occur as a result of parenteral administration, ritodrine should be discontinued; an appropriate beta-blocking agent may be used as an antidote. Ritodrine is dialyzable.

Dosage And Administration: In the management of preterm labor, the initial i.v. treatment should usually be followed by oral administration. The optimum dose is determined by a clinical balance of uterine response and unwanted effects.

I.V.: Do not use i.v. if the solution is discolored or contains any precipitate or particulate matter.

Diluted solution should be used promptly after preparation, but in no case after 48 hours of preparation.

To minimize the risks of hypotension, the patient should be maintained in the left lateral position during infusion and careful attention given to her state of hydration; fluid overload must be avoided.

For appropriate control and dose titration, a controlled infusion device is recommended to adjust the rate of flow in drops/minute. An i.v. microdrip chamber (60 drops/mL) can provide a convenient range of infusion rates within the recommended dosage range.

Recommended Dilution: The volume of fluid administered should be kept to a minimum. With a syringe pump the concentration of the drug infused is 3 mg/mL (150 mg ritodrine hydrochloride solution in 50 mL fluid). If a syringe pump is not available the concentration should be 0.3 mg/mL (150 mg ritodrine hydrochloride (3 ampuls) in 500 mL fluid. Ritodrine should be diluted with one of the following: 0.9% w/v sodium chloride solution, 5% w/v dextrose solution, 10% w/v dextran 40 in 0.9% w/v sodium chloride solution, 10% w/v invert sugar solution, compound sodium chloride solution (Ringer’s solution), Hartmann’s solution.

Saline diluents should be reserved for cases where dextrose solution is medically undesirable, for example, diabetes mellitus, due to an increased probability of pulmonary edema.

I.V. therapy should be started as soon as possible after diagnosis. The usual initial dose is 0.1 mg/minute (0.33 mL/min, 20 drops/min using a microdrip chamber at the recommended dilution), to be gradually increased according to the results by 0.05 mg/minute (0.17 mL/min, 10 drops/min using a microdrip chamber at the recommended dilution) every 10 minutes until the desired result is attained or labor progresses despite treatment at the maximum dose. The effective dosage usually lies between 0.15 and 0.35 mg/minute (0.50 to 1.17 mL/min, 30 to 70 drops/min using a microdrip chamber at the recommended dilution). The infusion should generally be continued for at least 12 and no more than 48 hours after uterine contractions cease. With the recommended dilution, the maximum volume of fluid that might be administered after 12 hours at the highest dose (0.35 mg/min) will be approximately 840 mL. The amount of i.v. fluids administered and the rate of administration should be monitored to avoid circulatory fluid overload (over-hydration) (see Precautions, Laboratory Tests). Frequent monitoring of maternal uterine contractions, heart rate, and blood pressure, and of fetal heart rate is required, with dosage individually titrated according to response.

Oral Maintenance: 10 mg may be given approximately 30 minutes before the termination of i.v. therapy. The usual dosage schedule for the first 24 hours of oral administration is 10 mg every 2 hours. Thereafter the usual maintenance dose is 10 to 20 mg every 4 to 6 hours, the dose depending on uterine activity and unwanted effects. The total daily dose of oral ritodrine should not exceed 120 mg. The treatment may be continued as long as the physician considers it desirable to prolong pregnancy.

Recurrence of unwanted preterm labor may be treated with repeated parenteral administration of ritodrine.

Availability And Storage: Injection: Each ampul of clear, colorless, sterile aqueous solution contains: ritodrine hydrochloride 50 mg (10 mg/mL). pH 5.0 to 5.5. Nonmedicinal ingredients: acetic acid, sodium chloride, sodium hydroxide, sodium metabisulphite and water for injection. Sodium hydroxide and hydrochloric acid for pH adjustment. Ampuls of 5 mL, boxes of 10.

Tablets: Each round, yellow tablet, inscribed YUTOPAR on one side and scored on the other, contains: ritodrine hydrochloride 10 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, povidone, talc and yellow iron oxide. Bottles of 50.

Store at room temperature, preferably below 30°C. Protect from excessive heat.

YUTOPAR® Bristol Ritodrine HCl Uterine Relaxing Agent

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