RAGEX

Package leaflet: Information for the patient

RAGEX

1 g powder and solvent for injectable solution for intramuscular use
Ceftriaxone
Equivalent medicine
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What RAGEX is and what it is used for
2. What you need to know before using RAGEX
3. How to use RAGEX
4. Possible side effects
5. How to store RAGEX
6. Contents of the pack and other information

1. What RAGEX is and what it is used for

RAGEX contains the active substance ceftriaxone, which belongs to the class of medicines known as
broad-spectrum beta-lactam antibiotics. These act by inhibiting specific bacterial enzymes (PBPs)
responsible for bacterial cell wall growth.
RAGEX is specifically and preferentially indicated for the treatment of severe bacterial infections
confirmed or suspected to be caused by resistant "difficult" Gram-negative bacteria or mixed flora
containing Gram-negative bacteria (a type of bacteria) resistant to more common antibiotics.
In particular, this medicine is used to treat the above-mentioned infections in severely weakened
and debilitated patients and/or in patients with reduced immune defenses.
It is also used for the prevention of surgical infections.
Consult your doctor if you do not feel better or if you feel worse.

2. What you need to know before using RAGEX

Do not use RAGEX

• If you are allergic to ceftriaxone, beta-lactam antibiotics (penicillins), cephalosporins (similar antibiotics), or to any of the other ingredients of this medicine (listed in section 6).
• If you have previously experienced a sudden or severe allergic reaction to penicillin or similar antibiotics (such as cephalosporins, monobactams, and carbapenems). Possible signs include sudden swelling of the throat or face, which may make breathing or swallowing difficult, sudden swelling of hands, feet, and ankles, chest pain, and a severe rash that develops rapidly. In patients hypersensitive to penicillin, cross-allergic reactions to both penicillin and RAGEX should be considered.
• If you are pregnant or in the case of very young infants. In these cases, this medicine should only be administered when strictly necessary and under direct medical supervision. Hyperbilirubinemic newborns (with increased bilirubin levels in the blood), i.e., those with jaundice (yellowish skin discoloration), and premature infants must not be treated with ceftriaxone. These patients may develop bilirubin encephalopathy (a brain disorder), as free bilirubin in the blood deposits in the brain, impairing nerve transmission.
• If you are being treated with calcium, due to the risk of calcium-ceftriaxone precipitate formation in full-term newborns (see sections “Warnings and precautions”, “Possible side effects”, and “Other medicines and RAGEX”).

Ceftriaxone is also contraindicated in:

• Premature newborns until a corrected age of 41 weeks (gestational weeks + weeks of life);
• Full-term newborns (up to 28 days of age):
  • with jaundice or hypoalbuminemia (reduced levels of albumin, an important blood protein), or acidosis (increased blood acidity), as these are conditions in which bilirubin may be altered;
  • if they require (or are expected to require) intravenous calcium treatment or infusions containing calcium, due to the risk of ceftriaxone-calcium precipitation (see sections “Warnings and precautions”, “Possible side effects”, and “Other medicines and RAGEX”).

Inform your doctor, pharmacist, or nurse before RAGEX is administered to you if:

• You currently have or have previously experienced any combination of the following symptoms: skin rash, skin redness, blistering on lips, eyes, or mouth, skin peeling, high fever, flu-like symptoms, increased liver enzyme levels detectable in blood tests, increased levels of a type of white blood cells (eosinophilia), and swollen lymph nodes (signs of severe skin reactions, see also section 4 “Possible side effects”).

Warnings and precautions
Talk to your doctor or pharmacist before taking RAGEX.
Fatal reactions due to calcium-ceftriaxone precipitates in the lungs and kidneys have been reported in premature and full-term newborns under 1 month of age. At least one of these cases had received ceftriaxone and calcium at different times and through different intravenous lines. Among available scientific data, there are no confirmed reports of intravascular precipitates in patients other than newborns treated with ceftriaxone and calcium-containing solutions or any other calcium-containing product. Newborns are at increased risk of calcium-ceftriaxone precipitation compared to other age groups.
Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions for intravenous use in patients of any age, even through different infusion lines or at different infusion sites. However, in patients older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially, one after the other, provided that different infusion lines at different sites are used, or provided that the infusion lines are either replaced or thoroughly flushed with saline solution between infusions to prevent precipitation.
In patients requiring continuous infusion of total parenteral nutrition (TPN, intravenous feeding) solutions containing calcium, healthcare providers may consider using alternative antibacterial treatments that do not carry a similar precipitation risk. If ceftriaxone use is considered necessary in patients requiring continuous feeding, TPN solutions and ceftriaxone may be administered simultaneously, provided they are given through separate infusion lines at different sites. Alternatively, the TPN infusion may be interrupted during the ceftriaxone infusion, ensuring that infusion lines are flushed between administrations (see sections “Do not take RAGEX”, “Possible side effects”).
Before starting RAGEX therapy, a thorough investigation should be conducted to determine whether you have previously experienced hypersensitivity reactions to cephalosporins, penicillins, or other drugs.
The medicine should be administered with caution if you are allergic to penicillin, as cross-hypersensitivity reactions between penicillins and cephalosporins have been reported. Due to immature organ function, premature infants should not be treated with RAGEX doses exceeding 50 mg/kg/day.
As with other antibiotics, prolonged use may promote the growth of resistant bacteria, and appropriate measures should be taken in case of superinfections.
Acute hypersensitivity reactions may require the use of adrenaline and other emergency measures. Preparations containing lidocaine must not be administered intravenously or in patients allergic to this local anesthetic.
If signs of infection appear, the causative microorganism should be isolated and appropriate therapy based on sensitivity testing should be initiated.
Tests on samples collected before starting therapy should be performed to determine the sensitivity of the causative microorganism to ceftriaxone. RAGEX therapy may be initiated while awaiting the results of these tests; treatment should then be adjusted accordingly if necessary based on test results. Before using RAGEX in combination with other antibiotics, the instructions for use of the other drugs should be carefully reviewed to identify any contraindications, warnings, precautions, and adverse reactions.
Renal function should be closely monitored.
Pseudomembranous colitis (severe inflammation of the intestinal wall) has been reported following the use of cephalosporins (or other broad-spectrum antibiotics); this diagnosis should be considered in patients who develop diarrhea after antibiotic use.
RAGEX is eliminated approximately 56% via urine and the remaining 44% via bile in microbiologically active form. In feces, it is predominantly present in inactive form. In cases of reduced renal function, a higher proportion is eliminated via the biliary route in feces. Since the half-life is only slightly prolonged under these circumstances, dosage adjustment of RAGEX is generally not required, provided liver function is normal. Only in cases of severe renal impairment should the maintenance dose every 24 hours be reduced by half compared to the usual dose.
Like other cephalosporins, ceftriaxone has been shown to partially interfere with bilirubin binding sites on plasma albumin. Third-generation cephalosporins, like other beta-lactams, may induce microbial resistance, particularly in opportunistic organisms such as Enterobacteriaceae and Pseudomonas, especially in immunocompromised patients (with reduced immune system function), and possibly when multiple beta-lactams are combined.
As with any antibiotic therapy, regular hematological monitoring (blood cell counts and ratios) should be performed during prolonged treatments.
In extremely rare cases, ultrasound examinations of the gallbladder in patients treated with high doses have revealed findings suggestive of biliary sludge. This condition promptly resolves upon discontinuation or completion of therapy. Even if these findings are symptomatic, conservative management is recommended.
Positive Coombs test results (sometimes false positives) have been reported during treatment with cephalosporins.

Children
The safety and efficacy of RAGEX in newborns, infants, and children have been established for the dosages described in section “How to take RAGEX”. Clinical studies have shown that ceftriaxone, like certain other cephalosporins, can displace bilirubin from albumin in the blood. RAGEX must not be used in newborns (especially premature infants) at risk of developing bilirubin encephalopathy (a brain disorder).

Other medicines and RAGEX
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
RAGEX must not be added to calcium-containing solutions such as Hartmann’s or Ringer’s solutions.
Concurrent administration of high doses of RAGEX with potent diuretics (e.g., furosemide, used in high blood pressure and heart failure) at high doses has not shown renal function disturbances to date. There is no evidence that RAGEX increases the renal toxicity of aminoglycosides (a type of antibiotic). The elimination of RAGEX is not affected by probenecid (used to reduce blood uric acid levels).
Experimental studies have demonstrated synergistic action (similar and additive effects) between RAGEX and aminoglycosides against many Gram-negative bacteria. The enhanced activity of such combinations, although not always predictable, should be considered in severe infections resistant to other treatments caused by organisms such as Pseudomonas aeruginosa. Due to physical incompatibilities, the two drugs must be administered separately at the recommended doses.

RAGEX with food, drinks, and alcohol
Alcohol consumption after RAGEX administration does not produce disulfiram-like effects (used in alcoholism treatment); indeed, ceftriaxone does not contain the N-methylthiotetrazole group believed responsible for possible alcohol intolerance and hemorrhagic manifestations observed with other cephalosporins.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
In pregnant women, during breastfeeding, and in very young infants, this product should only be administered when strictly necessary and under direct medical supervision.

Driving and using machines
RAGEX may in some cases cause dizziness; therefore, your ability to drive vehicles or operate machinery may be impaired.

RAGEX contains sodium. This medicine contains 82.91 mg of sodium per vial. This should be taken into account in patients with impaired renal function or those on a low-sodium diet.

3. How to use RAGEX

Use this medicine exactly as directed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Diluents containing calcium (e.g. Ringer's solution or Hartmann's solution) must not be used to
reconstitute ceftriaxone vials or to further dilute reconstituted vials for
intravenous administration, as a precipitate may form. Precipitation of ceftriaxone
with calcium may also occur when ceftriaxone is mixed with calcium-containing solutions in the
same intravenous administration line.
Therefore, ceftriaxone and calcium-containing solutions must not be mixed together or
administered simultaneously (see sections “Do not take RAGEX”, “Warnings and
precautions”, “Possible side effects”).

Dosage
Adults and children over 12 years: the recommended dose is 1 g of RAGEX once daily (every 24
hours). In more severe cases or in infections caused by microorganisms with moderate sensitivity, the dose may
be increased up to 4 g administered as a single dose.
Elderly: the adult dosage regimen does not require modification in elderly patients.
The duration of therapy depends on the course of the infection.
As with all antibiotic therapies, in general, administration of RAGEX should be continued for
at least 48–72 hours after defervescence or until complete bacterial eradication has been demonstrated.

Prophylaxis of surgical infections
To prevent postoperative infections, 1 g administered intramuscularly or 1–2 g administered intravenously as a single dose one hour before surgery, depending on the type and risk of contamination associated with the procedure.

Dosage in particular conditions
Renal impairment: in patients with creatinine clearance greater than 10 ml/min (a renal function test), the dosage remains unchanged. In cases of creatinine clearance equal to or less than 10 ml/min, up to a maximum of 2 g once daily may be administered.
Hepatic impairment: normal dosage.
Concomitant renal and hepatic impairment: monitor ceftriaxone blood concentrations.
Premature infants: maximum dose of 50 mg/kg once daily.

Method of administration
From a microbiological standpoint, the medicine should be used immediately after reconstitution (opening and preparation of the injection mixture). If not used immediately, the storage conditions and duration prior to use are the responsibility of the user. Chemical and physical stability of the medicine after reconstitution has been demonstrated for 24 hours between +2°C and +8°C and for 6 hours when stored at temperatures below 25°C.
The solution may vary in color from pale yellow to amber depending on concentration and storage duration; this characteristic does not affect the efficacy or tolerability of the medicine.

Solution for intramuscular use
For intramuscular injection, dissolve RAGEX i.m. with the appropriate solvent (1% lidocaine solution), using 2 ml for RAGEX 250 mg and 500 mg, and 3.5 ml for RAGEX 1 g: inject the resulting freshly prepared solution deeply into the gluteal muscle, alternating buttocks with subsequent injections.
The lidocaine solution must not be administered intravenously.

Solution for intravenous use
For intravenous injection, dissolve RAGEX with the appropriate solvent (water for injections), using 10 ml for RAGEX 1 g, and inject directly into the vein over 2–4 minutes.

Solution for infusion
For intravenous infusion, dissolve RAGEX at a rate of 2 g in 40 ml of infusion fluid free of calcium ions (normal saline, 5% or 10% glucose solution, 5% levulose solution, glucose-dextran 6% solution).
The infusion should last at least 30 minutes.
RAGEX solutions should not be mixed with solutions containing other antimicrobial drugs or with diluents other than those listed above due to possible incompatibilities.

Use in children and adolescents
Neonates (up to 2 weeks): daily dose is 20–50 mg/kg body weight administered once daily; due to immaturity of their enzymatic systems, doses should not exceed 50 mg/kg (see section “Children”).
Children (3 weeks to 12 years): daily dose may range between 20 and 80 mg/kg. For intravenous doses equal to or exceeding 50 mg/kg, it is recommended to administer via infusion lasting at least 30 minutes.
For children weighing more than 50 kg, adult dosing should be used.

If you take more RAGEX than you should
No cases of acute intoxication have been reported to date.

If you stop treatment with RAGEX
If you have any questions about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
Below are listed the serious side effects:

• The occurrence of anaphylactic shock (an allergic reaction with severe drop in blood pressure and heart failure) is extremely rare and requires immediate countermeasures such as intravenous administration of adrenaline followed by a glucocorticoid (cortisone and similar). Ceftriaxone must not be mixed or administered simultaneously with solutions or products containing calcium, even through different infusion lines.
• Rarely, serious adverse effects, and in some cases fatal, have been reported in premature infants and full-term newborns (age <28 days) who have been treated with ceftriaxone and calcium intravenously.
• Post-mortem examinations have revealed calcium-ceftriaxone salt precipitation in the lungs and kidneys. The high risk of precipitation in newborns is due to their reduced plasma volume and the longer half-life of ceftriaxone compared to adults (see sections "Do not take RAGEX" and "Warnings and Precautions").
• Diarrhea associated with Clostridium difficile (CDAD), which may range in severity from mild diarrhea to fatal colitis (severe inflammation of the intestine) (see section "Warnings and precautions"). If CDAD is suspected or confirmed, it may be necessary to discontinue antibiotics not directly targeting C. difficile. Depending on clinical indications, appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment for C. difficile, and surgical evaluation should be initiated (see section "Warnings and precautions").

Serious skin reactions (frequency not known; cannot be estimated from available data)
If you develop a serious skin reaction, inform your doctor immediately.
Signs may include:

• Severe rash developing rapidly, with blistering or skin peeling and possible blistering in the mouth (Stevens-Johnson syndrome and toxic epidermal necrolysis, also known as SJS and TEN).
• Any combination of the following symptoms: widespread rash, high body temperature, elevated liver enzymes, abnormalities in blood tests (eosinophilia), swollen lymph nodes, and involvement of other body organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).
• Jarisch-Herxheimer reaction, which may cause fever, chills, headache, muscle pain, and rash, usually resolving spontaneously. These symptoms may occur shortly after starting treatment with RAGEX for spirochete infections such as Lyme disease.

Conditions to which you should pay attention
Allergic reactions:
Chest pain occurring in the context of allergic reactions, which may be a symptom of an allergy-induced heart attack (Kounis syndrome).
Problems with the gallbladder and/or liver (frequency not known; cannot be estimated from available data), which may cause pain, nausea, vomiting, yellowing of the skin, itching, unusually dark urine, and clay-colored stools.

The following side effects are generally mild and short-lived.
General side effects
Gastrointestinal disorders (about 2% of cases): loose stools or diarrhea, nausea, vomiting, stomatitis (inflammation of the mouth), and glossitis (inflammation of the tongue), rarely bile thickening.
Blood abnormalities (about 2%): eosinophilia (increase in a type of white blood cells called eosinophils), leucopenia (reduction in all types of white blood cells), granulocytopenia (reduction in granulocytes, blood cells), haemolytic anaemia (anaemia due to destruction of red blood cells), thrombocytopenia (reduction in platelets, blood cells responsible for clotting).
Skin reactions (about 1%): rash, allergic dermatitis, itching, urticaria, oedema.

Other rare side effects: headache, dizziness, increased transaminases, oliguria (reduced urine output), increased serum creatinine (a kidney function test), genital fungal infections (mycosis), fever, chills, and anaphylactic or anaphylactoid reactions (severe allergic reactions), for example bronchospasm (constriction of the airways).
Rare cases of pseudomembranous enterocolitis and changes in coagulation parameters have been reported following the use of cephalosporins. Cases of haemolytic anaemia have been reported following treatment with cephalosporins.
Rare, serious, and in some cases fatal adverse reactions have been reported in preterm and full-term neonates (age <28 days) treated with ceftriaxone and calcium IV.
Post-mortem findings have confirmed the presence of ceftriaxone and calcium salt precipitates in the lungs and kidneys.
The high risk of precipitation in neonates is due to their low blood volume and the long half-life of ceftriaxone compared to adults (see Contraindications, Precautions for use, and Dosage, method and duration of administration).

Local side effects
Phlebitic reactions have occurred rarely after intravenous administration; these reactions can be avoided by slow injection (2-4 minutes) of the drug.
Intramuscular injection without lidocaine solution is painful.
In susceptible individuals, hypersensitivity reactions may occur.

If any of the side effects worsens, or if you notice any side effect not listed in this leaflet, inform your doctor or pharmacist.

Additional side effects in children
Very rare cases of renal precipitation have been reported, particularly in children over 3 years of age who received high daily doses (e.g., ≥ 80 mg/kg/day) or total doses exceeding 10 grams and who had significant risk factors (e.g., fluid restriction, bed rest, etc.).
In children, clinical studies have shown a variable incidence of calcium-ceftriaxone salt precipitation in the gallbladder following intravenous administration, exceeding 30% in some studies. The incidence appears to be lower with slow infusion (20-30 minutes).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store RAGEX

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp". The expiry date refers to the last day of that month.
The expiry date indicated refers to the product in its original, unopened packaging, correctly stored.
For the reconstituted solution, see section "How to take RAGEX".
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What RAGEX contains

• The active substance is ceftriaxone. One vial contains ceftriaxone disodium 3,5 H2O 1,193 mg equivalent to ceftriaxone 1000 mg;
• The other component is 1% aqueous lidocaine solution. One solvent vial contains 3.5 ml of 1% aqueous lidocaine solution.

Description of the appearance of RAGEX and contents of the pack
RAGEX "1 g powder and solvent for injectable solution for intramuscular use" 1 vial + 1 solvent vial of 3.5 ml

Marketing Authorization Holder
AGIPS FARMACEUTICI srl – via Amendola, 4 – 16035 Rapallo

Manufacturer
Laboratorio Farmaceutico C.T. S.r.l. - Via Dante Alighieri, 71 - 18038 Sanremo (IM)