RETO
COMPOSITION
Each Tablet contains:
Ritodrine Hydrochloride USP 10mg
INTRODUCTION:
Ritodrine is a tocolytic drug,belongs to beta-2 adrenergic receptor agonist - a class of medication used for smooth muscle relaxation used to stop premature labor. It is available in oral tablets or as an injection, and is typically used as the hydrochloride salt, ritodrine hydrochloride. Ritodrine is approved by US FDA as tololytic agent in 1980.
PHARMACOLOGY:
PHARMACODYNAMIC
The uterus has beta-2 adrenergic
receptors. Stimulation of these beta-2 receptors by Ritodrine causes the
muscles of the uterus to relax. In premature labour, when Ritodrine is given it
reduces the intensity & frequency of uterine contractions, allowing the
pregnancy to prolong.
Ritodrine is beta-adrenergic
agonist, it stimulate beta-2 adrenergic receptor, increases cAMP level and
decreases of calcium concentration leads to a relaxation of uterine smooth
muscle.
Since ritodrine has a bulky
N-substituent, it has high β2-selectivity. Also, the 4'-hydroxy on the benzene
ring is important for activity as it is needed to form hydrogen bonds. However,
the 4'-hydroxy makes it susceptible to metabolism by COMT. Since it is
β2-selective it is used for premature labor.
PHARMACOKINETICS
Absorption: Not Available
Toxicity (Overdose): LD50=64mg/kg (mice, IV); LD50=540 mg/kg (mice, oral); LD50=85 mg/kg (rat, IV)
Protein Binding: ~56%
Biotransformation: Hepatic, by both the mother and fetus
Half Life: 1.7-2.6 hours
Toxicity (Overdose): LD50=64mg/kg (mice, IV); LD50=540 mg/kg (mice, oral); LD50=85 mg/kg (rat, IV)
Protein Binding: ~56%
Biotransformation: Hepatic, by both the mother and fetus
Half Life: 1.7-2.6 hours
INDICATIONS:
Management of Uncomplicated
Premature Labour
DOSAGE:
By intravenous infusion (important:
minimum fluid volume, see below), initially 50 micrograms/minute,
increased gradually according to response by 50 micrograms/minute every 10
minutes until contractions stop or maternal heart rate reaches 140 beats per
minute; continue for 12–48 hours after contractions cease (usual rate
150–350 micrograms/minute); max. rate 350 micrograms/minute; or by intramuscular injection, 10 mg every 3–8 hours
continued for 12–48 hours after contractions have ceased; then by
mouth (but see notes above), 10 mg 30 minutes before termination of
intravenous infusion, repeated every 2 hours for 24 hours, followed by
10–20 mg every 4–6 hours, max. oral dose 120 mg daily
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.
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.
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%).
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 Ritodrine 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.
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 Ritodrine 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.
CONTRAINDICATIONS:
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.
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
- Pregnancy: Teratogenicity:
Studies have
been performed in pregnant rats and rabbits at daily oral dose up to 15 and 30
mg/kg/day, respectively and have revealed no evidence of impaired fertility or
harm to the fetus. There are however, no adequate and well control tests
carried out in pregnant women, the drug, should therefore be used in pregnancy
only if clearly indicated.
- Nursing Mothers:
Ondansetron is
excreted in the breast milk of rats. It is not known whether ondansetron is
excreted in human milk, caution should be exercised when ondansetron is
administered to a nursing woman.
- Pediartic Use:
Little
information is available about dosage in pediatric patients 4 years of age or
younger.
- Geriartic Use:
Of the total
number of subjects enrolled in the cancer chemotherapy induced and post
operative nausea and vomiting clinical trials, no overall differences in the
safety and effectiveness were observed in young and geriartic (over 65years)
subjects. Dose adjustment in not needed in patients over the age of 65 years.
