Cromezin

Patient Information Leaflet

Cromezin 1 g/4 ml powder and solvent for injectable solution

cefazolin
equivalent medicinal product
Please read this leaflet carefully before using this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult 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 may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cromezin is and what it is used for

Cromezin contains the active substance cefazolin.
Cefazolin belongs to a class of medicines called beta-lactam antibiotics, which are used to treat infections caused by bacteria susceptible to this active ingredient.
Cromezin is used to treat the following infections:

• acute and chronic respiratory tract infections,
• ear and throat infections,
• liver and biliary tract infections,
• genitourinary infections,
• skin, soft tissue, bone, and joint infections,
• obstetric and gynecological infections,
• eye infections,
• inflammation of the membrane lining the internal walls of the abdominal cavity (peritoneum), of the blood (septicaemia), and of the tissue lining the internal chambers and valves of the heart (endocardium) caused by bacteria.

Cefazolin is also indicated for perioperative prophylaxis, i.e. before, during, and after surgery, in order to reduce the risk of developing certain post-surgical infections, both in patients undergoing procedures with potential risk of bacterial contamination and in patients undergoing procedures where infection could pose a serious risk (see section 3).

2. What you should know before taking Cromezin

Do not take Cromezin

• If you are allergic (hypersensitive) to cefazolin, to other similar substances (beta-lactam antibiotics such as other cephalosporins and penicillins), or to any of the other ingredients of this medicine (listed in section 6).
• If you are allergic to lidocaine or to other similar local anesthetics. Do not administer Cromezin to premature infants or children under one month of age.

Warnings and precautions

Consult your doctor or pharmacist before taking Cromezin if:

• You suffer or have suffered from allergy to cefazolin, cephalosporins, penicillins, or other antibiotics acting via the same mechanism (beta-lactams), or to other drugs. Patients allergic to antibiotics of the cephalosporin class are likely to also be allergic to penicillins. Cases of severe reactions (including anaphylaxis) to both classes of drugs have been reported.
• You are allergic to lidocaine or to other local anesthetics (see "Do not take Cromezin").
• You are being treated with other injectable medicines. Although rare, cases of patients experiencing severe anaphylactic reactions (severe, sudden-onset allergic reactions) after administration have been reported.
• You suffer or have suffered from gastrointestinal disorders, particularly colitis (inflammation of the colon), as the use of Cromezin may promote the growth of bacteria resistant (insensitive) to the bactericidal action of antibiotics and, rarely, may alter the normal colonic flora, possibly leading to overgrowth of a bacterium (Clostridium) responsible for pseudomembranous colitis.
• You have kidney problems, are over 50 years old, or are taking medicines that are toxic to the kidneys (see "Other medicines and Cromezin").
• You have contracted an infection. Your doctor will perform tests (antibiogram) to identify the microorganism responsible for the infection and, based on the results, will prescribe the most appropriate antibiotic therapy. However, treatment with Cromezin may be started even before the test results are available.
• You are taking other antibiotics. Always inform your doctor, as potential interactions, contraindications, warnings, precautions, and adverse effects must be considered (see "Other medicines and Cromezin").
• You suffer from high blood pressure or heart problems. Please note that the injectable solution contains sodium.

While using Cromezin, keep in mind that:

• If allergic reactions to cefazolin occur, you must immediately stop administering the medicine and contact your doctor or go to the nearest hospital, where you will be treated with appropriate medications (e.g., epinephrine, antihistamines, or corticosteroids).
• If you develop diarrhea, it may be a consequence of antibacterial therapy. Cefazolin, like other antibiotics belonging to the macrolide, penicillin, and cephalosporin classes, may lead to pseudomembranous colitis, ranging from mild to severe and occasionally fatal. In any case, discontinue Cromezin and contact your doctor for appropriate treatment. Avoid absolutely using medications that slow intestinal transit.
• Coagulation disorders may occur. If you are taking medications that inhibit blood clot formation, your doctor will monitor your therapy and may adjust your dosage as needed (see "Other medicines and Cromezin").
• You may develop a positive Coombs test (i.e., test positive for antibodies capable of attacking and destroying red blood cells). This may also occur in newborns whose mothers received Cromezin before delivery.
• The solvent vial supplied with the package contains lidocaine and is intended for intramuscular use only.
• If you have kidney problems, the daily dose of Cromezin you can take must be appropriately reduced (see the table below and section 3).

• If you have kidney problems, are over 50 years old, or are being treated with medicines that are harmful to the kidneys, your doctor will regularly monitor your kidney function (see "Other medicines and Cromezin").
• Administration of Cromezin directly into the intrathecal space, where fluid flows around the spinal cord, is not recommended due to the possible occurrence of severe central nervous system toxicity, including seizures.
• Administration of cephalosporins may interfere with the results of certain laboratory tests (Benedict, Fehling, and "Clinitest" methods, but not with enzymatic methods; see also "Other medicines and Cromezin"), causing false-positive results for glucose (sugar) in the urine.

Children
In early infancy, this product should be administered only when strictly necessary and under direct medical supervision. The prepared solution should be stored in the refrigerator if needed and must be used within 48 hours.
Other medicines and Cromezin
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, contact your doctor if you are taking:

• Probenecid (a medicine used in the treatment of hyperuricemia and gout). Concomitant use may increase blood levels of Cromezin.
• Medicines that cause kidney damage (such as aminoglycosides, colistin, polymyxin B, or vancomycin). Concurrent administration may increase the risk of kidney toxicity and should therefore be avoided if possible.
• Other antibacterial medicines. Several studies indicate that other antibiotics such as aminoglycosides, penicillins, or chloramphenicol, taken together with cefazolin, may enhance the effects of cephalosporins against certain microorganisms.
• Oral anticoagulants (medicines that inhibit blood clot formation). Cephalosporins very rarely may cause coagulation disorders. If co-administration of oral anticoagulants or high-dose heparin is necessary, your doctor will adjust the appropriate therapy by modifying the dose of cefazolin and/or anticoagulants and will monitor your coagulation parameters (by measuring INR or prothrombin time) (see "Warnings and precautions").

Inform your doctor if you need to undergo tests to assess sugar in the urine (glycosuria), such as tests using Benedict's or Fehling's solutions, or Clinitest tablets, as these tests may yield false results. This does not occur with enzymatic tests such as Clinistix or Tes-tape.
Cromezin with food, drinks, and alcohol
Consumption of alcohol during treatment with cefazolin has not resulted in any disulfiram-like reaction typical of drugs that inhibit alcohol metabolism (the typical effect of medicines used in the treatment of alcoholism).
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
If you are pregnant, you should take Cromezin only under direct medical advice, after your doctor has evaluated whether the potential benefits outweigh the possible risks for you and your baby.
If cefazolin is administered before a caesarean section, it may pass into the fetal bloodstream in variable amounts, lower than those found in the mother's blood. However, although cefazolin does not appear to cause adverse effects on the fetus, it should only be administered after clamping of the umbilical cord.
Breastfeeding
Cefazolin is excreted in breast milk in very small amounts. Nevertheless, you should consult your doctor if you are breastfeeding.
Driving and using machines
No effects on the ability to drive or use machinery have been reported.
Cromezin contains sodium
This medicine contains 50.6 mg of sodium (the main component of table salt) per vial of powder. This corresponds to 2.6% of the maximum daily recommended dietary intake of sodium for an adult.

3. How to take Cromezin

Take this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Adults
The recommended dose of cefazolin is 1–3 g/day, divided into 2–3 equal doses depending on
the type and severity of the infection, as shown in the following table:

*In exceptional cases, doses of cefazolin up to 12 g/day have been used.
Use in children
The recommended total daily dosage is 25–50 mg/kg body weight, divided into 3–4 equal doses; this is effective in treating most mild to moderately severe infections. The total daily dosage may be increased up to 100 mg/kg body weight in severe infections.
Since safety of use has not been established in premature infants and neonates under 1 month of age, administration of cefazolin is not recommended in these patients.
Paediatric dosing guidelines

Use in patients with renal impairment
In patients with renal impairment, doses should be appropriately reduced according to the degree of
renal impairment, as shown in the following table:

N.B. In particularly severe infections, an appropriate loading dose is recommended before reducing the dosages as indicated above.
Use in patients undergoing peritoneal dialysis (physical therapy used for the treatment of chronic renal failure)
In patients undergoing peritoneal dialysis (2 L/h), blood concentrations of cefazolin were found to average 10 and 30 mg/ml after 24-hour instillation of dialysate solutions containing 50 mg/L and 150 mg/L of the drug, respectively. Peak blood levels were 29 mg/ml (range: 13–44 mg/ml) with 50 mg/L (3 patients) and 72 mg/ml (range: 26–142 mg/ml) with 150 mg/L (6 patients). Intraperitoneal administration of cefazolin is generally well tolerated.
Use in perioperative prophylaxis
To prevent post-surgical infections in procedures with potential risk of bacterial contamination, the recommended dosage is:

• 1 g intramuscularly (I.M.), administered 30 to 60 minutes before surgery;
• For prolonged procedures (e.g., 2 hours or longer), 0.5–1 g I.M. during surgery (to be adjusted according to the duration of the procedure);
• 0.5–1 g I.M. every 6–8 hours for 24 hours after surgery.

It is important that:

1. the initial dose is administered 30 minutes to one hour before the start of surgery to ensure adequate blood and tissue levels of the antibiotic at the time of incision;
2. if significant exposure to pathogens is likely, cefazolin should be administered at regular intervals during surgery to maintain consistent blood levels;
3. the use of cefazolin for prophylactic purposes should end within 24 hours after completion of the procedure;
4. in surgical procedures where infection could be particularly devastating (e.g., open-heart surgery, joint prosthesis implantation), prophylaxis with cefazolin may continue for 3–5 days after surgery.
   Method of administration
   Once reconstituted, the solution may be administered by intramuscular route.
   Cefazolin should be reconstituted by dissolving the vial contents with the solvent ampoule supplied in the package, or with 0.9% sodium chloride solution for injections or water for injections, as shown in the table below; shake well until complete dissolution is achieved.
   The solution should be used immediately after reconstitution.
   DILUTION SCHEME

* If the solvent vial (4 ml) supplied with the pack is not used, the 1 g vial must be reconstituted
only with water for injections.
Warning: the 4 ml solvent vial supplied with the 1 g packs, containing 0.5% lidocaine
hydrochloride, is intended for intramuscular use only.
If you take more Cromezin than you should
If you have been given too much cefazolin, stop taking the medicine immediately and contact your doctor or go to the nearest hospital.
Symptoms and signs of excessive cefazolin administration include pain, inflammation and phlebitis at the injection site, fainting, numbness in the limbs, and headache. Overdose may sometimes trigger seizures, particularly in patients with kidney problems in whom drug accumulation may occur. Laboratory test abnormalities: increased levels of creatinine (creatininemia) and blood urea nitrogen (azotemia), liver enzymes and bilirubin; positive Coombs test; changes in blood cell counts (thrombocytosis, thrombocytopenia, eosinophilia, leukopenia); and prolonged prothrombin time (a parameter evaluating blood clotting ability).
If you experience any of the symptoms listed above, your doctor or the hospital physician will provide the most appropriate treatment based on your symptoms.
If you forget to take Cromezin
Do not take a double dose to make up for a forgotten dose. Inform your doctor, who will advise you on how to continue the treatment.
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine may cause adverse reactions, although not everyone experiences them.
If you experience any of the following serious adverse reactions, stop taking CROMEZIN immediately and contact your doctor straight away or go to the nearest hospital.

• severe skin reactions, some of which may be fatal, such as severe skin inflammation (erythema multiforme), widespread skin irritation with skin peeling (exfoliative dermatitis), severe skin reaction with skin peeling and swelling, skin blisters, affecting mouth, eyes, genitals (Stevens-Johnson Syndrome), often accompanied by malaise, chills, myalgia and fever (toxic epidermal necrolysis);
• swelling around the eyes, face, lips, mouth or throat, leading to difficulty in swallowing and breathing (angioedema);
• severe acute and generalized reactions characterized by breathing difficulties, often followed by a severe drop in blood pressure (systolic value below 80 mmHg), usually associated with weak and rapid pulse (cardiovascular collapse) or shock;
• severe and persistent diarrhoea with blood or mucus due to a disease called Clostridium difficile-associated pseudomembranous colitis;

Other adverse reactions that may occur with CROMEZIN
Allergic reactions
Urticaria, pruritus, skin rashes (maculopapular, erythematous or morbilliform), fever, chills, urticaria, joint pain and inflammation, swelling, lymph node enlargement, increased eosinophil count (white blood cells involved in allergic reactions), erythema, anal and genital pruritus. Rarely, pruritus and urticaria with or without skin or mucosal swelling (angioedema), nausea, vomiting, crampy abdominal pain and diarrhoea. These allergic reactions occur more frequently in patients with a history of allergy, particularly to penicillin.

Effects on blood
Positive Coombs test (a test used in diagnosing anaemias) occurs in 3% or more of patients treated with cephalosporins. Rarely, mild and transient alterations in blood cell levels (neutropenia, thrombocytosis or thrombocytopenia, leucopenia). Rarely agranulocytosis, pancytopenia, anaemia due to insufficient bone marrow production of all types of blood cells (aplastic anaemia), anaemia due to low haemoglobin concentration in the blood (haemolytic anaemia), bleeding.

Effects on the liver
Increased liver enzymes (such as transaminases (AST/SGOT, ALT/SGPT), alkaline phosphatase, lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGTP)), increased bilirubin (a yellowish-red pigment released as a waste product during red blood cell breakdown), liver dysfunction, including backward flow of bile into the bloodstream (cholestasis). These effects are generally mild and resolve upon discontinuation of therapy.

Effects on the kidneys
Occasionally, transient increase in creatinine and blood nitrogen levels (azotemia and creatininemia). Rarely, severe kidney problems.

Gastrointestinal effects
Nausea, vomiting, diarrhoea and fungal infections of the oral mucosa (oral thrush) are frequent. Generally these effects are mild and transient, but rarely they may require discontinuation of the medicine. Other effects include abdominal pain, feeling of needing to defecate even when the bowel is empty (tenesmus), indigestion, inflammation of the tongue, gastric burning.

Local effects
Pain, tissue hardening and tenderness commonly occur after intramuscular administration.

Nervous system effects
Dizziness, headache, malaise, fatigue.

Reactions at the injection site
Rarely, pain after intramuscular administration, swelling, phlebitis.

Other adverse reactions
Genital and anal pruritus, fungal infections of the female genital area.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, please consult your doctor or pharmacist. You may also report adverse reactions directly via the national reporting system at the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store Cromezin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp.". The expiry date refers to the last day of that month and to the product in its original, undamaged packaging stored correctly. The reconstituted solution must be used within 24 hours.
Store in the original packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Cromezin contains
The active substance is cefazolin.
One vial of Cromezin lyophilisate contains 1050 mg of cefazolin sodium equivalent to 1000 mg of cefazolin.
One 4 ml solvent ampoule for intramuscular use contains lidocaine hydrochloride and water for injections.

Description of the appearance of Cromezin and contents of the pack
Cromezin is available as a powder and solvent for injectable solution for intramuscular use.
Carton pack containing one 1 g glass vial of powder and one 4 ml glass ampoule containing the solvent.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
So.Se.PHARM S.r.l.
Via dei Castelli Romani, 22
00040 Pomezia (RM)
Italy

Manufacturer
ESSETI Farmaceutici S.r.l.
Via Campobello, 15
00071 Pomezia (RM)
Italy

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