RITODRINE HCL
DESCRIPTION:
Yutopar contains the betamimetic (beta sympathomimetic amine) ritodrine
hydrochloride. Yutopar is a clear, colorless, sterile, aqueous solution; each
milliliter contains either 10 mg or 15 mg of ritodrine hydrochloride, 4.35 mg of
acetic acid, 2.4 mg of sodium hydroxide, 1 mg of sodium metabisulfite, and 2.9
mg of sodium chloride in Water for Injection, USP. Hydrochloric acid and/or
additional sodium hydroxide is used to adjust pH. Filled under nitrogen.
FOR INTRAVENOUS USE ONLY. MUST BE DILUTED BEFORE USE. FOR DOSAGE AND
ADMINISTRATION INSTRUCTIONS, SEE PRODUCT INFORMATION BELOW. DO NOT USE IF
INJECTION IS DISCOLORED OR CONTAINS A PRECIPITATE.
Ritodrine hydrochloride is a white, odorless crystalline powder, freely soluble
in water, with a melting point between 196 deg and 205 deg C. The chemical name
of ritodrine hydrochloride is erythro-p-hydroxy-alpha-(1-((p-hydroxyphenethyl)-
amino)ethyl)benzyl alcohol hydrochloride.
ACTIONS/CLINICAL PHARMACOLOGY:
Yutopar (ritodrine hydrochloride) is a beta- receptor agonist, which has been
shown by In Vitro and In Vivo pharmacologic studies in animals to exert a
preferential effect on the beta2 adrenergic receptors such as those in the
uterine smooth muscle. Stimulation of the beta2 receptors inhibits contractility
of the uterine smooth muscle.
In humans, intravenous infusions of 0.05 to 0.30 mg/min decreased the intensity
and frequency of uterine contractions. These effects were antagonized by beta-
blocking compounds. Intravenous administration induced an immediate dose-related
elevation of heart rate with maximum mean increases between 19 and 40 beats per
minute. Widening of the pulse pressure was also observed; the average increase
in systolic blood pressure was 4.0 mm Hg, and the average decrease in diastolic
pressure was 12.3 mm Hg.
During intravenous infusion in humans, transient elevations of blood glucose,
insulin, and free fatty acids have been observed. Decreased serum potassium has
also been found, but effects on other electrolytes have not been reported.
Serum kinetics in humans (non-pregnant females) of an intravenous infusion of 60
minutes duration were determined by measuring serum ritodrine levels by a
radioimmunoassay technique. The distribution half-life was found to be 6 to 9
minutes, and the effective half-life 1.7 to 2.6 hours. Ninety percent of the
excretion was completed within 24 hours after the dose.
Intravenous infusion at a rate of 0.15 mg/min for 1 hour yielded maximum serum
levels ranging between 32 and 52 ng/mL in a group of 6 non- pregnant female
volunteers.
Placental transfer was confirmed by measurement of drug concentrations in cord
blood showing that ritodrine and its conjugates reach the fetal circulation.
INDICATIONS AND USAGE:
Yutopar is indicated for the management of preterm labor in suitable patients.
Administered intravenously, the drug will decrease uterine activity and thus
prolong gestation in the majority of such patients. Additional acute episodes
may be treated by repeating the intravenous infusion. The incidence of neonatal
mortality and respiratory distress syndrome increases when the normal gestation
period is shortened.
Since successful inhibition of labor is more likely with early treatment,
therapy with Yutopar should be instituted as soon as the diagnosis of preterm
labor is established and contraindications ruled out in pregnancies of 20 or
more weeks gestation. The efficacy and safety of Yutopar in advanced labor, that
is, when cervical dilatation is more than 4 cm or effacement is more than 80%,
have not been established.
CONTRAINDICATIONS:
Yutopar is contraindicated before the 20th week of pregnancy.
Yutopar is also contraindicated in those conditions of the mother or fetus in
which continuation of pregnancy is hazardous; specific contraindications
include:
1. Antepartum hemorrhage which demands immediate delivery
2. Eclampsia and severe preeclampsia
3. Intrauterine fetal death
4. Chorioamnionitis
5. Maternal cardiac disease
6. Pulmonary hypertension
7. Maternal hyperthyroidism
8. Uncontrolled maternal diabetes mellitus (See PRECAUTIONS.)
9. 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
10. Known hypersensitivity to any component of the product
WARNINGS:
*************************************************
* *
* Maternal pulmonary edema has been reported *
* in patients treated with Yutopar, sometimes *
* after delivery. It has occurred more often *
* when patients were treated concomitantly *
* with corticosteroids. Maternal death from *
* this condition has been reported with or *
* without corticosteroids given concomitantly *
* with drugs of this class. *
* Patients so treated must be closely *
* monitored in the hospital. The patient's *
* state of hydration should be carefully *
* monitored; fluid overload must be avoided. *
* (See DOSAGE AND ADMINISTRATION.) *
* Intravenous fluid loading may be aggravated *
* by the use of betamimetics with or without *
* corticosteroids and may turn into manifest *
* circulatory overloading with subsequent *
* pulmonary edema. If pulmonary edema *
* develops during administration, the drug *
* should be discontinued. Edema should be *
* managed by conventional means. *
* *
*************************************************
Intravenous administration of Yutopar 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. Beta-adrenergic drugs
increase cardiac output, and even in a normal healthy heart this added
myocardial oxygen demand can sometimes lead to myocardial ischemia.
Complications may include: myocardial necrosis, which may result in death;
arrhythmias, including premature atrial and ventricular contractions,
ventricular tachycardia, and bundle branch block; anginal pain, with or without
ECG changes. BECAUSE CARDIOVASCULAR RESPONSES ARE COMMON AND MORE PRONOUNCED
DURING INTRAVENOUS ADMINISTRATION OF YUTOPAR, 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 PER MINUTE) MAY BE ONE OF
THE SIGNS OF IMPENDING PULMONARY EDEMA WITH DRUGS OF THIS CLASS. OCCULT CARDIAC
DISEASE MAY BE UNMASKED WITH THE USE OF YUTOPAR. 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.
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.
Yutopar Injection contains sodium metabisulfite, a sulfite that may cause
allergic-type reactions including anaphylactic symptoms and life- threatening or
less severe asthmatic episodes in certain susceptible people. The overall
prevalence of sulfite sensitivity in the general population is unknown and
probably low. Sulfite sensitivity is seen more frequently in asthmatic than in
nonasthmatic people.
PRECAUTIONS:
When Yutopar is used for the management of preterm labor in a patient with
premature rupture of the membranes, the benefits of delaying delivery should be
balanced against the potential risks of development of chorioamnionitis.
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
reinitiate the administration of Yutopar will depend on an assessment of fetal
maturity. In addition to clinical parameters, other studies, such as sonography
or amniocentesis, may be helpful in establishing the state of fetal maturity if
it is in doubt.
BASELINE EKG
This should be done to rule out occult maternal heart disease.
LABORATORY TESTS
Because intravenous administration of Yutopar has been shown to elevate plasma
insulin and glucose and to decrease plasma potassium concentrations, monitoring
of glucose and electrolyte levels is recommended during protracted infusions.
Decrease of plasma potassium concentrations is usually transient, returning to
normal within 24 hours. Special attention should be paid to biochemical
variables when treating diabetic patients or those receiving potassium-depleting
diuretics.
Serial hemograms may be helpful as an index of state of hydration.
DRUG INTERACTIONS
Corticosteroids used concomitantly may lead to pulmonary edema. (See WARNINGS.)
Cardiovascular effects of Yutopar Injection (especially cardiac arrhythmia or
hypotension) may be potentiated by concomitant use of the following drugs:
1. magnesium sulfate
2. diazoxide
3. meperidine
4. potent general anesthetic agents
Systemic hypertension may be exaggerated in the presence of parasympatholytic
agents such as atropine.
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
intravenous administration, 90% of the excretion of Yutopar is completed within
24 hours after the dose. (See ACTIONS/CLINICAL PHARMACOLOGY.)
Beta-adrenergic blocking drugs inhibit the action of Yutopar, coadministration
of these drugs should, therefore, be avoided.
With anesthetics used in surgery, the possibility that hypotensive effects may
be potentiated should be considered.
MIGRAINE HEADACHE
Transient cerebral ischemia associated with beta sympathomimetic therapy has
been reported in two patients with migraine headache.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
In rats given oral doses of 1, 10, and 150 mg/kg/day of ritodrine hydrochloride
for 82 weeks, benign and malignant tumors were found in the various dosage
groups. Since there were no important differences between untreated controls and
treated groups and no dose-related trends, it was concluded that there was no
evidence of tumorigenicity. The incidence (2-4%) of tumors of the type found in
this study is not unusual in this species.
Reproduction studies in rats and rabbits have revealed no evidence of impaired
fertility due to ritodrine hydrochloride.
PREGNANCY
Teratogenic Effects
(Pregnancy Category B)
Reproduction studies were performed in rats and rabbits. The doses employed
intravenously were 1/9 (1 mg/kg), 1/3 (3 mg/kg), and 1 (9 mg/kg) times the
maximum human daily intravenous dose (but given to the animals as a bolus rather
than by infusion). The oral doses, 10 and 100 mg/kg represented 5 and 50 times
the maximum human daily oral maintenance dose. The results of these studies have
revealed no evidence of impaired fertility or harm to the fetus due to ritodrine
hydrochloride.
No adverse fetal effects were encountered when single intravenous doses of 1, 3,
and 9 mg/kg/day or oral doses of 10 and 100 mg/kg/day were given to rats and
rabbits on Days 6 through 15 and 6 through 18 of gestation, respectively.
Intravenous doses of 1 and 8 mg/kg/day or oral doses of 10 and 100 mg/kg/day
administered to the mother from Day 15 of pregnancy to Day 21 postpartum did not
affect perinatal or postnatal development in rats. A slight increase in fetal
weight in the rat was observed. Oral administration to both sexes did not impair
fertility or reproductive performance. Lethal doses to pregnant rats did not
cause immediate fetal demise. There are no adequate and well- controlled studies
of Yutopar effects in pregnant women before 20 weeks gestation; THEREFORE, THIS
DRUG SHOULD NOT BE USED BEFORE THE 20TH WEEK OF PREGNANCY. Studies of Yutopar
administered to pregnant women from the 20th week of gestation 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 demonstrate a risk of permanent adverse fetal effects from
Yutopar, the possibility cannot be excluded; therefore, Yutopar 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 Yutopar should result in an overall increase in
neonatal survival. Handicapped infants who might not have otherwise survived may
survive.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
Corticosteroids used concomitantly may lead to pulmonary edema. (See WARNINGS.)
Cardiovascular effects of Yutopar Injection (especially cardiac arrhythmia or
hypotension) may be potentiated by concomitant use of the following drugs:
1. magnesium sulfate
2. diazoxide
3. meperidine
4. potent general anesthetic agents
Systemic hypertension may be exaggerated in the presence of parasympatholytic
agents such as atropine.
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
intravenous administration, 90% of the excretion of Yutopar is completed within
24 hours after the dose. (See ACTIONS/CLINICAL PHARMACOLOGY.)
Beta-adrenergic blocking drugs inhibit the action of Yutopar, coadministration
of these drugs should, therefore, be avoided.
With anesthetics used in surgery, the possibility that hypotensive effects may
be potentiated should be considered.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The unwanted effects of Yutopar are related to its betamimetic activity and
usually are controlled by suitable dosage adjustment.
EFFECTS ASSOCIATED WITH INTRAVENOUS ADMINISTRATION
Usual Effects (80-100% Of Patients)
Intravenous infusion of Yutopar 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 per 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.)
Yutopar infusion is associated with transient elevation of blood glucose and
insulin, which decreases toward normal values after 48 to 72 hours despite
continued infusion. Elevation of free fatty acids and cAMP has been reported.
Reduction of potassium levels should be expected; other biochemical effects have
not been reported.
Frequent Effects (10-50% Of Patients)
Intravenous Yutopar, in about one-third of the patients, was associated with
palpitation. Tremor, nausea, vomiting, headache, or erythema was observed in 10
to 15% of patients.
Occasional Effects (5-10% Of Patients)
Nervousness, jitteriness, restlessness, emotional upset, or anxiety was reported
in 5 to 6% of patients and malaise in similar numbers.
Infrequent Effects (1-3% Of Patients)
Cardiac symptoms including chest pain or tightness (rarely associated with
abnormalities of ECG) and arrhythmia were reported in 1 to 2% of patients. (See
WARNINGS.)
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) HAS ALSO BEEN REPORTED INFREQUENTLY
(LESS THAN 1%) WITH THE USE OF RITODRINE AND OTHER BETA SYMPATHOMIMETICS.
Enlargement of the salivary glands and an increased amylase secretion, with a
complete recovery within several days of discontinuation of ritodrine treatment,
have been reported infrequently.
There have been cases of leukopenia and/or agranulocytosis reported in patients
who have received Yutopar (ritodrine HCl) for management of preterm labor. These
cases occurred in conjunction with intravenous infusion for 2 to 3 weeks or
more. Leukocyte count spontaneously returned to normal after cessation of
therapy in all patients. Some patients were also receiving indomethacin and
magnesium sulfate as concomitant medication. At present, there has been no
elucidation of the mechanism of this adverse event.
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.
OVERDOSAGE:
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. When symptoms
of overdose occur as a result of intravenous administration, ritodrine should be
discontinued; an appropriate beta-blocking agent may be used as an antidote.
Ritodrine hydrochloride is dialyzable.
Acute intravenous toxicity was studied in rats and rabbits and acute oral
toxicity in mice, rats, guinea pigs, and dogs. The LD50 values in the most
sensitive of the species used were 64 mg/kg intravenously in the nonpregnant
rabbit and 540 mg/kg orally in the nonpregnant mouse. The intravenous LD50 value
in the pregnant rat was 85 mg/kg. The amount of drug required to produce
symptoms of overdose in humans is individually variable. No reports of human
mortality due to overdose have been received.
DOSAGE AND ADMINISTRATION:
The optimum dose of Yutopar is determined by a clinical balance of uterine
response and unwanted effects.
INTRAVENOUS THERAPY
Do not use intravenous Yutopar if the solution is discolored or contains any
precipitate or particulate matter.
Yutopar Injection should be used promptly after preparation, but in no case
after 48 hours of preparation.
Method Of Administration: To minimize the risks of hypotension, the patient
should be maintained in the left lateral position throughout infusion and
careful attention given to her state of hydration, but 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 IV microdrip chamber
(60 drops/mL) can provide a convenient range of infusion rates within the
recommended dose range for Yutopar.
Recommended Dilution: 150 mg ritodrine hydrochloride in 500 mL fluid yielding a
final concentration of 0.3 mg/mL*. Ritodrine for intravenous infusion should be
diluted with 5% w/v dextrose solution. Because of the increased probability of
pulmonary edema, saline diluents such as:
-- 0.9% w/v sodium chloride solution
-- compound sodium chloride solution (Ringer's solution)
-- and Hartmann's solution, should be reserved for cases where dextrose solution
is medically undesirable, e.g., diabetes mellitus.
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* In those cases where fluid restriction is medically desirable, a more
concentrated solution may be prepared.
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Intravenous therapy should be started as soon as possible after diagnosis. The
usual initial dose is 0.05 mg/minute (0.17 mL/min, 10 drops/min using a
microdrip chamber at the recommended dilution), to be gradually increased by
0.05 mg/min (0.17 mL/min, 10 drops/min using a microdrip chamber at the
recommended dilution) every 10 minutes until the desired result is obtained, OR
THE MATERNAL HEART RATE REACHES 130 BEATS PER MINUTE. The effective dosage
usually lies between 0.15 and 0.35 mg/minute (0.50 to 1.17 mL/min, 30-70
drops/min using a microdrip chamber at the recommended dilution).
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. If other drugs need to be given intravenously, the use of
"piggyback" or other site of intravenous administration permits the continued
independent control of the rate of infusion of the Yutopar.
The infusion should generally be continued for between 12 and 24 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 IV FLUIDS ADMINISTERED AND THE RATE OF ADMINISTRATION SHOULD BE
MONITORED TO AVOID CIRCULATORY FLUID OVERLOAD (OVER-HYDRATION). (SEE
PRECAUTIONS, LABORATORY TESTS.)
Recurrence of unwanted preterm labor may be treated with repeated infusion of
Yutopar.
ORAL DOSAGE :- Oral therapy is to be initiated minimum 30 mts before termination of parentral therapy. FOR FIRST 24 HRS 1 TAB EVERY 2 HRS., THEN 1-2 TAB EVERY 4-6 HRS TOTAL DAILY DOSE SHOULD NOT EXCEED 120 MG.
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