Tricexone

Each 1 g of vial contains: Ceftriaxone (as sodium) 1 g.
Each ampoule contains: Sterile Water for Injection BP 10 mL.
Ceftriaxone (Ceftriaxone sodium) is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. It is a white to yellowish orange crystalline powder with a molecular formula of: C₁₈H₁₆N₈Na₂O₇S₃·3½H₂O and molecular weight of 661.6. It is freely soluble in water.

Pharmacology: Pharmacodynamics: Ceftriaxone is a third-generation cephalosporin that is used for a variety of infections such as meningitis, gonorrhoea and community-acquired pneumonia. The most important aspects of its pharmacokinetics include a long half-life, excellent tissue penetration and saturable (dose-dependent) serum protein binding of the drug.
Pharmacokinetics: The pharmacokinetics of Ceftriaxone is largely determined by its concentration-dependent binding to plasma albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300 mg/L. Owing to the lower albumin content, the proportion of free Ceftriaxone in interstitial fluid is correspondingly higher than in plasma.
Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120 mg/L following a 500 mg dose and about 200 mg/L following a 1 g dose; mean levels of 250 mg/L are achieved after infusion of 2 g over 30 minutes. Bioavailability after intramuscular injection is 100%.
Excretion: Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10-22 mL/min. The renal clearance is 5-12 mL/min. A notable feature of Ceftriaxone is its relatively long plasma elimination half-life of approximately eight hours which makes single or once daily dosage of the drug appropriate for most patients. The half-life is not significantly affected by the dose, the route of administration or by repeated administration.

Ceftriaxone is indicated in the treatment of the following infections either before the infecting organism has been identified or when known to be caused by bacteria of established sensitivity: Pneumonia (community acquired, hospital acquired); Bacterial meningitis; Complicated skin and soft tissue infections; Infections in neutropenic patients; Gonorrhoea; Peri-operative prophylaxis of infections associated with surgery.

Adults and adolescents aged over 12 years with a body weight ≥50 kg: The usual dose is 1-2 g of Ceftriaxone, administered once a day. In cases of serious infections or infections caused by moderately sensitive micro-organisms the dose can be raised up to 4 g, administered once a day.
Newborn infants (age 0 - 14 days): 20-50 mg per kg bodyweight intravenously once daily. In severe infections the daily dose of 50 mg per kg bodyweight must not be exceeded.
Children 15 days to 2 years of age with a body weight of <50 kg: 20-80 mg per kg bodyweight intravenously once daily. In severe infections the daily dose of 80 mg per kg bodyweight must not be exceeded, except in meningitis.
Children with a bodyweight of 50 kg or more receive the usual adult dosage once daily.
Elderly: The normal adult dose can usually be given to elderly patients, unless renal and hepatic function is significantly impaired.
Dosage in special situations: Meningitis: In children with bacterial meningitis the therapy should be started with 100 mg/kg (not exceeding 4 g), administered once a day. After determining the sensitivity of the pathogen the dose may be reduced accordingly.
In new-born infants below 2 weeks of age the dose should not exceed 50 mg/kg/24 h.
Renal insufficiency: In patients with impaired renal function, alteration of the Ceftriaxone dose is not necessary, provided that the hepatic function is normal. Only in cases of extreme renal insufficiency (creatinine clearance <10 mL/min) the daily dose of the Ceftriaxone should not exceed 2 g.
In co-existing severe renal and hepatic insufficiency and in children with extreme renal insufficiency the serum Ceftriaxone concentrations should be regularly monitored, and the dosage adjusted appropriately. Patients undergoing haemodialysis or peritoneal dialysis do not need an additional dose of Ceftriaxone after the dialysis.
Serum concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.
Hepatic insufficiency: The dose does not need to be altered in patients with a liver disease provided that the renal function is normal.
Direction For Reconstitution: Dissolve the contents of vial in 9.6 mL Sterile Water for Injection for IV injections or in 3.6 mL Sterile Water for Injection for IM injections.

No case of overdose has been reported.

Hypersensitivity to the active substance, to other cephalosporins. Previous immediate and/or severe hypersensitivity reaction to penicillin or to any other beta-lactam medicinal products.

In suspected or proven infections with Pseudomonas aeruginosa, high resistance rates (>60%) for Ceftriaxone in at least some European countries should be taken into consideration. In infections caused by Pseudomonas aeruginosa with proven sensitivity to Ceftriaxone a combination with amino-glycosides is warranted to avoid secondary resistance.
In infections caused by other bacteria in patients with neutropenic fever interventional treatment with Ceftriaxone should be combined with an aminoglycoside. Special caution is required to determine any other type of previous hypersensitivity reactions to penicillin or to other beta-lactam-medicinal products because patients hypersensitive to these medicines may be hypersensitive to Ceftriaxone as well (cross-allergy).
Hypersensitivity reactions against Ceftriaxone are more likely in patients with any other type of hypersensitivity reaction or asthma bronchiale. Injections with Ceftriaxone should be used with special caution in patients with allergic diathesis, because hypersensitivity reactions emerge faster and proceed more severely after intravenous injection.
Hypersensitivity reactions may occur in all degrees of severity up to anaphylactic shock. In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required.
In case of simultaneous impairment of renal and liver function, serum-level of Ceftriaxone should be monitored in regular intervals.
Monitoring of renal and hepatic function and haematological parameters at regular intervals is indicated during long-term treatment.
Each administration of antibiotics can lead to multiplication of pathogens resistant to the active substance used. Signs of consecutive secondary infections with such pathogens (including candida and fungi) are to be heeded. Secondary infections are to be treated accordingly.
Antibiotic-associated diarrhoea, colitis and pseudomembranous colitis have all been reported with the use of Ceftriaxone. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Ceftriaxone should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted. Drugs that inhibit peristalsis must not be given.
Ceftriaxone should be used with caution in individuals with a previous history of gastro-intestinal disease, particularly colitis.
Ceftriaxone may precipitate in the gallbladder and kidneys and then be detectable as shadows on ultrasound. This can happen in patients of any age, but is more likely in infants and small children who are usually given a larger dose of Ceftriaxone on a body weight basis. In children, doses greater than 80 mg/kg body weight should be avoided - except for meningitis - because of the increased risk of biliary precipitates. There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with Ceftriaxone, and conservative management of Ceftriaxone precipitate in the gallbladder is recommended.
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with Ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of Ceftriaxone-related biliary precipitation cannot be ruled out.
Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the medicinal product to produce a positive Coombs' test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins. In vivo and in vitro studies have shown that Ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Clinical data obtained in neonates have confirmed this finding.
Ceftriaxone should therefore not be used in jaundiced newborns or in those who are hypoalbuminaemic or acidotic, in whom bilirubin binding is likely to be impaired. Particular caution should be exercised in babies born prematurely.
As with other antibiotics, incidental occurrences of vitamin K-deficiency should be considered. High intravenous doses (>1 g or ≥50 mg/kg bodyweight) of Ceftriaxone should be administered slowly (over a minimum period of 30 minutes) in order to avoid high concentrations in the bile.
This medicinal product contains 3.6 mmol (82.8 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Pregnancy: There are no data on use of Ceftriaxone in pregnant women. Ceftriaxone crosses the placenta. Animal studies indicate no reproductive toxicity. As a precautionary measure, Ceftriaxone should only be used during pregnancy after benefit/risk assessment by the physician in charge, especially during the first trimester.
Lactation: Ceftriaxone is excreted in low concentrations in breast milk. Caution should be exercised when prescribing to breast-feeding women. Diarrhoea and fungal infection of the mucous membrane could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitization should be born in mind.

The undesirable effects usually are mild and short-term.
Gastrointestinal: Common (≥1% - <10%): Loose stools or diarrhoea (diarrhoea may sometimes be a symptom of pseudomembranous colitis), nausea, vomiting, stomatitis, glossitis and pancreatitis.
Rare (≥0.01% - <0.1%): Abdominal pain.
Infections: Superinfection caused by microorganisms non-susceptible to Ceftriaxone such as yeasts, fungi (mycosis of the genital tract) or other resistant microorganisms may develop. Pseudomembranous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with Ceftriaxone. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use. Also, genital fungal infection.
Hypersensitivity: Uncommon (≥0.1% - <1%): Maculopapular rash or exanthema, pruritus, urticaria, oedema, shivering and anaphylactic or anaphylactoid reactions (e.g. bronchospasm) and allergic dermatitis have occurred.
Rare (≥0.01% - <0.1%): Drug fever, shivering. Anaphylactic-type reactions such as bronchospasm are rare.
Very rare (<0.01%): Isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome, Lyell's Syndrome/toxic epidermal necrolysis and acute generalized exanthematous pustulosis) have been reported.
Blood and lymphatic system disorders: Common (≥1% - ≤10%): Haematological reactions have included anaemia (all grades), haemolytic anaemia, granulocytopenia, leucopenia, neutropenia, agranulocytosis, thrombocytopenia and eosinophilia. Coagulation disorders have been reported as very rare side effects.
Unknown frequency: Immune mediated haemolytic anaemia.
Unknown frequency of agranulocytosis (<500/mm³) has been reported, mostly after 10 days of treatment and following total doses of 20 g or more.
Rarely, severe, and in some cases fatal, adverse reactions have been reported in preterm and full term newborns (aged <28 days) who had been treated with intravenous Ceftriaxone and calcium. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.
There have been rare reports of fatal haemolysis in association with Ceftriaxone. Ceftriaxone has rarely been associated with prolongation of prothrombin time, however, bleeding and bruising due to hypoprothrombinaemia may be more prevalent in patients with renal or hepatic impairment, malnourished patients or those with low vitamin K levels and patients receiving prolonged Ceftriaxone therapy.
Central Nervous system: Rare (≥0.01% - <0.1%): Headache, vertigo and dizziness.
Administration of high doses of cephalosporins, particularly in patients with renal insufficiency, may result in convulsions.
Renal and Urinary: Rare (≥0.01% - <0.1%): Glycosuria, oliguria, haematuria, increase in serum creatinine.
Very rare (<0.01%): Cases of renal precipitation have been reported, mostly in children older than 3 years and who have been treated with either high daily doses (e.g. ≥80 mg/kg/day) or total doses exceeding 10 grams and presenting other risk factors (e.g. fluid restrictions, confinement to bed, etc.). The risk of precipitate formation is increased in immobilized or dehydrated patients. This event may be symptomatic or asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon discontinuation of Ceftriaxone.
Acute renal tubular necrosis may occur rarely with Ceftriaxone.
Hepatobiliary system: Rare (≥0.01% - <0.1%): Hepatitis and/or cholestatic jaundice, kernicterus, increase in liver enzymes. Transient elevations in liver function tests have been reported in a few cases.
Shadows which have been mistaken for gallstones, but which are precipitates of calcium Ceftriaxone, have been detected by sonograms. These abnormalities are commonly observed after an adult daily dose of two grams per day or more, or its equivalent in children; these abnormalities were particularly observed in children with an incidence of above 30% in isolated reports. At doses of two grams a day or above these biliary precipitates may occasionally cause symptoms. Should patients develop symptoms, non-surgical management is recommended, and discontinuation of Ceftriaxone should be considered. The evidence suggests biliary precipitates usually disappear once Ceftriaxone has been stopped. The risk of biliary precipitates may be increased by treatment duration greater than 14 days, renal failure, dehydration or total parenteral nutrition.
Local effects: Rare (≥0.01% - <0.1%): Pain or discomfort may be experienced at the site of intramuscular injection immediately after administration but is usually well tolerated and transient, edema, chills, pyrexia. Intramuscular injection without lidocaine solution is painful. Local phlebitis has occurred rarely following intravenous administration but can be minimized by slow injection over at least 2-4 minutes.

Aminoglycosides: In case of concomitant administration of cephalosporins and aminoglycosides there has been reported an increased risk of oto- and nephrotoxicity. Dose adjustment may be necessary.
Furthermore, these medicinal products must be administered separately to avoid physicochemical incompatibility between Ceftriaxone and the aminoglycoside.
Bacteriostatic antibiotics, such as chloramphenicol and tetracycline, may antagonize the activity of Ceftriaxone, especially in acute infections accompanied by rapid proliferation of micro-organisms. Simultaneous use of Ceftriaxone and bacteriostatic antibiotics is, therefore, not recommended.
Probenecid: Contrary to other cephalosporins, probenecid does not impede tubular secretion of Ceftriaxone.
Oral contraceptives: Ceftriaxone may adversely affect the efficacy of hormonal contraceptives. Consequently, it is advisable to use supplementary non-hormonal contraceptive measures.
Other: Laboratory-diagnostic tests: The Coombs test may be false-positive in rare cases during treatment with Ceftriaxone. Non-enzymatic methods for glucose determinations in urine may yield false-positive results. For this reason, urine glucose determination during therapy with Ceftriaxone should be carried out enzymatically. Ceftriaxone may lead to false-positive results of galactose determination in blood. The Ceftriaxone molecule does not contain the N-methylthio-tetrazole substituent which has been associated with a disulfiram-like effect when alcohol is taken during therapy with certain cephalosporins.

Incompatibilities: Solutions containing Ceftriaxone should not be mixed with or added to solutions containing other agents. In particular, Ceftriaxone is not compatible with calcium-containing solutions such as Hartmann's solution and Ringer's solution. Based on literature reports, Ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole, aminoglycosides and labetalol.

Store at temperatures not exceeding 30°C.
Shelf-Life: 36 Months.

Cephalosporins

J01DD04 - ceftriaxone ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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