RAGEX 1 mg /3.5 Ml Powder And Solvent For Injectable Solution

Зміст інструкції

1. RAGEX
   1. What is RAGEX and what is it 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

RAGEX

1 g powder and solvent for injectable solution for intramuscular use
Ceftriaxone
Generic medicine

Read this leaflet carefully before taking this medicine as 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 pass it on to others, even if they have the same symptoms as you, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell 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 you use 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 is RAGEX and what is it used for

RAGEX contains the active ingredient ceftriaxone, belonging to the class of medicines called
general-use beta-lactam antibiotics, which work by blocking specific bacterial enzymes (PBPs)
responsible for the growth of the bacterial cell wall.
RAGEX is used electively and specifically in severe bacterial infections of confirmed or presumed origin from
"difficult" Gram-negative bacteria or mixed flora with the presence of Gram-negative bacteria (a type of bacteria) resistant to
the most common antibiotics.
In particular, this medicine is used in the treatment of these infections in very weak
and debilitated patients and/or with reduced immune defenses.
It is also used in the prevention of surgical infections.
See 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 any of the other ingredients of this medicine (listed in section 6).
• If you have had a sudden or severe allergic reaction to penicillin or similar antibiotics (such as cephalosporins, monobactams and carbapenems). Possible signs include a sudden swelling of the throat or face, which may make it difficult to breathe or swallow, a sudden swelling of hands, feet and ankles, chest painand a severe skin rash that develops rapidly. In patients hypersensitive to penicillin, the possibility of common 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 if absolutely necessary and under the direct supervision of a doctor. Hyperbilirubinemic newborns (with increased bilirubin levels in the blood), i.e. with jaundice (yellowing of the skin), and premature infants should not be treated with ceftriaxone. It is possible for bilirubin to deposit in the brain in these patients, limiting nerve transmission, and bilirubin encephalopathy (a brain problem) may develop.
• If you are being treated with calcium, due to the risk of calcium-ceftriaxone precipitates forming in term infants (see sections “Warnings and precautions”, “Possible side effects” and “Other medicines and RAGEX”).

Ceftriaxone is also contraindicated in:

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

Tell your doctor, pharmacist or nurse before you are given RAGEX if:

• You experience or have experienced in the past any combination of the following symptoms: skin rash, skin redness, blisters on lips, eyes and mouth, skin peeling, high fever, flu-like symptoms, increased levels of liver enzymes detectable in blood tests and an increase in 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.
Cases of fatal calcium-ceftriaxone precipitates in the lungs and kidneys in premature infants and term newborns less than 1 month old have been reported. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines of administration. There are no reports in the available scientific data of precipitation within the vessels confirmed in patients who were not newborns treated with ceftriaxone and solutions containing calcium or any other calcium-containing product. Newborns have an increased risk of calcium-ceftriaxone precipitation compared to other age groups.
Ceftriaxone should not, however, be mixed or administered simultaneously with solutions containing calcium for IV administration in patients of any age, even through different infusion lines or at different infusion sites. However, in patients over 28 days of age, ceftriaxone and calcium-containing solutions can be administered sequentially, one after the other, provided different infusion lines are used or if, between one infusion and the other, the infusion lines are replaced or thoroughly flushed with saline solution, to avoid precipitation.
In patients requiring continuous infusion with total parenteral nutrition (TPN, intravenous nutrition) solutions containing calcium, healthcare professionals may consider the use of alternative antibacterial treatments that do not involve a similar risk of precipitation. If the use of ceftriaxone is considered necessary in patients requiring continuous feeding, TPN solutions and ceftriaxone can be administered simultaneously, provided they are through different infusion lines and at different sites. Alternatively, the TPN solution infusion may be stopped for the duration of the ceftriaxone infusion, observing the precaution of flushing the infusion lines between one administration and the other (see sections “Do not take RAGEX”, “Possible side effects”).
Before starting therapy with RAGEX, a thorough investigation should be carried out to establish whether you have experienced hypersensitivity to cephalosporins, penicillins and other drugs in the past.
The medicine should be administered with caution if you are allergic to penicillin as cases of cross-hypersensitivity between penicillins and cephalosporins have been reported. Due to the immaturity of organ functions, premature infants should not be treated with doses of RAGEX exceeding 50 mg/kg/day.
As with other antibiotics, prolonged use may promote the development of resistant bacteria and, in case of superinfections, appropriate measures should be taken.
Acute hypersensitivity reactions may require the use of adrenaline and other emergency measures. Preparations containing lidocaine should not be administered intravenously and in case of allergy to this local anesthetic.
If signs of infection appear, the responsible microorganism should be isolated and appropriate therapy, based on sensitivity tests, should be adopted.
Analyses on samples collected before the start of therapy should be carried out to determine the sensitivity to ceftriaxone of the responsible microorganism. Therapy with RAGEX may nevertheless be started while awaiting the results of these analyses; and the treatment should still, if necessary, be subsequently modified according to the results of the analyses. Before using RAGEX in association with other antibiotics, the instructions for use of the other drugs should be carefully reread to learn about any contraindications, warnings, precautions and undesirable reactions.
Renal function should be carefully monitored.
Clostridium difficile-associated pseudomembranous colitis (severe inflammation of the intestinal wall) has been reported following the use of cephalosporins (or other antibiotics capable of acting against many bacteria); it is important to consider this diagnosis in patients who develop diarrhea after antibiotic use.
RAGEX is eliminated by about 56% through the urine and by the remaining 44% through the bile in microbiologically active form. It is present in the feces predominantly in inactive form. In case of reduced renal function, it is eliminated to a greater extent via the bile, with the feces. Since even in this circumstance the half-life is only slightly increased, in most cases it is not necessary to reduce the dosage of RAGEX, provided that liver function is normal. Only in the presence of severe renal insufficiency 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 the binding sites of bilirubin with plasma albumin. Third-generation cephalosporins, like other beta-lactams, can induce microbial resistance and this event is greater towards opportunistic organisms, especially Enterobacteriaceae and Pseudomonas, in immunocompromised subjects (with reduced immune system function) and probably, by combining beta-lactams together.
As with any antibiotic therapy, regular blood tests (quantity and ratio between the various components of the blood) should be performed in case of prolonged treatments.
In extremely rare cases, in patients treated with high doses, ultrasound of the gallbladder has revealed findings interpretable as thickening of the bile. This condition resolves promptly upon discontinuation or termination of therapy. Even if these findings are symptomatic, a purely conservative treatment is recommended.
Positive Coombs' tests (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 use RAGEX”. Clinical studies have shown that ceftriaxone, like some other cephalosporins, can remove bilirubin from albumin in the blood.
RAGEX should not be used in newborns (especially premature infants) at risk of developing bilirubin encephalopathy (brain problem).

Other medicines and RAGEX
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
RAGEX must not be added to solutions containing calcium, such as Hartmann's and Ringer's solutions.
The simultaneous administration of high doses of RAGEX with high-activity diuretics (e.g. furosemide, used for high blood pressure and heart failure) has not so far shown disturbances of renal function. There is no evidence that RAGEX increases the renal toxicity of aminoglycosides (a type of antibiotic). The elimination of RAGEX is not modified by probenecid (used to reduce blood uric acid levels).
Synergistic action (similar and additive actions) between RAGEX and aminoglycosides against many Gram-negative germs (type of bacteria) has been demonstrated in experimental conditions. The potentiation of activity of these associations, although not always predictable, should be taken into consideration in all severe infections, resistant to other treatments, due to 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
The ingestion of alcohol following the administration of RAGEX does not give effects similar to those of disulfiram (used in the treatment of alcoholism); ceftriaxone, in fact, does not contain the N-methyltetrazolyl group considered responsible for both possible alcohol intolerance and the hemorrhagic manifestations that have occurred with other cephalosporins.

Pregnancy and breastfeeding
If you are pregnant, suspect you are pregnant or are planning to become pregnant, or if you are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
In pregnant women, during breastfeeding and in early infancy, the product should be administered only if absolutely necessary and under the direct supervision of a doctor.

Driving and operating machinery
RAGEX can sometimes cause dizziness, so your ability to drive vehicles and use machinery may be impaired.

RAGEX contains sodium.This medicine contains 82.91 mg of sodium per vial. This should be taken into consideration in people with impaired renal function or who are following a low-sodium diet.

3. How to use RAGEX

Use this medicine following exactly the instructions of 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 the reconstituted vials for
intravenous administration, as a precipitate may form. Precipitation of ceftriaxone
with calcium can also occur when ceftriaxone is mixed with solutions containing calcium in the
same intravenous administration line.
Therefore, ceftriaxone and solutions containing calcium must not be mixed together or
administered simultaneously (see paragraphs “Do not take RAGEX”, “Warnings and
precautions”, “Possible side effects”).
Dosage

Adults and children over 12 years: the recommended dose is 1g of RAGEX once a day (every 24
hours). In more severe cases or in infections caused by moderately sensitive microorganisms, the dose may
reach 4 g administered in a single solution.

Elderly: the dosage regimen for adults does not require modifications in elderly patients.
The duration of therapy depends on the course of the infection.
As with all antibiotic therapies, in general the administration of RAGEX should be prolonged for
at least 48-72 hours after defervescence or after demonstration of complete bacterial eradication.

Prophylaxis of surgical infections
For the prevention of post-operative infections, 1 g will be administered intramuscularly or 1-2 g intravenously in a single dose,
one hour before surgery, depending on the type and risk of contamination of the surgery.

Dosage in particular conditions

Renal insufficiency:in subjects with creatinine clearance greater than 10 ml/min (a renal
function test) the dosage remains unchanged. If creatinine clearance is equal to or less than
10 ml/min, up to 2 g can be administered once a day.

Hepatic insufficiency: normal dosage.

Associated renal and hepatic insufficiency: monitor ceftriaxone concentrations in the blood.

Premature infants: maximum dose 50 mg/kg once a day.
Route of administration
From a microbiological point of view, the medicine should be used immediately after
reconstitution (opening and preparation of the mixture to be injected). If not used immediately, the
conditions and period of conservation before use are the responsibility of the user. The 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 for the medicine stored at a temperature below 25°C.
They may vary in color from pale yellow to amber depending on the concentration and
period of storage; this characteristic does not affect the efficacy or tolerability of the
medicine.

Solution for intramuscular use
To perform the intramuscular injection, dissolve RAGEX i.m. with the appropriate solvent (lidocaine 1% solution) which is 2 ml for RAGEX 250 mg and 500 mg, and 3.5 ml for RAGEX 1 g: inject
deeply the freshly prepared solution into the gluteus muscle, alternating the glutei in subsequent
injections.
Lidocaine solution must not be administered intravenously.

Solution for intravenous use
To perform the intravenous injection, dissolve RAGEX with the appropriate solvent (water for
injections) which is 10 ml for RAGEX 1 g, and inject directly into the vein over 2-4 minutes.

Solution for infusion
To perform the intravenous perfusion, dissolve RAGEX in a ratio of 2 g in 40 ml of
calcium-ion-free perfusion liquid (physiological saline, 5% or 10% glucose solution, 5% levulose solution, 6% dextran glucose solution).
The perfusion will last at least 30 minutes.
RAGEX solutions should not be mixed with solutions containing other antimicrobial drugs or with diluent solutions other than those listed above due to possible incompatibility.

Use in children and adolescents

Neonates (up to 2 weeks): the daily dose is 20-50 mg/kg of body weight in a single
administration; due to the immaturity of their enzymatic systems, no more than 50
mg/Kg should be given, see paragraph “Children”.

Children (from 3 weeks to 12 years): the daily dose may vary between 20 and 80 mg/Kg. For intravenous doses equal to or greater than
50 mg/Kg, it is recommended to use an infusion lasting at least
30 minutes.
For children weighing more than 50 Kg, the dosage for adults should be used.

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

If you stop taking RAGEX
If you have any doubts about the use of this medicine, please consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The following are listed as serious side effects:

• The appearance of anaphylactic shock (allergic reaction with severe drop in blood pressure and cardiac insufficiency) 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 at the same time as solutions or products containing calcium, even through different infusion lines.
• Rarely, serious side effects, and in some cases with fatal outcome, have been reported in premature infants and full-term newborns (age <28 days) who have been treated with ceftriaxone and calcium intravenously.
• In the lungs and kidneys, precipitation of calcium-ceftriaxone salt has been observed post mortem. 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) whose severity can range 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 the use of antibiotics not directly opposed to C. difficile. Depending on the clinical indications, adequate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficileand surgical evaluation must be instituted (see section “Warnings and precautions”)

Serious skin reactions(frequency not known, cannot be defined on the basis of available data)
If you develop a serious skin reaction, tell your doctor immediately.
Signs may include

• Severe rash that develops rapidly, with blistering or peeling of the skin and possible formation of blisters in the mouth (Stevens-Johnson syndrome and toxic epidermal necrolysis, also known by the acronyms SJS and TEN).
• Any combination of the following symptoms: widespread rash,high body temperature, increased liver enzymes, abnormalities in blood tests (eosinophilia), enlarged lymph nodes, and involvement of other organs ofthe body (drug reaction with eosinophilia and systemic symptoms, also known by theacronym DRESS or drug hypersensitivity syndrome).
• Jarisch-Herxheimer reaction, which can cause fever, chills, headache,muscle pain, and rash, which generally tends to resolve spontaneously. These symptoms occur shortly after starting treatment withRAGEX to treat infections from spirochetes such as Lyme disease.

Conditions for which you should pay attention
Allergic reactions:
Chest pain in the context of allergic reactions, which may be a symptom of a heart attack
triggered by an allergy (Kounis syndrome).
Problems with the gallbladder and/or liver (frequency not known, cannot be defined on the basis of available data), which can cause pain, nausea, vomiting, jaundice, itching, unusually dark urine, and clay-colored stools.
The side effects listed below are generally mild and short-lived.

General side effects
Gastrointestinal disorders (approximately 2% of cases): soft or diarrheal stools, nausea, vomiting, stomatitis
(inflammation of the mouth) and glossitis (inflammation of the tongue), rarely thickening of the bile.
Blood changes (approximately 2%): eosinophilia (increased number of white blood cells called eosinophils),
leukopenia (reduction of all types of white blood cells), granulocytopenia (reduction only of granulocytes,
blood cells), hemolytic anemia (anemia due to the breakdown of red blood cells), thrombocytopenia
(reduction of platelets, blood cells responsible for coagulation).
Skin reactions (approximately 1%): rash, allergic dermatitis, itching, urticaria, edema.

Other rare side effects:headache, dizziness and increased transaminases, oliguria (reduction
in urine production), increased serum creatinine (kidney function test), genital fungal infection, fever, chills and anaphylactic or anaphylactoid reactions (severe allergic
reactions), for example bronchospasm (closure of the bronchi).
Rare cases of pseudomembranous enterocolitis and changes in coagulation parameters have been
reported following the use of cephalosporins. Cases of hemolytic anemia have been reported following
treatment with cephalosporins.
Rare, serious, and in some cases fatal adverse reactions have been reported in premature and full-term
neonates (age <28 days) who have been treated with ceftriaxone and intravenous calcium.
The presence of ceftriaxone and calcium salt precipitates in the lung
and kidney has also been verified post-mortem.
The high risk of precipitation in newborns 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 time of administration).

Local side effects
In rare cases, phlebitic reactions have appeared after i.v. administration; however, these reactions can
be avoided by slow injection (2-4 minutes) of the drug.
Intramuscular injection withoutlidocaine solution is painful.
Hypersensitivity reactions may occur in predisposed individuals.
If any of the side effects worsen, or if you notice the appearance of any effect

Additional side effects in children
Very rare cases of renal precipitation have been reported, particularly in children over
3 years of age and who had been treated with high daily doses (e.g. ≥ 80 mg/kg/day) or with total doses
greater than 10 grams and who presented high 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 with intravenous administration, which in some studies was
greater than 30%. The incidence appears to be lower with slow infusion (20-30 minutes).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, tell
your doctor or pharmacist. You can also report side effects directly through
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 which is stated on the packaging after Scad. The expiry
date refers to the last day of that month.
The expiry date indicated refers to the product in intact packaging, correctly
stored.
For the reconstituted solution see the paragraph “How to take RAGEX”.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What RAGEX contains

• The active substance is ceftriaxone. One vial contains ceftriaxone bisodium3.5 H2O 1,193 mg equivalent to ceftriaxone 1000 mg;
• The other component is 1% lidocaine aqueous solution. One solvent vial contains 3.5 ml of 1% lidocaine aqueous 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 vial of
solvent of 3.5 ml

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

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