OBJECTIVES. Unsolicited reports regarding potentially serious adverse drug reactions in neonates and young infants were reported to the Food and Drug Administration, leading to changes in the package label for ceftriaxone. This report describes and summarizes the reported cases that led to safety concerns regarding the concurrent administration of intravenous ceftriaxone and calcium in this age group.
METHODS. Nine reported cases were assessed. The Food and Drug Administration Adverse Event Reporting System database was searched for potential drug interactions in patients who were receiving concomitant ceftriaxone and calcium therapy.
RESULTS. Eight of the reported 9 cases (7 were ≤2 months of age) represented possible or probable adverse drug events. There were 7 deaths. None of the cases were reported from the United States. The dosage of ceftriaxone that was administered to 4 of 6 infants for whom this information was available was between 150 and 200 mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot be accurately determined from available data.
CONCLUSIONS. The concurrent use of intravenous ceftriaxone and calcium-containing solutions in the newborn and young infant may result in a life-threatening adverse drug reaction. Contributing factors for infants in this report may include the use of ceftriaxone at dosages higher than those approved by the Food and Drug Administration, intravenous “push” administration, and administration of the total daily dosage as a single infusion.
On September 11, 2007, the US Food and Drug Administration (FDA) issued an alert that highlighted important revisions to the prescribing information for ceftriaxone (Rocephin; Roche Pharmaceuticals, Nutley, NJ) for young infants. This Information for Healthcare Professionals addressed the interaction between ceftriaxone and calcium-containing products on the basis of reports of fatal cases in neonates. The alert stated that this information was based on postmarketing reports of 5 neonatal deaths related to the interaction between ceftriaxone and calcium-containing products submitted to the FDA by Roche Pharmaceuticals, the manufacturer of Rocephin, and 4 additional postmarketing reports of interactions between ceftriaxone and calcium-containing products in patients up to 1 year of age received by FDA since Rocephin was approved in 1984.1 As of August 2007, the Rocephin product label contraindicates the co-administration of ceftriaxone with calcium-containing intravenous solutions, including calcium-containing infusions such as parenteral nutrition, in neonates (<28 days of age) because of the risk for precipitation of ceftriaxone-calcium salt.2
On November 30, 2006, the French Health Products Safety Agency issued a warning letter to French medical practitioners regarding incompatibilities between ceftriaxone and calcium-containing solutions that led to a modification in the product label. The letter stated that a fatal report in 2002 had led to a national pharmacovigilance investigation, and on the basis of the findings of this investigation, the product label had been modified.3
The purpose of this communication is to summarize these reports and to increase the awareness of clinicians regarding this potentially lethal adverse effect. Unusual or uncommon adverse events after drug therapy are most likely to be observed by clinicians in medical practice. Their observations and reports serve as a reminder of the critical role that health care professionals play in communicating postmarketing safety events of concern to regulatory agencies that are charged with monitoring and updating the safety of approved drugs.
MedWatch, the FDA Safety Information and Adverse Event Reporting Program, serves both health care professionals and the medical product–using public and provides safety information involving medical products, including prescription and over-the-counter drugs, biologics, medical and radiation-emitting devices, and special nutritional products (eg, medical foods, dietary supplements, infant formulas). MedWatch allows health care professionals and consumers to report serious reactions, product quality problems, therapeutic inequivalence/failure, and product use errors that they suspect are associated with the drugs and medical devices that they prescribe, dispense, or use.4 In addition, drug manufacturers are required to report to FDA adverse drug experience information that they receive from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiologic/surveillance studies, reports in the scientific literature, and unpublished scientific papers.5 The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's postmarketing safety surveillance program for all approved drugs and therapeutic biological products.
The 8 cases described herein were unsolicited, voluntary reports from health care professionals that were submitted to the FDA by the manufacturers of ceftriaxone under the mandatory reporting requirements. The ninth case included in the FDA alert is not included in this report because a follow-up autopsy report suggested that the infant died of pneumonia and sepsis with disseminated intravascular coagulation. The reporter, however, did not rule out the possibility of intravascular precipitates as a result of ceftriaxone and calcium gluconate.
Drug interaction searches in the AERS database were conducted to identify reports in which both calcium chloride and calcium gluconate were listed as either a suspect or a concomitant product associated with ceftriaxone administration. These searches were conducted across the entire database without qualifiers and, therefore, included patients of any age. Searches were also conducted of calcium-containing solutions, including Ringer's injection, lactated Ringer's, Plasma-Lyte R, Isolyte-R, Plasma-Lyte M, Calphosan, and Hartmann's solution. A separate search was conducted for all adverse event reports received with ceftriaxone in patients up to 2 months of age to ensure that no reports were missed as a result of variations in reporting and coding.
The reports described 8 neonates and young infants, most younger than 2 months, who experienced apparent cardiorespiratory arrest while receiving the combination of ceftriaxone and calcium. No cases have been reported from the United States. These infants were being treated for a variety of infections. Seven neonates died. Information about underlying diseases, doses of drugs administered, drug infusion times, and other concurrent drug therapies was often incomplete in these adverse event reports. Limited information was available from the postmortem examinations that were conducted of 5 infants. The cases are outlined in Table 1.
All infants received intravenous ceftriaxone, with dosages of 200 mg/kg per day administered to 3 of 6 infants for whom a dosage was reported. For 2 of the 3 infants who received this dosage, the total daily dosage was given once daily. Five of the infants were reported to be preterm, with the youngest born at 30 weeks' gestation. The chronological ages of the infants at the time they received ceftriaxone ranged from 1 day to 50 days. At least 3 of the infants had received multiple doses of ceftriaxone.
Seven of the 8 infants received intravenous calcium gluconate, and 1 infant received calcium intravenously as part of hyperalimentation. For 1 infant who received calcium gluconate, a white precipitate was noted in the distal end of the intravenous tubing 2 hours after administration of intravenous ceftriaxone, 30 minutes after administration of intravenous calcium gluconate, and during intravenous amikacin administration. The infant's nurse cleared the tubing by “pushing” the precipitate into the infant, which was immediately followed by cardiopulmonary arrest, with a white precipitate noted in the pulmonary artery at autopsy. No analysis was performed of this precipitate.
The autopsy findings from 4 of the 5 infants for whom information was available documented the presence of “crystalline” material or white precipitate in vascular beds, most often in the lungs. No analysis of the crystalline material was performed in any of these cases.
Ceftriaxone was first approved in the United States in 1984 under the trade name Rocephin.2 The product label states that safety and effectiveness of Rocephin in neonates, infants, and pediatric patients have been established. The current, updated product label specifically contraindicates the co-administration of Rocephin with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, in neonates because of the risk for precipitation of ceftriaxone-calcium salt.2
These cases were collected through a passive surveillance reporting system (eg, voluntary reporting). The number of ceftriaxone treatment courses that have been administered to infants who were younger than 2 months is not known; therefore, the number of young infants who have received the combination of ceftriaxone and calcium cannot also be determined. In addition, the actual number of cardiopulmonary events in young infants that are related to ceftriaxone and calcium is unknown. Reporting rates (ie, number of cardiopulmonary event reports in infants per total ceftriaxone prescriptions) can be used to assess the magnitude of the problem; however, because of underreporting and possibly selective reporting, reporting rates do not provide an accurate estimate of incidence that would allow clinicians to put risks and benefits of ceftriaxone therapy into a clinically relevant perspective. Reporting rates, however, do provide some context (association) for the number of adverse events reported with the amount of drug use. It is expected that adverse event reports are proportional to use, particularly in the first few years of marketing. Because these events can be lethal and relatively equivalent antimicrobial agents are available, it is prudent to approach the risk/benefit assessment conservatively.
Several aspects of the reported cases deserve comment. To our knowledge, the dosage of ceftriaxone provided to some infants, 200 mg/kg once daily, is greater than that evaluated for any age group by Roche Laboratories and pediatric investigators in the United States. Current package labeling for all age groups advises a dosage of 50 to 75 mg/kg per day, either every 24 hours or divided every 12 hours for infections other than meningitis. For meningitis, the approved dosage is 100 mg/kg per day.2
Ceftriaxone is known to form precipitates when administered with calcium-containing solutions such as Ringer's Lactate.6,7 The current product label states that ceftriaxone should not be used with diluents that contain calcium, such as Ringer's solution or Hartmann's solution, because particulate formation can result.2 It is biologically plausible, however, to assume that ceftriaxone given to a young infant at higher than a routinely prescribed dose and administered intravenously together with a calcium-containing solution could also cause precipitate formation. These calcium precipitates might act as emboli, resulting in vascular spasm or infarction. It is this precaution that is being shared with clinicians.
In some of the reported cases, ceftriaxone was administered by intravenous “push” over 2 to 4 minutes, rather than by a more prolonged intravenous infusion of 30 minutes as recommended in the product label. Ceftriaxone administration by rapid intravenous infusion, particularly at the highest dosages reported in this case series, will result in transiently high serum concentrations and might also contribute to formation of calcium-ceftriaxone salts. Precipitate formation was noted to occur when both ceftriaxone and intravenous calcium were infused simultaneously, as well as when given at different time intervals. These observations suggest that, in certain infants, the serum concentration of ceftriaxone may be sufficiently high for hours after infusion to interact with subsequently administered intravenous calcium. It is also not known whether neonates are particularly susceptible to this cardiopulmonary event as a result of the greater tone and reactivity noted in the neonatal pulmonary circulation, compared with older children.8
It is noteworthy that no cases have been reported from the United States. Many explanations are possible, such as the preferential use of other third-generation cephalosporins (eg, cefotaxime) for neonates in the United States,9–11 the use of lower dosages of ceftriaxone in the United States than those reported in these cases from Europe, differences in passive reporting between the United States and Europe, differences in calcium formulations and other concurrent drugs administered to neonates, or differences in the manner in which multiple drugs are infused (eg, sequentially versus simultaneously through a “Y” connector). It is not known which, if any of these possibilities, singly or in combination, are relevant to the occurrence of the lethal cardiorespiratory event or whether other currently unidentified risk factors may also be responsible for this adverse event.
Other intravenously administered third-generation cephalosporin antimicrobial agents with a spectrum of activity similar to ceftriaxone are FDA approved for use in neonates and should be considered preferred agents for intravenous use in this age group. It is not known whether the risk for precipitate formation occurs with other antibacterial agents, particularly when used in extremely high dosages, infused rapidly, or administered with intravenous calcium.
On the basis of these reports, children who are older than 2 to 3 months might be less likely to experience these cardiorespiratory complications; however, reasonable caution should be exercised when using the combination of intravenously administered ceftriaxone and calcium in older age groups. For any age group, crystalline material in the intravenous tubing may present a risk and should not be pushed into the child.
Risk for complications after the administration of oral calcium and intramuscular ceftriaxone may exist, but it remains to be defined. No cases have been reported with oral calcium administration or after intramuscular ceftriaxone injection, suggesting that the risk for calcium-ceftriaxone precipitation may be less under these conditions. Neither milk nor oral calcium supplementation is likely to create the same transient serum concentrations in the young infant as intravenously administered calcium. Similarly, the peak serum concentrations of ceftriaxone after intramuscular injection are lower than those achieved after intravenous administration of an equivalent dosage; therefore, the risk for complications from intravascular precipitation is likely to be less than the risk after intravenous injection, particularly rapid intravenous push administration. The use of intramuscular ceftriaxone in an FDA-approved dosage in situations in which intravenous access may be difficult or for daily outpatient parenteral therapy should not be associated with risks that would outweigh the benefits of ceftriaxone, particularly when intravenous calcium gluconate is not being co-administered.
When considering antibacterial treatment for any neonate or infant, the risks and benefits of therapy should be individually assessed, on the basis of the most likely pathogen(s), site of infection, seriousness of infection, comorbidities, and available safety and efficacy data for dosages considered for use. These 8 cases provide additional information for those who treat neonates and young infants regarding a potentially lethal adverse event that may occur after the concurrent use of intravenous ceftriaxone and calcium. Ceftriaxone administered in dosages ≤100 mg/kg per day, by the intramuscular route, with oral calcium supplements, seem less likely to create the conditions that are associated with the serious events reported in these 8 infants. No contraindication to the use of ceftriaxone exists in these situations, but increased vigilance for possible adverse events is prudent.
Reporting of suspected adverse events is a critical mechanism to collect safety data after FDA drug approval and after widespread use and may be 1 of few ways to identify very low frequency serious adverse events. The AERS is a computerized information database designed to support the FDA's postmarketing safety surveillance program for all approved drug and therapeutic biological products. The FDA receives adverse drug reaction reports from manufacturers as required by regulation (85%–90% of reports). Health care professionals and consumers send reports voluntarily through the MedWatch program (10%–15% of reports). The database includes both foreign and domestic reports. The main utility of a spontaneous reporting system such as AERS is to provide signals of potential drug safety issues. Hence, when considering counts of cases generated from AERS, it should be realized that accumulated case reports cannot be used to calculate incidence or estimates of drug risk for a particular product, because reporting of adverse events is a voluntary process and underreporting is likely to exist.
Clinicians are encouraged to take the time to report suspect adverse events through the FDA's MedWatch Program (www.fda.gov/medwatch/ or 1-800-FDA-1088) to ensure the ongoing safety of drugs and to allow the most appropriate and informed decisions regarding the benefits and risks of therapy for children.
With ongoing investigation of the submitted reports from Europe, it is now known that one of the cases was reported independently by two sources. These two reports were submitted 6 months apart, citing two different ages at the time of the adverse event, one at 3 weeks of age (correct), and the other at 2 months of age (incorrect). In the Table, Cases 4 and 7 represent the same infant. Therefore, our corrected report now describes 7 infants total. Of the 6 infants who died, age-at-event data were reported in 5; all were 3 weeks of age or younger. Our conclusions regarding potential risks remain unchanged.
- Accepted December 17, 2008.
- Address correspondence to John S. Bradley, MD, 3020 Children's Way, Mail Code 5041, San Diego, CA 92123. E-mail:
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Food and Drug Administration.
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
The package label for ceftriaxone was changed in August 2007 to contraindicate the co-administration of ceftriaxone with calcium-containing intravenous solution.
What This Study Adds
The cases reported to the FDA and the FDA AERS database search are provided and discussed to provide clinicians the basis for these new precautions.
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- Copyright © 2009 by the American Academy of Pediatrics