Ceftriaxone Sodium

(BANM, USAN, rINNM)
Ceftriaxone Sodium Chemical formula
Synonyms: Ceftriakson sodowy; Ceftriaksono natrio druska; Ceftriaxon sodná sůl trihemihydrát; Ceftriaxona sódica; Ceftriaxone sodique; Ceftriaxonnatrium; Ceftriaxon-nátrium; Ceftriaxonum natricum; Ceftriaxonum Natricum Trihemihydricum; Keftriaksoninatrium; Natrii Ceftriaxonum; Ro-139904; Ro-13-9904/000 (ceftriaxone); Seftriakson Sodyum. (Z)-7-[2-(2-Aminothiazol-4-yl)-2methoxyiminoacetamido]-3-[(2,5-dihydro-6-hydroxy-2-methyl5-oxo-1,2,4-triazin-3yl)thiomethyl]-3-cephem-4-carboxylic acid, disodium salt, sesquaterhydrate.
Cyrillic synonym: Натрий Цефтриаксон.

💊 Chemical information

Chemical formula: C18H16N8Na2O7S3,3 H2O = 661.6.
CAS — 73384-59-5 (ceftriaxone); 74578-69-1 (anhydrous ceftriaxone sodium); 104376-79-6 (ceftriaxone sodium sesquaterhydrate).
ATC — J01DD04.
ATC Vet — QJ01DD04.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2

(Ceftriaxone Sodium). A semi-synthetic product derived from a fermentation product. An almost white to yellowish, slightly hygroscopic, crystalline powder. Freely soluble in water; very slightly soluble in dehydrated alcohol; sparingly soluble in methyl alcohol. A 12% solution in water has a pH of 6.0 to 8.0. Store in airtight containers. Protect from light.

USP 31

(Ceftriaxone Sodium). A white to yellowish-orange crystalline powder. Freely soluble in water; very slightly soluble in alcohol; sparingly soluble in methyl alcohol. pH of a 10% solution in water is between 6.0 and 8.0. Store in airtight containers.

Incompatibility.

UK licensed product information warns of incompatibility if ceftriaxone sodium is mixed with calcium-containing solutions or with aminoglycosides, amsacrine, fluconazole, labetalol, or vancomycin. Published reports of incompatibility have included that between ceftriaxone and vancomycin 1 or pentamidine. 2 1. Pritts D, Hancock D. Incompatibility of ceftriaxone with vancomycin. Am J Hosp Pharm 1991; 48: 77. 2. Lewis JD, El-Gendy A. Cephalosporin-pentamidine isethionate incompatibilities. Am J Health-Syst Pharm 1996; 53: 1461–2.

Stability.

References. 1. Nahata MC. Stability of ceftriaxone sodium in peritoneal dialysis solutions. DICP Ann Pharmacother 1991; 25: 741–2. 2. Canton E, Esteban MJ. Stability of ceftriaxone solution. J Antimicrob Chemother 1992; 30: 397–8. 3. Bailey LC, et al. Stability of ceftriaxone sodium in injectable solutions stored frozen in syringes. Am J Hosp Pharm 1994; 51: 2159–61. 4. Plumridge RJ, et al. Stability of ceftriaxone sodium in polypropylene syringes at −20, 4, and 20°C. Am J Health-Syst Pharm 1996; 53: 2320–3.

💊 Adverse Effects and Precautions

As for Cefotaxime Sodium. Changes in bowel flora may be more marked than with cefotaxime because of the greater biliary excretion of ceftriaxone; diarrhoea may occur more often, especially in children. Biliary sludge or pseudolithiasis due to a precipitate of calcium ceftriaxone has been seen occasionally in patients given ceftriaxone. Similarly, deposition of the calcium salt has occurred rarely in the urine. Isolated cases of death in term or premature neonates have been associated with precipitation of calcium ceftriaxone in lungs and kidneys, and in some of these cases a calcium-containing product has been given by a different route or line, or at a different time. US licensed product information therefore contra-indicates the use of ceftriaxone within 48 hours of products or solutions containing calcium, particularly in neonates. Ceftriaxone is highly protein bound and is able to displace bilirubin from albumin binding sites, causing hyperbilirubinaemia; its use should be avoided in jaundiced neonates. Neutropenia has been reported with most cephalosporins; a complex mechanism has been attributed to that associated with ceftriaxone. There have been rare reports of fatal haemolysis associated with ceftriaxone. Although ceftriaxone has an N-methylthiotriazine ring rather than an N-methylthiotetrazole side-chain, it might still have the potential to cause hypoprothrombinaemia.

Breast feeding.

A study of drug distribution and protein binding between maternal blood and breast milk post partum in a 26year-old woman given ceftriaxone 2 g daily by intravenous infusion for 10 days found that penetration of ceftriaxone into breast milk increased at these doses as protein binding capacity was saturated, although no adverse effects occurred in the infant.1 The authors advised caution in breast-feeding mothers given acidic drugs which also have high protein binding such as ceftriaxone1although, on the basis that no adverse effects have been observed in breast-fed infants whose mothers were receiving ceftriaxone, the American Academy of Pediatrics considers2 that it is therefore usually compatible with breast feeding.
1. Bourget P, et al. Ceftriaxone distribution and protein binding between maternal blood and milk postpartum. Ann Pharmacother 1993; 27: 294–7
2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 25/05/04)

Effects on the biliary tract.

Using abdominal ultrasonography, biliary sludge or pseudolithiasis was found in about 40% of severely ill children being treated with high doses of ceftriaxone1and was later reported in adults.2-4 The sludge has been identified as a calcium salt of ceftriaxone.5 Patients are often asymptomatic and the sludge usually dissolves once ceftriaxone is stopped. Gallstones with ceftriaxone as a major component have been identified in a patient given long-term high-dose treatment.6Similarly, a bile-duct stone composed of ceftriaxone occurred with high-dose ceftriaxone in a child.7 In another report, intractable hiccups were associated with ceftriaxone-related pseudolithiasis in a 10-year-old boy.8
1. Schaad UB, et al. Reversible ceftriaxone-associated biliary pseudolithiasis in children. Lancet 1988; ii: 1411–13
2. Pigrau C, et al. Ceftriaxone-associated biliary pseudolithiasis in adults. Lancet 1989; ii: 165
3. Heim-Duthoy KL, et al. Apparent biliary pseudolithiasis during ceftriaxone therapy. Antimicrob Agents Chemother 1990; 34: 1146–9
4. Bickford CL, Spencer AP. Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and review of the literature. Pharmacotherapy 2005; 25: 1389–95
5. Park HZ, et al. Ceftriaxone-associated gallbladder sludge: identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate. Gastroenterology 1991; 100: 1665–70
6. Lopez AJ, et al. Ceftriaxone-induced cholelithiasis. Ann Intern Med 1991; 115: 712–14
7. Robertson FM, et al. Ceftriaxone choledocholithiasis. Pediatrics 1996; 98: 133–5
8. Bonioli E, et al. Pseudolithiasis and intractable hiccups in a boy receiving ceftriaxone. N Engl J Med 1994; 331: 1532.

Effects on the blood.

References.
1. Haubenstock A, et al. Hypoprothrombinaemic bleeding associated with ceftriaxone. Lancet 1983; i: 1215–16
2. Rey D, et al. Ceftriaxone-induced granulopenia related to a peculiar mechanism of granulopoiesis inhibition. Am J Med 1989; 87: 591–2
3. Bernini JC, et al. Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. J Pediatr 1995; 126: 813–15
4. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J Pediatr 1995; 126: 816–17
5. Scimeca PG, et al. Hemolysis after treatment with ceftriaxone. J Pediatr 1996; 128: 163
6. Moallem HJ, et al. Ceftriaxone-related fatal hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection. J Pediatr 1998; 133: 279–81
7. Meyer O, et al. Fatal immune haemolysis due to a degradation product of ceftriaxone. Br J Haematol 1999; 105: 1084–5
8. Viner Y, et al. Severe hemolysis induced by ceftriaxone in a child with sickle-cell anemia. Pediatr Infect Dis J 2000; 19: 83–5
9. Seltsam A, Salama A. Ceftriaxone-induced immune haemolysis: two case reports and a concise review of the literature. Intensive Care Med 2000; 26: 1390–4
10. Citak A, et al. Ceftriaxone-induced haemolytic anaemia in a child with no immune deficiency or haematological disease. J Paediatr Child Health 2002; 38: 209–10.

Effects on the pancreas.

References.
1. Zimmermann AE, et al. Ceftriaxone-induced acute pancreatitis. Ann Pharmacother 1993; 27: 36–7
2. Maranan MC, et al. Gallstone pancreatitis caused by ceftriaxone. Pediatr Infect Dis J 1998; 17: 662–3.

Neonates.

References to the displacement of bilirubin by ceftriaxone in neonates.
1. Gulian J-M, et al. Bilirubin displacement by ceftriaxone in neonates: evaluation by determination of ‘free’ bilirubin and erythrocyte-bound bilirubin. J Antimicrob Chemother 1987; 19: 823–9
2. Fink S, et al. Ceftriaxone effect on bilirubin-albumin binding. Pediatrics 1987; 80: 873–5.

Sodium content.

Each g of ceftriaxone sodium contains about 3.0 mmol of sodium.

💊 Interactions

Ceftriaxone has an N-methylthiotriazine side-chain
and may have the potential to increase the effects of anticoagulants and to cause a disulfiram-like reaction with alcohol. Unlike many cephalosporins, probenecid does not affect the renal excretion of ceftriaxone.

💊 Antimicrobial Action

As for Cefotaxime Sodium, although ceftriaxone has no active metabolite.
1. Goldstein FW, et al. Resistance to ceftriaxone and other βlactams in bacteria isolated in the community. Antimicrob Agents Chemother 1995; 39: 2516–19.

💊 Pharmacokinetics

Ceftriaxone demonstrates nonlinear dose-dependent pharmacokinetics because of its protein binding; about 85 to 95% is bound to plasma proteins depending on the concentration of ceftriaxone. Mean peak plasma concentrations of about 40 and 80 micrograms/mL have been reported 2 hours after intramuscular injection of 0.5 and 1 g of ceftriaxone respectively. The plasma half-life of ceftriaxone is not dependent on the dose and varies between 6 and 9 hours; it may be prolonged in neonates. The half-life does not change appreciably in patients with moderate renal impairment, but it may be prolonged in severe impairment especially when there is also hepatic impairment. Ceftriaxone is widely distributed in body tissues and fluids. It crosses both inflamed and non-inflamed meninges, generally achieving therapeutic concentrations in the CSF. It crosses the placenta and low concentrations have been detected in breast milk. High concentrations are achieved in bile. About 40 to 65% of a dose of ceftriaxone is excreted unchanged in the urine, principally by glomerular filtration; the remainder is excreted in the bile and is ultimately found in the faeces as unchanged drug and microbiologically inactive compounds.
1. Hayton WL, Stoeckel K. Age-associated changes in ceftriaxone pharmacokinetics. Clin Pharmacokinet 1986; 11: 76–86
2. Yuk JH, et al. Clinical pharmacokinetics of ceftriaxone. Clin Pharmacokinet 1989; 17: 223–35
3. Perry TR, Schentag JJ. Clinical use of ceftriaxone: a pharmacokinetic-pharmacodynamic perspective on the impact of minimum inhibitory concentration and serum protein binding. Clin Pharmacokinet 2001; 40: 685–94.

Hepatic impairment.

References.
1. Stoeckel K, et al. Single-dose ceftriaxone kinetics in liver insufficiency. Clin Pharmacol Ther 1984; 36: 500–9
2. Hary L, et al. The pharmacokinetics of ceftriaxone and cefotaxime in cirrhotic patients with ascites. Eur J Clin Pharmacol 1989; 36: 613–16
3. Toth A, et al. Pharmacokinetics of ceftriaxone in liver-transplant recipients. J Clin Pharmacol 1991; 31: 722–8.

Pregnancy.

References.
1. Bourget P, et al. Pharmacokinetics and protein binding of ceftriaxone during pregnancy. Antimicrob Agents Chemother 1993; 37: 54–9.

Renal impairment.

The pharmacokinetics of ceftriaxone are not markedly altered in mild to moderate renal impairment,1 but the half-life can be prolonged in severe or end-stage renal disease.1-4 Ceftriaxone is generally not removed by peritoneal dialysis4 or by haemodialysis1-3 although a decrease in half-life has been reported during haemodialysis.5 In many patients no alteration in dosage is necessary, but some individuals have reduced non-renal clearance despite apparently normal hepatic function.2,3 It is advisable to monitor plasma ceftriaxone in patients with severe renal impairment and unknown non-renal clearance.
1. Patel IH, et al. Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment. Antimicrob Agents Chemother 1984; 25: 438–42
2. Stoeckel K, et al. Single-dose ceftriaxone kinetics in functionally anephric patients. Clin Pharmacol Ther 1983; 33: 633–41
3. Cohen D, et al. Pharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis. Antimicrob Agents Chemother 1983; 24: 529–32
4. Ti T-Y, et al. Kinetic disposition of intravenous ceftriaxone in normal subjects and patients with renal failure on hemodialysis or peritoneal dialysis. Antimicrob Agents Chemother 1984; 25: 83–7
5. Garcia RL, et al. Single-dose pharmacokinetics of ceftriaxone in patients with end-stage renal disease and hemodialysis. Chemotherapy 1988; 34: 261–6.

💊 Uses and Administration

Ceftriaxone is a third-generation cephalosporin antibacterial used similarly to cefotaxime for the treatment of susceptible infections. They include chancroid, endocarditis, gastro-enteritis (invasive salmonellosis; shigellosis), gonorrhoea, Lyme disease, meningitis are 20 to 50 mg/kg once daily; for severe infections up to 80 mg/kg daily may be given. In neonates, the maximum dose should not exceed 50 mg/kg daily; intravenous doses in neonates should be given over 60 minutes. Doses above 50 mg/kg should be given by intravenous infusion only. A single intramuscular dose of 250 mg is recommended for the treatment of uncomplicated gonorrhoea. For surgical infection prophylaxis, a single dose of 1 g may be given 0.5 to 2 hours before surgery; a 2-g dose is suggested before colorectal surgery. For the prevention of secondary cases of meningococcal meningitis, a single intramuscular dose of 250 mg may be used for adults and 125 mg for children.
1. Brogden RN, Ward A. Ceftriaxone: a reappraisal of its antibacterial activity and pharmacokinetic properties, and an update on its therapeutic use with particular reference to once-daily administration. Drugs 1988; 35: 604–45
2. Lamb HM, et al. Ceftriaxone: an update of its use in the management of community-acquired and nosocomial infections. Drugs 2002; 62: 1041–89
3. Bijie H, et al. In vitro activity, pharmacokinetics, clinical efficacy, safety and pharmacoeconomics of ceftriaxone compared with third and fourth generation cephalosporins: review. J Chemother 2005; 17: 3–24.

Administration in hepatic and renal impairment.

A reduction in dosage of ceftriaxone may be necessary in patients with severe renal impairment (creatinine clearance below 10 mL/minute), in whom the daily dose should not exceed 2 g. In patients undergoing dialysis, and in those with both renal and hepatic impairment, plasma concentrations of ceftriaxone should be monitored to determine whether dose adjustment is needed.

💊 Preparations

BP 2008: Ceftriaxone Injection; USP 31: Ceftriaxone for Injection; Ceftriaxone Injection.

Proprietary Preparations

Arg.: Acantex; Bioteral; Cefomax; Ceftriaz†; Exempla; Rivacefin; Soltrimox; Austral.: Rocephin; Austria: Exogran; Rocephin; Belg.: Rocephine; Braz.: Amplospec†; Bioteral†; Ceft†; Ceftriax; Glicocef; Mesporan; Neoceftriona; Prodoxin; Rocefin; Rofoxin†; Triaxon; Triaxton; Trioxina; Canad.: Rocephin; Chile: Acantex; Grifotriaxona; Cz.: Cefaxone†; Lendacin; Longaceph†; Megion; Novosef†; Oframax†; Rocephin†; Samixon; Denm.: Cefotrix; Rocephalin; Fin.: Rocephalin; Fr.: Rocephine; Ger.: Cefotrix; Rocephin; Gr.: Antibacin; Azatyl; Bresec; Ceftrixon; Farcef; Gladius; Glorixone; Labilex; Medaxone; Rocephin; Rolisporin; Travilan; Ugotrex; Veracol; Hong Kong: Medaxonum; Mesporin; Rocephin; Hung.: Cefotrix; Lendacin; Megion; Rocephin; India: Cefocef; Ciplacef; Lyceft; Monocef; Monotax; Oframax; Powercef; Stericef†; Indon.: Biotriax; Bioxon; Broadced; Brospec; Cefaxon; Cefriex; Ceftrox; Cefxon; Cephaflox; Criax; Ecotrixon; Elpicef; Erocef; Foricef; Intrix; Rocephin; Socef; Starxon; Terfacef; Termicef; Tricefin; Trijec; Tyason; Zeftrix; Irl.: Rocephin; Israel: Keftriaxon; Rocephin; Triax; Ital.: Axobat; Bixon; Davixon; Daytrix; Deixim; Eftry; Fidato; Frineg; Iliaxone; Kappacef; Kocefan; Monoxar; Nilson; Panatrix; Pantoxon; Ragex; Rocefin; Setriox; Sirtap; Valexime; Jpn: Rocephin; Malaysia: Cefaxone; Ceftrex; Eftriax; Mesporin; Rocephin; Trixone; Mex.: Amcef; Aurofox; Axtar; Benaxona; Cefaxona; Cefraden; Ceftrex; Ceftrilem; Centrifal; Limiprol; Megion; Primotox; Rocephin; Tacex; Terbac; Triaken; Triox; Xonatil; Neth.: Elfaxone; Exogran; Lopratin; Rocephin; Norw.: Rocephalin; NZ: Rocephin; Philipp.: Acrexon; CEF-3; Cikedrix; Cryaxon; Eurosef; Fenadef; Forgram; Keptrix; Megion; Monocrin; Noxoram; Pantrixon; Retrokor; Rocephin; Roxon; Samjizon; Sergimax; Trixophin; Xtenda; Pol.: Biotrakson; Lendacin; Rocephin; Tartriakson; Port.: Betasporina; Ceriax; Kemudin; Mesporin; Rocephin; Rus.: Azaran (Азаран); Ceftrifin (Цефтрифин); Ificef (Ифицеф); Lendacin (Лендацин); Loraxone (Лораксон); Medaxone (Медаксон); Novosef (Новосеф); Oframax (Офрамакс); Stericef (Стерицеф); Tercef (Терцеф); To r oce f ( Тороцеф); S.Afr.: Fraxone†; Oframax; Rocephin; Rociject; Singapore: Antibacin; Cefaxone; Cefin†; Oframax; Rocephin; Trexofin; Tricefin; Spain: Rocefalin; Swed.: Rocephalin; Switz.: Rocephine; Thai.: CEF-3; Cef-Zone; Cefine†; Ceftrex; Ceftriphin; Lephin†; Oframax; Rinxofay; Rocephin; Sedalin†; Triacef; Tricephin; Trixone; Zefaxone; Turk.: Baktisef; Cefaday; Cephaxon; Desefin; Equiceft; Forsef; Iesef; Nevakson; Novosef; Rocephin; Unacefin; UAE: Tr iaxone; UK: Rocephin; USA: Rocephin; Venez.: Bioceftrax; Cefin; Cefix; Ceftrialin; Ciplacef; Eftrival; Feliden†; Megion; Rocephin; Strixone; Tricefi. Multi-ingredient: India: Axone; Dibact†; Keftragard.
Published January 16, 2019.