ROSIN

Trade name: Rosin

International nonproprietary name: Ceftriaxon

Dosage band: white crystalline powder of yellow-orange colour; ampoule with dissolvent.

Formula: each vial contains 1g of ceftriaxon for mixing solutions for i/m injections.

1 ampoule with dissolvent for i/m injections contains 3,5ml of 1% lidocaine hydrochloride solution.

PHARMACALOGICAL QUALITIES:

Rosin- is antibiotic of cephalosporin group of III generation for parenteral administration.

Bactericidal activity of Rosin is subject to suppression of cellular membranes synthesis. In vitro, Rosin possesses pluripotential in regard to gram-negative and gram-positive microorganisms. It is resistant to β -lactamase action (both penicillinase and cephalosporinase), produced by gram-negative and gram-positive bacteria. Rosin is normally highly efficient in regard to the following microorganisms:

Gram-positive aerobes:

Staphylococcus aureus (methicillin-sensitive), coagulase-negative staphylococcus, Streptococcus pyogenes (β-hemolytic group A), Streptococcus agalactiae (β- hemolytic group B), Streptococcus viridans, Streptococcus pneumoniae.

Note: Methicillin-resistant Staphylococcus spp is refractory to cephalosporins, including ceftriaxon. As a rule, Enterococcus faecium and Listeria monocytogenes are also resistant to ceftriaxon.

Gram-negative aerobes:

Acinetobacter lwofi, Acinetobacter anitratus (mainly, А. baumanii)*, Aeromonas hydrophila, Alcaligenes faecalis, Alcaligenes odorans, alcaligenelike bacteria, Borrelia burgdorferi, Capnocytophaga spp., Citrobacter diversus (incliding, С.amalonaticus), Citrobacter freundii*, Escherichia coli, Enterobacter aerogenes*, Enterobacter cloacae*, Enterobacter spp. (other)*, Haemophilus ducreyi, Haemophilus influenzae, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae**, Moraxella catarhalis (previously called Branhamellacatarrhalis), Moraxella osloensis, Moraxella spp. (other),Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitides, Pasteurell multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus penneri*, Proteus vulgaris*, Pseudomonas fluorescens*, Pseudomonas spp.(other), Providentia rettgeri*, Providentia spp. (other), Salmonella typhi, Salmonella spp. (non- typhoid), Serratia marcescens*, Serratia (other)*, Shigella spp., Vibrio spp., Yersinia enterocolitica, Yersinia spp. (other).

Note: Many strains of the mentioned microorganisms, multiresistant to other antibiotics, such as aminopenicillins and ureidepenicillins, cephalosporins of the first and second generation and aminoglycosides, are sensitive to ceftriaxon. Treponema pallidum is sensitive to ceftriaxon in vitro and in animal experiments. Clinical testing shows that ceftriaxon is highly effective in regard to primary and secondary syphilis.

Anaerobes:

Bacteroides spp. (bile-sensitive*, Clostridium spp. (excluding C. difficile), Fusobacterium nucleatum, Fusobacterium spp (other), Gaffkia anaerobica (previously called Peptococcus), Peptosreptococcus spp.

PHARMACOKINETICS:

All basic pharmacokinetic options, based on common concentrations of the preparation, excluding half-life, depend on dosage.

Absorption:

Maximal concentration in plasma after single i/m injection comprises about 81mg/l and is reached during 2–3 hours after the injection. The areas under plasma concentration — time curves are equal for both intravenous and intramuscular injections. It means that bioavailability of ceftriaxon after intravenous injection comprises 100%.

Distribution:

Capacity volume of ceftriaxon is 7-12l. After injection of 1-3g ceftriaxon perfectly penetrates into body tissues and fluids. During more than 24 hours its concentrations greatly exceed minimal inhibitory concentrations for most infectious agents in more than 60 tissues and fluids (including lungs, heart, biliary tracts, liver, tonsils, middle ear and pituitary membrane, bones, cerebrospinal, pleural and synovial fluids, prostate gland secretion). After intravenous injection ceftriaxon quickly penetrates into the cerebrospinal fluid where bactericidal concentrations in regard to sensitive microorganisms are preserved during 24 hours.

Protein-binding:

Ceftriaxon inversely binds with albumin, degree of binding lowers with the increase of concentration, decreasing, for e.g., from 95% in concentration in plasma less of than 100mg/l up to 85% in concentration of 300mg/l. Due to lower concentration of albumin in tissue fluid, the ratio of free ceftriaxon is higher in tissue than in plasma.

Penetration in certain tissues:

In children (including newborns) Ceftriaxon penetrates through inflamed brain tunic. After 24 hours of intravascular injection of ceftriaxon in 50-100mg dose/kg of body weight (to newborns and infants), concentrations in cerebrospinal fluid exceed 1,4 mg/l. Maximal concentration in cerebrospinal fluid is reached approximately in 4 hours after intravascular injection and comprises 18mg/l in average. In bacterial meningitis mean ceftriaxon concentration in cerebrospinal fluid makes up 17% of concentration in plasma, in aseptic meningitis- 4%. In patients with bacterial meningitis in 2–24 hours after the injection of 50mg/kg of body weight, ceftriaxon concentrations in cerebrospinal fluid greatly exceed minimal inhibitory concentrations for most common meningitis causative agents.

Metabolism:

Ceftriaxon is not exposed to systemic metabolism but is transformed into non-active metabolites under the action of intestinal flora.

Elimination:

Half-life of ceftriaxon in adults comprises 8 hours. In newborns (under 8 days) and in elderly people above 75 half-life is app.16 hours. In adults 50–60% of ceftriaxon is eliminated in the unchanged form with urine, and 40–50%- in the unchanged form with bile. In newborn children 70% of the dose is eliminated through kidneys.

Pharmacokinetics in particular cases:

In patients with kidney or liver malfunction pharmacokinetics of ceftriaxon is not changed significantly, only slight increase of half-life is observed. If there is only kidney malfunction, increases elimination with bile; if there is only liver malfunction, increases elimination through kidneys.

INDICATIONS:

Infections caused by agents sensitive to ceftriaxon: sepsis, meningitis; disseminated Lyme borreliosis (early and advanced stages of the disease); infections of abdominal cavity organs (peritonitis, infections of biliary tracts and gastrointestinal tract); infections of bones, joints, soft tissue, skin and wound infections; infections in immunocompromised; kidney and urinary tract infections; respiratory infections; mainly pneumonia and ENT-organs infections; genital infections, including gonorrhea. Pre- and post surgical infection prophylaxis.

METHOD OF APPLICATION:

Standard dosage regimen:

Adults and children above 12: 1-2g once daily (every 24 hours).

In hard cases and infections which agents possess slight sensitivity to ceftriaxon, daily dose can be increased up to 4g.

Newborns (under 2 weeks): 20-50mg/kg of body weight once daily. Daily dose should not exceed 50mg/kg of body weight. The same dosage can be applied for both full-term and premature infants.

Infants and younger children (from 3d week till 12 years of age): 20–80 mg/kg of body weight once daily.

Adult dosage is prescribed for children with body eight more than 50kg.

Preparation in the dose of more than 50 mg/kg of body weight should be injected as intravenous infusion. Preparation should be injected during 30 min.

Elderly patients: normal adult dose regardless of age.

Duration of treatment: depends on the course of illness. As it usually is in antibiotic therapy, injection of ceftriaxon should be continued during at least 48–72 hours after normalization of temperature and confirmation of eradication of the causative agent.

Dosage in particular cases:

In bacterial meningitis in infants and younger children, treatment starts with the dose of 100mg/kg (not more than 4g) once daily. After identification of the causative agent and defining its sensitivity, the dose can be decreased. Best effect in meningococcal meningitis was reached at the 4-day course of treatment, in meningitis, caused by Haemophilus influenzae,- 6 days, Streptococcus pneumoniae- 7 days.

Gonorrhea (caused by penicillin forming and penicillin non-forming strains): single intramuscular injection of 0,25g of ceftriaxon.

Prophylaxis of the post surgical infections: depending on the degree of infectious risk, 1-2g of ceftriaxon is injected once 30–90 min prior to the beginning of the operation. In large and straight intestine operations it is recommended to inject ceftriaxon and one of the nitroimidazoles, for e.g. ornidazole, simultaneously (but separately).

In patients with kidney malfunction there is in no necessity to decrease the dose if liver function remains normal. In patients with liver malfunction is in no necessity to decrease the dose if kidney function remains normal.

In combination of severe kidney and liver in sufficiency, concentration of ceftriaxon in plasma should be regularly observed and its dose should be corrected in necessary.

Dialyzed patients do not require additional injection of the preparation after dialysis. Thus, concentration of ceftriaxon in the serum should be controlled as to possible dosage correction, because elimination rate in such patients can be decreased.

Injection:

As a rule, preparation dissolvents should be used immediately after mixing.

Mixed dissolvents usually keep their physical and chemical stability during 6 hours under indoor temperature 9 or during 24 hours under the temperature of +5˚С).

However, the common rule is applying dissolvents immediately after mixing. Depending on concentration and duration of storage the colour of dissolvents may vary from pale yellow to amber. The colour of dissolvent does not affect its efficiency or acceptability.

For the intramuscular injection 1g is dissolved in 3,5ml of 1% lidocaine hydrochloride solution and injected deep into the gluteus. It is recommended to inject not more than 1g into the same clunis.

In case of using lidocaine hydrochloride solution as a dissolvent, intravenous injection is strictly CONTRAINDICATED!

For intravenous injection 1g is dissolved in 10ml of water for injections; it is injected slowly intravenously (during 2–4 min).

Ceftriaxon solutions cannot be mixed of added into solutions containing other antibiotics or other dissolvents due to possible incompatibility.

Overdosage:

Exceedingly high concentrations of ceftriaxon in plasma cannot be decreased by dialysis or peritoneal dialysis. There is no specific antidote. For overdosage cases treatment symptomatic measures are recommended.

Contraindications:

• first pregnancy trimester;
• hypersensitivity to cephalosporins and penicillins;
• newborns with biliousness, hypoalbuminemia, acidosis and bilirubin binding failure.

SIDE EFFECTS:

Usually ceftriaxon is tolerated well. During its application following side effects were observed which disappeared independently or after the cancellation of the preparation:

Gastrointestinal tract (about 2% of patients): diarrhea, sickness, vomiting, stomatitis, glossitis.

Skin reactions (about 1%): rash, allergic dermatitis, itching, hives.

Other (rarely occur): headache and dizziness, precipitation of calcium salts of ceftriaxon in a gall bladder, increase of liver ferments activity.

Intramuscular injection without lidocaine hydrochloride application is painful.

Application during pregnancy and lactation:

Ceftriaxon is contraindicated during first pregnancy trimester.

Application of ceftriaxon during pregnancy is possible only when the intended benefit for mother exceeds potential risk for fetus. If it is necessary to prescribe the preparation during lactation, breast-feeding should be avoided.

Interaction with other medical preparations and other forms of interactions:

In simultaneous intake of large doses of ceftriaxon and strong diuretics (e.g. furosemide) no kidney malfunction was observed. There are no indications that ceftriaxon intensifies nephrotoxicity of aminoglycosides.

Nonsteroidal anti inflammatory drugs and other inhibitors of thrombocyte aggregation increase possibility of bleeding.

Ceftriaxon should not be mixed with other antibiotics in the same vial or syringe (particularly with aminoglycosides).

Ceftriaxon should not be added to infusive solutions, containing calcium, for e.g. Hartmann’s and Ringer’s. Ceftriaxon is incompatible and should not be mixed with amsacrine, vancomycin and aminoglycosides.

Form of issue:

Package for intramuscular injections:

1 vial with powder containing 1g of ceftriaxon;

1 ampoule containing 3,5ml of 1% lidocaine hydrochloride solution.

STORAGE CONDITIONS: Should be stored under temperature -not above 25˚ С, in the dark place.

Keep out of reach of children.

Conditions of delivery at chemistry stores:

Delivered according to prescription.

Expiry period: 2 years. Do not take the preparation after the expiry date.