ATC Class:B05BC02
VA Class:GU600
Urea 40-50% injections are hypertonic injections that are used as abortifacients.
Although not included in the labeling approved by the US Food and Drug Administration for the commercially available sterile urea preparation (Ureaphil®), injections of 40-50% urea are used by transabdominal intra-amniotic instillation†, in conjunction with continuous IV infusion of oxytocin, to induce abortion late in the second trimester of pregnancy (beyond the 16th week of gestation). Continuous IV infusion of dilute solutions of oxytocin is usually used in conjunction with intra-amniotic hypertonic urea† to shorten the induction-to-abortion time and decrease the incidence of failures. Intra-amniotic dinoprost tromethamine (no longer commercially available in the US) and laminaria tents also have been used as adjuncts to hypertonic urea for these purposes. The mean induction-to-abortion time following administration of usual dosages of intra-amniotic urea† (see Dosage and Administration) with IV oxytocin in second trimester pregnancies is 18-30 hours; abortion occurs in about 80% of patients within 76 hours.
When abortion fails to occur, the presence of uterine malformations or abnormalities (e.g., extrauterine pregnancy, ovarian cyst) should be considered; surgical intervention may be necessary. Oxytocin also has been used to induce abortion when the patient has failed to abort within 24-36 hours of urea and dinoprost administration. Additional infusion of dilute oxytocin solution or curettage may be used if the placenta fails to abort spontaneously within 1 hour after delivery of the fetus; however, some clinicians maintain that oxytocin may hinder, rather than assist in, expulsion of the placenta. Because concurrent use of urea and oxytocin may produce uterine contractions of such intensity that cervical laceration may be more likely to occur, patients should be carefully monitored.
For inducing second trimester abortions between the 12th and 16th week of gestation, most clinicians recommend dilatation and evacuation or intravaginal dinoprostone. Because the amount of amniotic fluid is small in relation to the size of the fetus and uterus between the 12th and 16th week of gestation, amniocentesis and subsequent intra-amniotic instillation of hypertonic urea may be difficult and technical failure may result. However, abortion should not be deferred until after the 16th week for purposes of administering intra-amniotic abortifacients.
Although some clinicians recommend dilatation and evacuation or, as a second choice, hypertonic abortifacients for abortions beyond the 16th week of gestation, other clinicians have preferred intra-amniotic dinoprost tromethamine, but the latter agent is no longer commercially available in the US. One multicenter study showed that when inducing second trimester abortions beyond 16-weeks' gestation, dilatation and evacuation was associated with a lower incidence of major complications than were the intra-amniotic abortion methods; however, these results may reflect the fact that physicians performing dilatation and evacuation procedures in this study were more skilled than are most physicians performing such procedures. Conflicting reports have shown that, when used for abortion beyond 16-weeks' gestation, the incidence of major complications with intra-amniotic dinoprost was greater than or less than intra-amniotic instillation of 20% sodium chloride injection. In addition, the fact that prostaglandin abortifacients, unlike hypertonic abortifacients, are not feticidal and some live births may occur late in the second trimester should be considered. Although use of intra-amniotic urea† (augmented with IV oxytocin) is associated with higher failure rates and longer induction-to-abortion times than is intra-amniotic hypertonic sodium chloride, some clinicians believe hypertonic urea may produce a lower incidence of life-threatening adverse effects and may be safer than hypertonic sodium chloride in high-risk patients (i.e., those with cardiac, renal, or hypertensive disease).
For information on the osmotic diuretic and topical uses of urea see Urea 40:28.12 and 84:28, respectively.
Although not included in the labeling approved by the US Food and Drug Administration for the commercially available sterile urea preparation (Ureaphil®), injections of 40-50% urea are administered intra-amniotically†. Care must be taken to ensure that the drug is administered directly into the amniotic fluid.
To prepare intra-amniotic hypertonic urea injection†, a sufficient volume of 5% dextrose injection is added to 80 g of lyophilized urea (2 commercially available vials) to make 150 or 200 mL of reconstituted solution providing approximately 50% (500 mg/mL) or 40% (400 mg/mL) urea solutions, respectively.
After performing a transabdominal tap of the amniotic sac, at least 1 mL of amniotic fluid is withdrawn and the nature of the fluid is determined. Amniotic fluid can be identified by its pH (7.4) and its ability to fern. If the fluid contains blood or if no amniotic fluid is obtained, the needle should be repositioned. All amniotic fluid (usually 30-250 mL) should then be removed to prevent sudden increases in intra-amniotic pressure when hypertonic urea is instilled and to ensure an adequate intra-amniotic concentration of urea. A solution of 40-50% urea, in volumes equal to the amount of amniotic fluid removed or a maximum of 200-250 mL (usually a total of about 80 g of urea), is then administered slowly over a period of 20-30 minutes while observing the patient for signs and symptoms that may indicate that the drug is not being administered into the amniotic fluid.(See Cautions: Precautions and Contraindications.) If adverse reactions occur at any time during administration of the drug, it should be discontinued and the condition of the patient and placement of the needle or catheter evaluated. Concurrent IV infusion of a dilute solution of oxytocin usually is started within 1-2 hours of urea instillation, generally at a rate of 10-100 milliunits/minute. An additional 80 g of urea may be instilled after 48 hours if uterine contractility, cervical effacement, and/or cervical dilation are inadequate or if the membranes are still intact and abortion does not appear imminent.
In patients who fail to respond to the second dose of hypertonic urea, additional IV infusion of a dilute solution of oxytocin or dilatation and evacuation may be used.
The most frequent adverse reactions of intra-amniotic urea are nausea and vomiting. Headaches and, rarely, diarrhea also may occur.
Cervical laceration and perforation have occurred during hypertonic urea-induced abortion. These effects have occurred in primigravida patients and in those receiving concomitant IV oxytocin and intra-amniotic hypertonic urea. Placentas may be retained in some patients undergoing abortion with hypertonic urea; when abortion is delayed, the risk of retained placenta with resultant hemorrhage, fever, and infection, including endometritis, is increased.
Coagulation changes, including decreases in platelet counts and levels of fibrinogen, have occurred following intra-amniotic instillation of hypertonic urea but less frequently than with hypertonic sodium chloride. The risk of hemorrhage caused by coagulation defects is virtually nonexistent, but a mild, asymptomatic, self-limiting form of disseminated intravascular coagulation occurs rarely in patients receiving intra-amniotic hypertonic urea.
Precautions and Contraindications
Intra-amniotic instillation of 40-50% urea injection should be performed only by physicians trained in amniocentesis, in a hospital where intensive care and surgical facilities are immediately available. Patients should be informed of the benefits and risks of hypertonic urea-induced abortions. A complete medical history and physical examination should be performed prior to administration of the drug.
When amniocentesis and subsequent intra-amniotic instillation of hypertonic urea are performed correctly, systemic absorption of urea is minimized and there is little risk of systemic effects. However, normal patients should take oral fluids freely during the procedure to prevent dehydration and facilitate urea excretion. Accidental intravascular, myometrial, or intraperitoneal injection of 40-50% urea solutions may produce myometrial necrosis and/or dehydration with secondary vomiting, hyponatremia, and hypokalemia or hyperkalemia. Intra-amniotic instillation of hypertonic urea is usually painless; therefore, instillation of the drug should be discontinued immediately if the patient complains of symptoms, such as lower abdominal pain, that may indicate the drug is not being administered into the amniotic fluid. Early signs of electrolyte depletion, such as muscle weakness or lethargy, may indicate the need for electrolyte supplementation before laboratory determinations confirm reduction of serum electrolyte concentrations. Patients receiving intra-amniotic urea should be monitored for signs of fluid and electrolyte imbalance and appropriate IV fluids should be infused if necessary.
Patients with cervical laceration with resultant retention of the placenta and severe hemorrhage may require blood transfusions. These hazards can be minimized by not administering urea to patients with a history of pelvic adhesions or pelvic surgery resulting in through-and-through uterine incisions. Because cervical trauma can occur without symptoms, each patient should be carefully examined after the abortion is completed to detect any cervical injuries.
Induction of abortion with intra-amniotic hypertonic urea is contraindicated in patients with severely impaired renal function (e.g., oliguric or uremic patients), frank liver failure, active intracranial bleeding, marked dehydration, or with major systemic disorders (e.g., diabetes mellitus, sickle cell anemia).
In one study, aspirin, in doses of 600 mg given with and once every 6 hours after instilling urea intra-amniotically, increased the normal intra-amniotic urea induction-to-abortion time in primigravida patients.
Intra-amniotic instillation of 40-50% urea injection induces abortion and fetal death. Although the mechanism has not been conclusively determined, some studies indicate that the drug's abortifacient activity may be mediated by prostaglandins released from decidual cells damaged by hypertonic solutions of urea. Hypertonic urea, in conjunction with continuous IV infusion of oxytocin, usually produces contractions sufficient to cause evacuation of both the fetus and placenta; however, abortion may be incomplete in 30-40% of patients.
Following intra-amniotic administration of 40-50% urea injection, about 10% of the drug diffuses rapidly into the maternal blood. Urea is distributed into maternal extracellular and intracellular fluids including lymph, bile, CSF, and blood in approximately equal concentrations. Following intra-amniotic instillation of 80 g of urea for midtrimester abortion, maximum mean BUN concentrations of 33-38 mg/dL occur within 4 hours, but BUN concentrations return to normal within 24 hours. The drug is excreted by the kidneys.
Urea, the diamide of carbonic acid, occurs as colorless to white, prismatic crystals or as a white, crystalline powder. The drug is freely soluble in water and soluble in alcohol and has a cooling, saline, unpleasant taste; it is practically odorless but may gradually develop a slight ammoniacal odor on long standing. Sterile urea is a lyophilized powder containing citric acid buffer; sodium hydroxide may be added to adjust the pH. Hypertonic injections used as abortifacients usually contain 40-50% urea and have a pH of 7-7.5. When reconstituted with 5% dextrose injection, a 40 or 50% urea solution has a calculated osmolarity of 6920 or 8586 mOsm/L, respectively.
The endothermic reaction which occurs on dissolution of urea may prolong reconstitution time. To shorten the reconstitution time, the diluent may be warmed in a water bath to a temperature of 60°C immediately before mixing with urea; the reconstituted urea solution should be at body temperature for administration.
Solutions of urea are unstable and cannot be sterilized by heat. Upon standing, heating, or exposure to acids or alkalies, urea is hydrolyzed to ammonia and carbon dioxide. Reconstituted solutions should be used within a few hours if stored at room temperature and within 48 hours if stored at 2-8°C.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.