3000791-B

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Pitocin PI 3/26/07-+Prescribing Information as of March 2007.

Pitocin'"(Oxytocin Injection, USP) Synthetic

3000791-8

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DESCRIPTIONPitocin (oxytocin injection, USP) is a ster-ile, clear, colorless aqueous solution ofsynthetic oxytocin, for intravenous infu-sion or intramuscular injection. Pitocin is anonapeptide found in pituitary extractsfrom mammals. It is standardized to con-tain10 units of oxytocic hormone/mL andcontains 0.5% Chlorobutanol, a chloro-form derivative as a preservative, with thepH adjusted with acetic acid. Pitocin maycontain up to 16% of total impurities. Thehormone is prepared synthetically toavoid possible contamination with vaso-

pressin (ADH) and other smallpolypeptides with biologic activity. Pitocinhas the empirical formula C43HooN12012S,

(molecular weight 1007.19). The structur-al formula is as follows:I I

H-Cys- Tyr-lle-Glu (NH2l- Asp(NH2)-Cys-Pro-Leu-Gly-NH2123456789

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CLINICAL PHARMACOLOGYUterine motility depends on the forma-tion of the contractile proteinactomyosin under the influence of theCa"-dependent phosphorylating enzymemyosin light-chain kinase. Oxytocin pro-motes contractions by increasing theintracellular Ca". Oxytocin has specificreceptors in the myometrium and thereceptor concentration increases greatlyduring pregnancy, reaching a maximumin early labor at term. The response to agiven dose of oxytocin is very individual-ized and depends on the sensitivity ofthe uterus, which is determined by theoxytocin receptor concentration.However, the physician should be awareof the fact that oxytocin even in its pureform has inherent pressor and antidiuret-ic properties which may becomemanifest when large doses are adminis-tered. These properties are thought tobe due to the fact that oxytocin and

vasopressin differ in regard to only twoof the eight amino acids (see PRECAU-TIONS section).Oxytocin is distributed throughout theextracellular fluid. Small amounts of thedrug probably reach the fetal circulation.Oxytocin has a plasma half-life of about1 to 6 minutes which is decreased in latepregnancy and during lactation.Following intravenous administration ofoxytocin, uterine response occursalmost immediately and subsides within1 hour. Following intramuscular injectionof the drug, uterine response occurs

within 3 to 5 minutes and persists for 2I

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J 3000791-B Pitocin PI 3/26/07Oxytocin has a plasma half-life of about1 to 6 minutes which is decreased in latepregnancy and during lactation.Following intravenous administration ofoxytocin, uterine response occursalmost immediately and subsides within1 hour. Following intramuscular injectionof the drug, uterine response occurs

within 3 to 5 minutes and persists for 2to 3 hours. Its rapid removal from plasmais accomplished largely by the kidney

and the liver. Only small amounts areexcreted in urine unchanged.INDICATIONS AND USAGE

IMPORTANT NOTICE

Elective induction of labor is defined asthe initiation of labor in a pregnant indi-vidual who has no medical indicationsfor induction. Since the available data

are inadequate to evaluate the benefits-to-risks considerations, Pitocin is notindicated for elective induction of labor.

Antepartum: Pitocin is indicated for theinitiation or improvement of uterine con-tractions, where this is desirable andconsidered suitable for reasons of fetalor maternal concern, in order to achievevaginal delivery. It is indicated for (1)

induction of labor in patients with a med-ical indication for the initiation of labor,such as Rh problems, maternal diabetes,preeclampsia at or near term, when

delivery is in the best interests of moth-er and fetus or when membranes areprematurely ruptured and delivery is indi-cated; (2) stimulation or reinforcement oflabor, as in selected cases of uterineinertia; (3) as adjunctive therapy in themanagement of incomplete or inevitableabortion. In the first trimester, curettageis generally considered primary therapy.In second trimester abortion, oxytocininfusion will often be successful in emp-tying the uterus. Other means oftherapy, however, may be required insuch cases.Postpartum: Pitocin is indicated to pro-duce uterine contractions during thethird stage of labor and to control post-partum bleeding or hemorrhage.CONTRAINDICATIONSAntepartum use of Pitocin is contraindi-cated in any of the followingcircumstances:1. Where there is significant

cephalopelvic disproportion;2. In unfavorable fetal positions or pre-

sentations, such as transverse lies,which are undeliverable without con-version prior to delivery;

3. In obstetrical emergencies where thebenefit-to-risk ratio for either thefetus or the mother favors surgicalintervention;

4. In fetal distress where delivery is notimminent;

5. Where adequate uterine activity failsto achieve satisfactory progress;

6. Where the uterus is already hyperac-tive or hypertonic;

7. In cases where vaginal delivery iscontraindicated, such as invasive cer-vical carcinoma, active herpesgenitalis, total placenta previa, vasaprevia, and cord presentation or pro-lapse of the cord;

8. In patients with hypersensitivity to

the drug.

WARNINGSPitocin, when given for induction of laboror augmentation of uterine activity,should be administered only by the intra-venous route and with adequate medicalsupervision in a hospitaL.

PRECAUTIONSGeneral1. All patients receiving intravenous

oxytocin must be under continuousobservation by trained personnel who

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should be administered only by the intra-venous route and with adequate medicalsupervision in a hospitaL.

PRECAUTIONSGeneral1. All patients receiving intravenous

oxytocin must be under continuousobservation by trained personnel whohave a thorough knowledge of thedrug and are qualified to identify com-plications. A physician qualified tomanage any complications should beimmediately available. Electronic fetalmonitoring provides the best meansfor early detection of overdosage

(see OVERDOSAGE section).However, it must be borne in mind

that only intrauterine pressure record-ing can accurately measure theintrauterine pressure during contrac-tions. A fetal scalp electrode providesa more dependable recording of thefetal heart rate than any external

monitoring system.2. When properly administered, oxytocin

should stimulate uterine contractions

comparable to those seen in normal

labor. Overstimulation of the uterus byimproper administration can be haz-

ardous to both mother and fetus. Evenwith proper administration and ade-

quate supervision, hypertoniccontractions can occur in patientswhose uteri are hypersensitive to oxy-tocin. This fact must be considered bythe physician in exercising his judg-

ment regarding patient selection.3. Except in unusual circumstances,

oxytocin should not be administered

in the following conditions: fetal dis-tress, hydramnios, partial placentaprevia, prematurity, borderlinecephalopelvic disproportion, and anycondition in which there is a predispo-sition for uterine rupture, such asprevious major surgery on the cervixor uterus including cesarean section,overdistention of the uterus, grand

multiparity, or past history of uterinesepsis or of traumatic delivery.Because of the variability of the com-binations of factors which may bepresent in the conditions listed above,the definition of "unusual circum-

stances" must be left to thejudgment of the physician. The deci-sion can be made only by carefullyweighing the potential benefits whichoxytocin can provide in a given case

against rare but definite potential forthe drug to produce hypertonicity ortetanic spasm.

4. Maternal deaths due to hypertensive

episodes, subarachnoid hemorrhage,

rupture of the uterus, and fetal deathsdue to various causes have beenreported associated with the use of

parenteral oxytocic drugs for induc-

tion of labor or for augmentation inthe first and second stages of labor.

5. Oxytocin has been shown to have anintrinsic antidiuretic effect, acting toincrease water reabsorption from theglomerular filtrate. Consideration

should, therefore, be given to the pos-sibility of water intoxication,particularly when oxytocin is adminis-tered continuously by infusion and thepatient is receiving fluids by mouth.

6. When oxytocin is used for inductionor reinforcement of already existentlabor, patients should be carefullyselected. Pelvic adequacy must beconsidered and maternal and fetalconditions evaluated before use ofthe drug.

Drug InteractionsSevere hypertension has been reportedwhen oxytocin was given three to fourhours following prophylactic administra-tion of a vasoconstrictor in conjunction

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3000791-B Pitocin PI 3/26/07 11:01 AM Page 1 (1,4)seleC180. /"eivic aoequacy mUST Deconsidered and maternal and fetalconditions evaluated before use ofthe drug.

Drug InteractionsSevere hypertension has been reportedwhen oxytocin was given three to fourhours following prophylactic administra-tion of a vasoconstrictor in conjunction

with caudal block anesthesia.Cyclopropane anesthesia may modifyoxytocin's cardiovascular effects, so as

to produce unexpected results such ashypotension. Maternal sinus bradycardia

with abnormal atrioventricular rhythmshas also been noted when oxytocin wasused concomitantly with cyclopropane

anesthesia.Carcinogenesis, Mutagenesis,Impairment of FertilityThere are no animal or human studies onthe carcinogenicity and mutagenicity ofthis drug, nor is there any information onits effect on fertility.PregnancyTeratogenic EffectsAnimal reproduction studies have notbeen conducted with oxytocin. There areno known indications for use in the firsttrimester of pregnancy other than in rela-tion to spontaneous or induced abortion.Based on the wide experience with thisdrug and its chemical structure and phar-macological properties, it would not beexpected to present a risk of fetal abnor-malities when used as indicated.Nonteratogenic EffectsSee ADVERSE REACTIONS in the fetusor neonate.Labor and DeliverySee INDICATIONS AND USAGE section.ADVERSE REACTIONSThe following adverse reactions havebeen reported in the mother:

Anaphylactic reactionPostpartum hemorrhageCardiac arrhythmiaFatal afibrinogenemiaHypertensive episodesNauseaVomitingPremature ventricular contractionsPelvic hematomaSubarachnoid hemorrhageHypertensive episodesRupture of the uterus

Excessive dosage or hypersensitivity tothe drug may result in uterine hyper-tonicity, spasm, tetanic contraction, orrupture of the uterus.

The possibility of increased blood lossand afibrinogenemia should be kept inmind when administering the drug.Severe water intoxication with convul-sions and coma has occurred,associated with a slow oxytocin infusionover a 24-hour period. Maternal death

due to oxytocin-induced water intoxica-tion has been reported.The following adverse reactions havebeen reported in the fetus or neonate:

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Due to induced uterine motility:BradycardiaPremature ventricular contractionsand other arrhythmias

Permanent CNS or brain damageFetal deathNeonatal seizures have been reported

with the use of Pitocin.Due to use of oxytocin in the mother:

Low Apgar scores at five minutesNeonatal jaundice

Neonatal retinal hemorrhageOVERDOSAGEOverdosage with oxytocin dependsessentially on uterine hyperactivity

whether or not due to hypersensitivity tothis agent. Hyperstimulation with strong(hypertonic) or prolonged (tetanic) con-tractions, or a resting tone of 15 to 20mm H,O or more between contractionscan lead to tumultuous labor, uterine rup-ture, cervical and vaginal lacerations,

postpartum hemorrhage, uteroplacentalhypoperfusion, and variable decelerationof fetal heart, fetal hypoxia, hypercapnia,perinatal hepatic necrosis or death.

Water intoxication with convulsions,which is caused by the inherent antidi-uretic effect of oxytocin, is a serious

complication that may occur if largedoses (40 to 50 milliunits/minute) areinfused for long periods. Managementconsists of immediate discontinuation ofoxytocin and symptomatic and support-ive therapy.DOSAGE AND ADMINISTRATIONParenteral drug products should beinspected visually for particulate matterand discoloration prior to administrationwhenever solution and container permit.The dosage of oxytocin is determined bythe uterine response and must thereforebe individualized and initiated at a verylow leveL. The following dosage informa-tion is based upon various regimens andindications in general use.A. Induction or Stimulation of Labor

Intravenous infusion (drip method) isthe only acceptable method of par-enteral administration of Pitocin forthe induction or stimulation of labor.Accurate control of the rate of infu-sion is essential and is bestaccomplished by an infusion pump. Itis convenient to piggyback the Pitocininfusion on a physiologic electrolytesolution, permitting the Pitocin infu-sion to be stopped abruptly without

interrupting the electrolyte infusion.Ti.:..:.. ......,,:.. ..1... +...11.....:.... ,......I

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~ 3000791-B Pitocin PI 3/26/07 11: 01 AM Page 2 (1,2) L~Ii.. II'......LI\." VI ..L"I'..'..UV', VI il..U..V,.Accurate control of the rate of infu-sion is essential and is bestaccomplished by an infusion pump. Itis convenient to piggyback the Pitocininfusion on a physiologic electrolytesolution, permitting the Pitocin infu-sion to be stopped abruptly without

interrupting the electrolyte infusion.

-i This is done in the following way. r-1. Preparation

a. The standard solution for infu-sion of Pitocin is prepared byadding the contents of one 1-mL vial containing 10 units ofoxytocin to 1000 mL of 0.9%aqueous sodium chloride orRinger's lactate. The combinedsolution containing 10 milliunits(mU) of oxytocin/mL is rotatedin the infusion bottle for thor-

ough mixing.b. Establish the infusion with a

separate bottle of physiologic

electrolyte solution not contain-ing Pitocin.

c. Attach (piggyback) the Pitocin-containing bottle with theinfusion pump to the infusionline as close to the infusion siteas possible.

2. AdministrationThe initial dose should be 0.5-1mU/min (equal to 3-6 mL of thedilute oxytocin solution per hour).

At 30-60 minute intervals the doseshould be gradually increased inincrements of 1-2 mU/min until thedesired contraction pattern hasbeen established. Once the desiredfrequency of contractions has beenreached and labor has progressedto 5- cm dilation, the dose may be

reduced by similar increments.Studies of the concentrations of

oxytocin in the maternal plasma

during Pitocin infusion have shownthat infusion rates up to 6 mU/mingive the same oxytocin levels thatare found in spontaneous labor. Atterm, higher infusion rates should

be given with great care, and ratesexceeding 9-10 mU/min are rarelyrequired. Before term, when thesensitivity of the uterus is lowerbecause of a lower concentration

of oxytocin receptors, a higher

infusion rate may be required.3. Monitoring

a. Electronically monitor the uter-ine activity and the fetal heartrate throughout the infusion ofPitocin. Attention should begiven to tonus, amplitude and

frequency of contractions, andto the fetal heart rate in relationto uterine contractions. If uter-ine contractions become toopowerful, the infusion can beabruptly stopped, and oxytocic

stimulation of the uterine mus-culature will soon wane (seePRECAUTIONS section).

b. Discontinue the infusion ofPitocin immediately in theevent of uterine hyperactivity

and/or fetal distress. Administer

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oxygen to the mother, who

+preferably should be put in a lat-eral position. The condition ofmother and fetus should imme-diately be evaluated by theresponsible physician and Lappropriate steps taken.

B. Control of Postpartum UterineBleeding1. Intravenous infusion (drip method).

If the patient has an intravenous

infusion running, 10 to 40 units ofoxytocin may be added to the bot-tle, depending on the amount ofI ..1,.,,+....1.,+1, ,... rl..v+rr".... ....1,.+;..'"

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3000791-B Pitocin PI 3/26/07 11'Of AM Page 2 (1,3)appropriate steps taken.

B. Control of Postpartum UterineBleeding1. Intravenous infusion (drip method).

If the patient has an intravenous

infusion running, 10 to 40 units ofoxytocin may be added to the bot-tle, depending on the amount ofelectrolyte or dextrose solution

remaining (maximum 40 units to1000 mL). Adjust the infusion rateto sustain uterine contraction and

control uterine atony.

2. Intramuscular administration. (OnemL) Ten (10) units of Pitocin can begiven after the delivery of the pla-

centa.C. Treatment of Incomplete,

Inevitable, or Elective AbortionIntravenous infusion of 10 units of

Pitocin added to 500 mL of a physio-logic saline solution or 5%dextrose-in-water solution may helpthe uterus contract after a suction orsharp curettage for an incomplete,

inevitable, or elective abortion.Subsequent to intra-amniotic injectionof hypertonic saline, prostaglandins,

urea, etc., for midtrimester elective

abortion, the injection-to-abortion timemay be shortened by infusion ofPitocin at the rate of 10 to 20 millunits(20 to 40 drops) per minute. The totaldose should not exceed 30 units in a12-hour period due to the risk of waterintoxication.

HOW SUPPLIEDPitocin (Oxytocin Injection, USP)Synthetic is available as follows:NDC 60793-265-25 Packages of twenty-five oversized 1-mL Steri-Vials~, eachcontaining 10 units of oxytocin.NDC 60793-267-01 A 10 mL multiple-doseSteri-VialÐ containing 10 units of oxyocinper mL (total = 100 units of oxyocin).STORAGEStore at 15°-25°C (59°-77°F).REFERENCES1. Seitchik J, Castillo M: Oxytocin aug-

mentation of dysfunctional labor. i.Clinical data. Am J Obstet Gyneco/1982; 144:899-905.

2. Seitchik J, Castillo M: Oxytocin aug-mentation of dysfunctional labor. II.Multiparous patients. Am J ObstetGyneco/1983; 145:777-780.

3. Fuchs A, Goeschen K, Husslein P. etal: Oxytocin and the initiation ofhuman parturition. III. Plasma con-centrations of oxytocin and 13,14-dihydro-15-keto-prostaglandinF2a in spontaneous and oxytocin-induced labor at term. Am J ObstetGyneco/1983; 145:497-502.

4. Seitchik J, Amico J, et al: Oxytocin

augmentation of dysfunctional labor.IV. Oxytocin pharmacokinetics. Am JObstet Gyneco/1984; 150:225-228.

5. American College of Obstetriciansand Gynecologists: ACOG TechnicalBulletin Number 110-November1987: Induction and augmentation

of labor.

Rx only.Prescribing Information as of March 2007.

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Material No 3000805 Rev ASize 3-5/32" x 3-5/32" x 1-25/64"

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Material No 3001083 RevSize 2-13/16" x 1-1/8"

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Contains 0.5% Chlorobutanolchloroform derivative as apreservative. Acidity adjustedwith acetic acid.For Intravenous Infusion orIntramuscular InjectionStore between 15°and 25°C(59° and n°F)Protect from excessive heat.See bottom of carton forlot number and expiration date.

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