Tienam - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Imipenem, Cilastatin

TIENAM 500 mg / 500 mg powder for solution for infusion

Indications Why is Tienam used? What is it for?

TIENAM belongs to a group of medicines called carbapenem antibiotics. Kills a wide range of bacteria (germs) that cause infections in various parts of the body in adults and children aged 1 year and over.

Treatment

Your doctor has prescribed TIENAM for you because you have one (or more than one) of the following types of infections:

  • Complicated abdominal infections
  • Infection affecting the lungs (pneumonia)
  • Infections that you may get during or after delivery of your baby
  • Complicated urinary tract infections
  • Complicated skin and soft tissue infections

TIENAM can be used to treat patients with low white blood cell counts who have a fever that is suspected to be caused by a 'bacterial infection.

TIENAM can be used to treat bacterial infections of the blood which could be associated with any of the infections described above.

Contraindications When Tienam should not be used

Do not use TIENAM

  • if you are allergic to imipenem, cilastatin or any of the other ingredients of TIENAM
  • if you are allergic to other antibiotics such as penicillins, cephalosporins, or carbapenems.

Precautions for use What you need to know before taking Tienam

Take special care with TIENAM

Tell your doctor about any medical conditions you have or have had including:

  • allergies to any type of medicine including antibiotics (sudden life-threatening allergic reactions that require immediate medical treatment)
  • colitis or any other gastrointestinal disease
  • problems affecting the kidneys or urinary tract, including impaired renal function (increased blood levels of TIENAM in patients with impaired renal function. Central nervous system adverse reactions may occur if the dose is not adjusted to renal function)
  • any central nervous system disorders such as localized tremors or seizures (fits)
  • liver problems.

It may have a positive response to a test (Coombs test) which indicates the presence of antibodies that can destroy red blood cells. Your doctor will discuss this with you.

Tell your doctor if you are taking medicines called valproic acid or sodium valproate (see Using with other medicines below).

Children

TIENAM is not recommended in children under 1 year of age or in children with kidney problems.

Interactions Which drugs or foods can modify the effect of Tienam

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Tell your doctor if you are taking ganciclovir which is used to treat some viral infections.

Also tell your doctor if you are taking valproic acid or sodium valproate (used to treat epilepsy, bipolar disorder, migraine or schizophrenia) or any other warfarin-like blood thinners.

Your doctor will decide whether you should use TIENAM in combination with these medicines.

Warnings It is important to know that:

Pregnancy and breastfeeding

It is important to tell your doctor if you are pregnant or planning to become pregnant before starting TIENAM therapy. TIENAM has not been studied in pregnant women. TIENAM should not be used during pregnancy unless your doctor decides that the potential benefits justify the potential risks to the child's development.

It is important that you tell your doctor if you are breastfeeding or intend to breastfeed before starting TIENAM therapy. Small amounts of this medicine may pass into the milk and as a result the infant may be affected. Therefore, the doctor will decide whether to use TIENAM during treatment. feeding time.

Ask your doctor or pharmacist for advice before using any medicine.

Driving and using machines

There are some side effects associated with this medicine such as seeing, hearing or feeling something that is not there, dizziness, sleepiness, feeling dizzy which may interfere with driving or using machines (see section 4).

Important information about some of the ingredients of TIENAM

In patients on a low sodium diet it should be taken into account that this medicinal product contains approximately 1.6 mEq (approximately 37.6 mg) of sodium in the 500 mg dose.

Dose, Method and Time of Administration How to use Tienam: Posology

TIENAM will be prepared and administered by a doctor or other healthcare professional. Your doctor will determine how much TIENAM you need.

Adults and adolescents

The usual dose of TIENAM for adults and adolescents is 500 mg / 500 mg every 6 hours or 1,000 mg / 1,000 mg every 6 or 8 hours. If you have kidney problems or weigh less than 70 kg your doctor may reduce your dose.

Children

The usual dose for children 1 year of age and older is a dose of 15/15 or 25/25 mg / kg every 6 hours. TIENAM is not recommended in children under 1 year of age and in children with kidney problems.

Method of administration

TIENAM is administered intravenously (into a vein) over 20-30 minutes when given at a dose less than or equal to 500 mg / 500 mg or over 40-60 minutes when given at a dose greater than 500 mg / 500 mg. The infusion rate may be slowed down if you feel sick.

Overdose What to do if you have taken too much Tienam

If you use more TIENAM than you should

Symptoms of overdose may include seizures (fits), confusion, tremors, nausea, vomiting, low blood pressure and slow heart rate. If you think you have been given too much TIENAM, contact your doctor or other healthcare professional immediately.

If you forget to use TIENAM

If you think you have not been given a dose, contact your doctor or other healthcare professional immediately.

Do not take a double dose to make up for a forgotten dose.

If you stop taking TIENAM

Do not stop taking TIENAM until your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Tienam

Like all medicines, TIENAM can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention:

  • very common: affects more than 1 user in 10
  • common: affects 1 to 10 users in 100
  • uncommon: affects 1 to 10 users in 1,000
  • rare: affects 1 to 10 users in 10,000
  • very rare: affects less than 1 user in 10,000
  • not known: frequency cannot be estimated from the available data

The following side effects occur rarely, however if these side effects occur during or after treatment with TIENAM, the administration should be stopped and your doctor contacted immediately.

  • Allergic reactions including skin rash, swelling of the face, lips, tongue and / or throat (with difficulty breathing or swallowing), and / or low blood pressure
  • Skin exfoliation (toxic epidermal necrolysis)
  • Severe skin reactions (Stevens Johnson syndrome and erythema multiforme)
  • Severe rash with loss of skin and hair (exfoliative dermatitis)

Other possible side effects:

common

  • Nausea, vomiting, diarrhea. Nausea and vomiting appear to occur more frequently in patients with a low white blood cell count
  • Swelling and redness along the vein which is extremely painful to touch
  • Rash
  • Abnormal liver function seen in blood tests
  • Increase in some types of white blood cells

Uncommon

  • Local skin redness
  • Local pain and induration at the injection site
  • Itchy skin
  • Urticaria
  • Fever
  • Blood disorders that involve cellular components of the blood and are usually detected in blood tests (symptoms may be fatigue, pale skin, and lasting bruising after injury)
  • Changes in kidney, liver and blood function seen in blood tests
  • Uncontrolled tremors and muscle spasms
  • Seizures (fits)
  • Mental disorders (such as mood swings and impaired judgment)
  • Seeing, hearing and feeling something that does not exist (hallucinations)
  • Confusion
  • Dizziness, sleepiness
  • Low blood pressure

Rare

  • Fungal infection (candidiasis)
  • Discoloration of the teeth and / or tongue
  • Inflammation of the colon with severe diarrhea
  • Changes in taste
  • Inability of the liver to perform its normal function
  • Inflammation of the liver
  • Inability of the kidney to perform its normal function
  • Changes in the amount of urine, changes in the color of the urine
  • Brain disease, tingling sensation, localized tremor
  • Loss of hearing

Very rare

  • Severe loss of liver function caused by inflammation (fulminant hepatitis)
  • Inflammation of the stomach or intestines (gastro-enteritis)
  • Inflammation of the intestine with bloody diarrhea (hemorrhagic colitis)
  • Red and swollen tongue, excessive growth of the protrusions normally found on the tongue which give it a hairy appearance, heartburn, sore throat, increased saliva production
  • Stomach pain
  • A spinning sensation (vertigo), headache
  • Ringing in the ears (tinnitus)
  • Pain in many joints, weakness
  • Irregular heartbeat, strong or rapid heartbeat
  • Chest pain, difficulty in breathing, abnormally rapid and shallow breathing, upper spine pain
  • Redness, blue discoloration of the face and lips, skin tissue changes, excessive sweating
  • Vulvar itching in women
  • Alteration in the number of red blood cells
  • Worsening of a rare disease associated with muscle weakness (aggravation of myasthenia gravis)

Not known

  • Abnormal movements
  • Agitation

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Keep TIENAM out of the reach and sight of children.

Do not use TIENAM after the expiry date which is stated on the pack. The expiry date refers to the last day of the month.

Do not store above 25 ° C.

After reconstitution: Diluted solutions should be used immediately. The time interval between the start of reconstitution and the end of the intravenous infusion should not exceed two hours.

Do not freeze the reconstituted solution.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What TIENAM contains

  • The active ingredients are imipenem and cilastatin. Each vial contains imipenem monohydrate equivalent to 500 mg of imipenem and cilastatin sodium equal to 500 mg of cilastatin.
  • The excipient is sodium bicarbonate.

Description of what TIENAM looks like and contents of the pack

TIENAM is a white to light yellow powder for solution for infusion contained in a glass vial. Packs of 1, 10 or 25 vials. Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Tienam can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

TIENAM 500 MG / 500 MG POWDER FOR SOLUTION FOR INFUSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains imipenem monohydrate equivalent to anhydrous imipenem 500 mg and cilastatin sodium salt equal to cilastatin 500 mg.

Excipient with known effects:

Each vial contains sodium bicarbonate equal to approximately 1.6 mEq of sodium (approximately 37.6 mg).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Powder for solution for infusion.

White to light yellow powder.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

TIENAM is indicated for the treatment of the following infections in adults and children aged 1 year and older (see sections 4.4 and 5.1):

• complicated intra-abdominal infections

• severe pneumonia including hospital pneumonia and ventilator-associated pneumonia

• intra- and post-partum infections

• complicated urinary tract infections

• complicated skin and soft tissue infections

TIENAM can be used in the treatment of febrile neutropenic patients suspected of having a "bacterial infection."

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections mentioned above.

Official guidelines on the appropriate use of antibacterial agents should be considered.


04.2 Posology and method of administration

Dosage

The recommended doses of TIENAM represent the amount of imipenem / cilastatin to be administered.

The daily dose of TIENAM should be determined according to the type of infection and administered in equally divided doses determined by the assessment of the sensitivity of the pathogen (s) and the patient's renal function (see also sections 4.4 and 5.1 ).

Adults and adolescents

For patients with normal renal function (creatinine clearance ≥ 90 ml / min), the recommended doses are:

500 mg / 500 mg every 6 hours or

1,000 mg / 1,000 mg every 8 hours or every 6 hours

It is recommended that suspected or documented infections caused by less sensitive bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with fever) are treated with 1,000 mg / 1,000 mg given every 6 hours.

A dose reduction is required when creatinine clearance is

The maximum total daily dose should not exceed 4,000 mg / 4,000 mg / day.

Renal impairment

Determination of the reduced dose for adults with impaired renal function:

1. The total daily dose (eg 2,000 / 2,000, 3,000 / 3,000 or 4,000 / 4,000 mg) should be selected and usually applied to patients with normal renal function.

2. From Table 1 the appropriate reduced dose is selected based on the patient's creatinine clearance. For infusion times see Method of administration.

Table 1

Creatinine clearance (mL / min) is: If the TOTAL DAILY DOSE is: 2,000 mg / day If the TOTAL DAILY DOSE is: 3,000 mg / day If the TOTAL DAILY DOSE is: 4,000 mg / day ≥90 (normal) 500 every 6 hours 1,000 every 8 hours 1,000 every 6 hours reduced dosage (mg) for patients with renal impairment: 400 every 6 hours 500 every 6 hours 750 every 8 hours 300 every 6 hours 500 every 8 hours 500 every 6 hours 200 every 6 hours 500 every 12 hours 500 every 12 hours

Patients with creatinine clearance

These patients should not receive TIENAM unless hemodialysis is performed within 48 hours.

Patients on hemodialysis

When treating patients with creatinine clearance

Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive TIENAM after hemodialysis and 12 hours after the end of hemodialysis treatment. Patients on dialysis, especially those with underlying central nervous system (CNS) disease, should be carefully monitored; for hemodialysis patients TIENAM is only recommended when the benefit outweighs the potential risk of seizures (see section 4.4).

There is currently insufficient data to recommend the use of TIENAM for patients on peritoneal dialysis.

Hepatic impairment

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

Elderly population

No dose adjustment is required in elderly patients with normal renal function (see section 5.2).

Pediatric population ≥ 1 year of age

For pediatric patients ≥1 year of age, the recommended dose is a dose of 15/15 or 25/25 mg / kg administered every 6 hours.

It is recommended that suspected or documented infections caused by less sensitive bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with fever) are treated with 25/25 mg / kg given every 6 hours.

Pediatric population

Clinical data are insufficient to recommend administration in children less than 1 year of age.

Pediatric population with impaired renal function

Clinical data are insufficient to recommend administration in pediatric patients with renal impairment (serum creatinine> 2 mg / dl). See section 4.4.

Method of administration

TIENAM must be reconstituted and then diluted (see sections 6.2, 6.3 and 6.6) prior to administration. Each dose ≤ 500 mg / 500 mg should be administered by intravenous infusion over 20 to 30 minutes. Each dose> 500 mg / 500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.


04.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Hypersensitivity to any other carbapenem antibacterial agent.

• Severe hypersensitivity (eg anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (eg penicillins or cephalosporins).


04.4 Special warnings and appropriate precautions for use

General

The choice of imipenem / cilastatin to treat a patient must consider the appropriateness of use of a carbapenem antibacterial agent based on factors such as the severity of the infection, the prevalence of resistance to other appropriate antibacterial agents, and the risk of selecting bacteria resistant to carbapenems.

Hypersensitivity

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibiotics. The onset of these reactions was more frequent in subjects with a history of hypersensitivity to multiple allergens. Before initiating therapy with TIENAM, particular attention should be paid to previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams and other allergens ( see section 4.3) If an allergic reaction to TIENAM should be stopped immediately Serious anaphylactic reactions require immediate emergency treatment.

Liver

Hepatic function should be closely monitored during treatment with imipenem / cilastatin due to the risk of hepatic toxicity (such as increased transaminases, liver failure and fulminant hepatitis).

Use in patients with liver disease: Patients with pre-existing liver disorders should undergo monitoring of liver function during treatment with imipenem / cilastatin. No dose adjustment is necessary (see section 4.2).

Hematology

A positive direct or indirect Coombs test may develop during treatment with imipenem / cilastatin.

Antibacterial spectrum

Before starting any empirical treatment, the antibacterial spectrum of imipenem / cilastatin should be considered, especially in life-threatening diseases. In addition, caution should be used due to the limited sensitivity of specific pathogens associated with e.g. skin and soft tissue infections to imipemen / cilastatin. The use of imipenem / cilastatin is not appropriate for the treatment of this type of infection unless the pathogen is already documented and is found to be susceptible or there is a high suspicion that the most likely pathogen is sensitive to treatment. concomitant with an appropriate anti-methicillin-resistant agent Staphylococcus aureus (MRSA) may be indicated when MRSA infections are suspected or proven to be involved in the approved indications. When infections are suspected or documented to be involved in the approved indications Pseudomonas aeruginosa concomitant use of an aminoglycoside may be indicated (see section 4.1).

Interaction with valproic acid

The concomitant use of imipenem / cilastatin and valproic acid / sodium valproate is not recommended (see section 4.5).

Clostridium difficile

Antibiotic-associated colitis and pseudomembranous colitis have been reported with imipenem / cilastatin and virtually all other antibacterial agents and can range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhea concomitantly with or after the use of imipenem / cilastatin (see section 4.8). Clostridium difficile. Medicinal products that inhibit peristalsis should not be given.

Meningitis

TIENAM is not recommended for the treatment of meningitis.

Renal impairment

Imipenem / cilastatin accumulates in patients with impaired renal function. CNS adverse reactions may occur if the dose is not adjusted to renal function, see sections 4.2 and 4.4 "Central nervous system" in this section.

Central nervous system

CNS adverse reactions such as myoclonic activity, confusional states or seizures have been reported, especially when prescribed dosages based on renal function and body weight are exceeded. These effects have been reported more frequently in patients with CNS disorders (e.g. brain injury or history of seizures) and / or in patients with impaired renal function where accumulation of the administered substances may occur. Therefore, careful adherence to recommended dosages is insisted upon especially in these patients (see section 4.2). In patients with known epileptic disorders, anticonvulsant therapy should be continued.

Particular attention should be paid to neurological symptoms or seizures in children with known risk factors for seizures or concomitant treatment with medicinal products that lower the seizure threshold.

If focal tremors, myoclonia, or seizures occur, patients should be neurologically evaluated and placed on anticonvulsant therapy if not already established. If CNS symptoms continue the dose of TIENAM should be decreased or discontinued.

Patients with a creatinine clearance

Pediatric population

Clinical data are insufficient to recommend the use of TIENAM in patients less than 1 year of age or in pediatric patients with impaired renal function (serum creatinine> 2 mg / dl). See also above Central nervous system.

TIENAM 500 mg / 500 mg contains 37.6 mg of sodium (1.6 mEq) which should be considered in patients on a controlled sodium diet.


04.5 Interactions with other medicinal products and other forms of interaction

Generalized seizures have been reported in patients treated with ganciclovir and TIENAM. These medicinal products should not be combined in treatment unless the potential benefits outweigh the risk.

Decreases in serum valproic acid which may fall below the therapeutic range have been reported when valproic acid was co-administered with carbapenem agents.

Reduced serum levels of valproic acid can lead to inadequate control of seizures; therefore concomitant use of imipenem and valproic acid / sodium valproate is not recommended and alternative antibacterial or anticonvulsant therapies should be considered (see section 4.4).

Oral anticoagulants

Co-administration of antibiotics with warfarin may increase its anticoagulant effects. There have been many reports of increased anticoagulant effects of orally administered anticoagulant agents, including warfarin in patients on concomitant therapy with antibacterial agents. The risk may vary according to the underlying infection, age and general health condition of the patient, so that it is difficult to assess the contribution of the antibiotic to the increase in the INR (international normalized ratio). It is recommended to monitor the patient. INR frequently during and shortly after co-administration of antibiotics with an oral anticoagulant agent.

Concomitant administration of TIENAM and probenecid resulted in minimal increases in plasma levels and half-life of imipenem. Urinary recovery of active (unmetabolized) imipenem decreased by approximately 60% of the dose when imipenem was administered with probenecid. Concomitant administration of TIENAM and probenecid doubled the plasma level and half-life of cilastatin but had no effect on the urinary recovery of cilastatin.

Pediatric population

Interaction studies have only been performed in adults.


04.6 Pregnancy and breastfeeding

Pregnancy

There are no adequate and well controlled studies on the use of imipenem / cilastatin in pregnant women.

Studies in pregnant monkeys have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

TIENAM should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Feeding time

Imipenem and cilastatin are excreted in breast milk in small quantities.Limited absorption of both components occurs following oral administration. Therefore it is unlikely that the nursing infant will be exposed to significant amounts. If the use of TIENAM is deemed necessary, the benefit of breastfeeding for the child must be weighed against the possible risk.

Fertility

There are no data available regarding the potential effects of imipenem / cilastatin treatment on male or female fertility.


04.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, there are some undesirable effects (such as hallucination, dizziness, somnolence and vertigo) associated with the medicine that may affect some patients' ability to drive and use. machinery (see section 4.8).


04.8 Undesirable effects

In clinical studies of 1,723 patients treated with intravenous imipenem / cilastatin the most frequent systemic adverse reactions that were reported at least as possibly related to therapy were nausea (2.0%), diarrhea (1.8%), vomiting. (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), convulsions (0.4%) (see section 4.4), dizziness (0.3 %), itching (0.3%), hives (0.2%), drowsiness (0.2%). Similarly, the most frequently reported local adverse reactions were phlebitis / thrombophlebitis (3.1%), injection site pain (0.7%), injection site erythema (0.4%) and vein induration ( 0.2%). Elevations in serum transaminases and alkaline phosphatase have been commonly reported.

The following adverse reactions were reported during clinical trials and commercial use of the medicinal product.

All adverse reactions are reported by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100,

Within each frequency grouping undesirable effects are listed in descending order of severity.

System and organ classification Frequency Event Infections and infestations Rare pseudomembranous colitis, candidiasis Very rare gastroenteritis Disorders of the blood and lymphatic system common eosinophilia Uncommon pancytopenia, neutropenia, leukopenia, thrombocytopenia, thrombocytosis Rare agranulocytosis Very rare haemolytic anemia, bone marrow depression Disorders of the immune system Rare anaphylactic reactions Psychiatric disorders Uncommon mental disorders including hallucinations and confusional states Nervous system disorders Uncommon convulsions, myoclonic activity, dizziness, somnolence Rare encephalopathy, paraesthesia, focal tremor, taste disturbance Very rare Not known worsening of myasthenia gravis, headache, agitation, dyskinesia Ear and labyrinth disorders Rare hearing loss Very rare vertigo, tinnitus Cardiac pathologies Very rare cyanosis, tachycardia, palpitations Vascular pathologies common thrombophlebitis Uncommon hypotension Very rare hot flashes Respiratory, thoracic and mediastinal disorders Very rare dyspnoea, hyperventilation, pharyngeal pain Gastrointestinal disorders common diarrhea, vomiting, nausea Drug-induced nausea and / or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with TIENAM Rare discoloration of the teeth and / or tongue Very rare haemorrhagic colitis, abdominal pain, heartburn, glossitis, hypertrophy of lingual papillae, increased salivation Hepatobiliary disorders Rare liver failure, hepatitis Very rare fulminant hepatitis Skin and subcutaneous tissue disorders common rash (e.g. exanthematous) Uncommon hives, itching Rare toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis Very rare hyperhidrosis, skin tissue changes Musculoskeletal and connective tissue disorders Very rare polyarthralgia, pain in the thoracic spine Renal and urinary disorders Rare acute renal failure, oliguria / anuria, polyuria, urine discolouration (this fact is of no importance and should not be confused with haematuria) It is difficult to assess the role of TIENAM in changes in renal function, as they are of usually present predisposing factors for the onset of pre-renal azotemia or impaired renal function. Diseases of the reproductive system and breast Very rare vulvar itching General disorders and administration site conditions Uncommon fever, local pain and induration at the injection site, injection site erythema Very rare chest discomfort, asthenia / weakness Diagnostic tests common increase in serum transaminases, increase in serum alkaline phosphatase Uncommon a positive direct Coombs test, prolonged prothrombin time, decreased hemoglobin, increased serum bilirubin, increased serum creatinine, increased blood urea nitrogen

Pediatric population (aged ≥ 3 months)

In studies involving 178 pediatric patients ≥ 3 months of age, adverse reactions reported were consistent with those reported in adults.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.


04.9 Overdose

Symptoms of overdose that may occur are consistent with the adverse reaction profile; these may include convulsions, confusions, tremors, nausea, vomiting, hypotension, bradycardia. No information is available on the treatment of overdose with TIENAM. Imipenem / cilastatin sodium is haemodialysable. However, the usefulness of this procedure in the event of an overdose is not known.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antibacterials for systemic use, carbapenems.

ATC code: J01DH51.

Mechanism of action

There are two components in TIENAM: imipenem and cilastatin sodium in a 1: 1 weight ratio.

Imipenem, also identified as N-formimidoyl thienamycin, is a semi-synthetic derivative of thienamycin, the original compound produced by the filamentous bacterium Streptomyces cattleya.

Imipenem exerts its bactericidal activity by inhibiting the synthesis of the bacterial cell wall in Gram-positive and Gram-negative bacteria by binding to penicillin-binding proteins (PBPs).

Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme that metabolizes and inactivates imipenem. It has no intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Pharmacokinetic / Pharmacodynamic (FC / FD) relationship

Similarly to other beta-lactam antibacterial agents, the time when imipenem concentrations are above the Minimum Inhibitory Concentration (MIC) (T> MIC) has been shown to better correlate with efficacy.

Resistance mechanism

Resistance to imipenem may be due to the following causes:

• Reduced permeability of the outer membrane of Gram-negative bacteria (due to decreased production of porins)

• Imipenem can be actively removed from the cell with an efflux pump

• Reduced affinity of Penicillin Binding Protein (PBPS) to imipenem

• Imipenem is stable on hydrolysis against most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of the relatively rare beta-lactamases which hydrolyze carbapenems. Resistant species to other carbapenems generally exhibit co-resistance to imipenem. There is no cross-resistance based on target between imipenem and agents belonging to the classes of quinolones, macrolide amino glycosides and tetracyclines.

Breakpoint

The EUCAST MIC breakpoints for imipenem to distinguish susceptible (S) from resistant (R) pathogens are as follows (v 1.1 2010-04-27):

Enterobacteriaceae1: S ≤ 2 mg / l, R> 8 mg / l

Pseudomonas spp. 2: S ≤ 4 mg / l, R> 8 mg / l

Acinetobacter spp .: S ≤ 2 mg / l, R> 8 mg / l

Staphylococcus spp. 3: inferred from cefoxitin sensitivity

Enterococcus spp .: S ≤ 4 mg / l, R> 8 mg / l

Streptococcus A, B, C, G: The sensitivity to beta lactamases of the streptococcus Hemolytic beta A, B, C and G is inferred from penicillin sensitivity

Streptococcus pneumoniae4: S ≤ 2 mg / l, R> 2 mg / l

• Other streptococci4: S ≤ 2 mg / l, R> 2 mg / l

Haemophilus influenzae 4: S ≤ 2 mg / l, R> 2 mg / l

Moraxella catarrhalis4: S. 2 mg / l, R> 2 mg / l

Neisseria gonorrhoeae: There is insufficient evidence that the Neisseria gonorrhoeae is a good target for imipenem therapy

• Gram positive anaerobes: S ≤ 2 mg / l, R> 8 mg / l

• Gram negative anaerobes: S ≤ 2 mg / l, R> 8 mg / l

• Non-species related breakpoints5: S ≤ 2 mg / l, R> 8 mg / l

1 Proteus and Morganella spp are considered suboptimal targets for imipenem.

2 The breakpoints for the Pseudomonas refer to a therapy with high doses administered frequently (1 g every 6 hours).

3 Susceptibility of staphylococci to carbapenems is inferred from susceptibility to cefoxitin.

4 Strains with MIC values ​​above the susceptibility breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on each of these isolates should be repeated and if the result is confirmed the isolate should be sent to the reference laboratory. Until there is evidence for clinical response for isolates with confirmed MICs greater than current resistance breakpoints they should be reported as resistant.

5 Non-species related breakpoints were determined primarily from FC / FD data and are independent of MIC distributions of specific species. They should only be used for species not mentioned in the overview of species related breakpoints or in the notes.

Sensitivity

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species: Gram-positive aerobes: Enterococcus faecalis Staphylococcus aureus (methicillin-sensitive)* Staphylococcus coagulase negative (methicillin-sensitive) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans group Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Serratia marcescens Gram-positive anaerobes: Clostridium perfringens ** Peptostreptococcus spp. ** Gram-negative anaerobes: Bacteroides fragilis Bacteroides fragilis group Fusobacterium spp. Porphyromonas asaccharolytica Prevotella spp. Veillonella spp. Species for which acquired resistance can be a problem: Gram-negative aerobes: Acinetobacter baumannii Pseudomonas aeruginosa Inherently resistant species: Gram-positive aerobes: Enterococcus faecium Gram-negative aerobes: Some strains of Burkholderia cepacia (in the past Pseudomonas cepacia) Legionella spp. Stenotrophomonas maltophilia (in the past Xanthomonas maltophilia And Pseudomonas maltophilia) Others: Chlamydia spp. Chlamydophila spp. Mycoplasma spp. Ureoplasma urealyticum

* All methicillin-resistant staphylococci are resistant to imipenem / cilastatin.

** A non-species related EUCAST breakpoint is used.


05.2 "Pharmacokinetic properties

Imipenem

Absorption

In healthy volunteers, TIENAM infusion lasting more than 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 mcg / ml at the 250 mg / 250 mg dose, and from 21 to 58 mcg / ml at the dose. of 500 mg / 500 mg, and 41 to 83 mcg / ml at a dose of 1,000 mg / 1,000 mg. The mean peak plasma levels of imipenem at doses of 250 mg / 250 mg, 500 mg / 500 mg and 1,000 mg / 1,000 mg were 17, 39, and 66 mcg / mL, respectively. At these doses, plasma levels of imipenem drop below 1 mcg / mL or less in 4-6 hours.

Distribution

The binding of imipenem to serum proteins is approximately 20%.

Biotransformation

Administered alone, imipenem is metabolised renally by dehydropeptidase-I. In several studies, individual urinary recoveries ranged from 5 to 40% with an average recovery of 15-20%.

Cilastatin is a specific inhibitor of the enzyme dehydropeptidase-I and effectively inhibits the metabolism of imipenem, so that the concomitant administration of imipenem and cilastatin allows the therapeutic antibacterial levels of imipenem to be reached in both urine and plasma.

Elimination

The plasma half-life of imipenem was one hour. Approximately 70% of the antibiotic administered was found unchanged in the urine within ten hours, and no further urinary excretion of the drug was detected. Urinary concentrations of imipenem remained above 10 mcg / ml for up to eight hours after a TIENAM 500 mg / 500 mg dose. The remainder of the administered dose was recovered in the urine in the form of antibacterially inactive metabolites and faecal elimination of imipenem was essentially nil.

With administration of TIENAM every six hours in patients with normal renal function, no accumulation of imipenem in plasma or urine was observed.

Cilastatin

Absorption

Peak plasma levels of cilastatin following a 20 minute infusion of TIENAM ranged from 21 to 26 mcg / mL per 250 mg / 250 mg dose, 21 to 55 mcg / mL per 500 mg / 500 mg dose and 56 to 88 mcg / mL per 1,000 mg / 1,000 mg dose. The mean peak plasma levels of cilastatin following doses of 250 mg / 250 mg, 500 mg / 500 mg, and 1,000 mg / 1,000 mg were 22, 42, and 72 mcg / ml, respectively.

Distribution

The serum protein binding of cilastatin is approximately 40%.

Biotransformation and elimination

The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the cilastatin dose was recovered unchanged in the urine as cilastatin within 10 hours of TIENAM administration. Subsequently cilastatin was no longer recovered in the urine. Approximately 10% was recovered as the N-acetyl metabolite, which it possesses an inhibitory activity towards dehydropeptidase comparable to that of the drug of origin. The activity of dehydropeptidase-I in the kidney returns to normal levels shortly after the elimination of cilastatin from the bloodstream.

Pharmacokinetics in special populations

Kidney failure

Following a single intravenous dose of TIENAM 250 mg / 250 mg, the area under the curve (AUC) of imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold, respectively, in subjects with mild ( Creatinine clearance (CC) 50-80 ml / min / 1.73 m2), moderate (CC 30-2), and severe (CC 2) renal impairment, compared to subjects with normal renal function (CC> 80 ml / min / 1.73 m2), and the AUC of cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold, respectively, in subjects with mild, moderate, and severe renal impairment, compared with subjects with normal renal function. Following a single intravenous dose of TIENAM 250 mg / 250 mg administered 24 hours after hemodialysis, the AUCs of imipenem and cilastatin were 3.7-fold and 16.4-fold higher, respectively, than in subjects with normal renal function. Urinary recovery, renal clearance and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of TIENAM. Dose adjustment is required in patients with impaired renal function (see section 4.2).

Hepatic insufficiency

The pharmacokinetics of imipenem in patients with hepatic insufficiency have not been determined. Due to the limited hepatic metabolism of imipenem pharmacokinetics are not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment (see section 4.2).

Pediatric population

The mean clearance (CL) and volume of distribution (Vdss) of imipenem were approximately 45% higher in pediatric patients (3 months to 14 years) than in adults. The AUC of imipenem following administration of 15/15 mg / kg body weight of imipenem / cilastatin to pediatric patients was approximately 30% higher than the exposure in adults treated with a 500 mg / 500 mg dose. higher doses, exposure after administration of 25/25 mg / kg imipenem / cilastatin to children was approximately 9% higher than exposure in adults treated with a dose of 1,000 mg / 1,000 mg.

Senior citizens

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of TIENAM 500 mg / 500 mg administered intravenously over 20 minutes were consistent with that expected in subjects with mild renal impairment in whom no dose adjustment is considered necessary.The mean plasma half-lives of imipenem and cilastatin were 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple doses had no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem / cilastatin was observed. (see section 4.2).


05.3 Preclinical safety data

Non-clinical data revealed no special risk for humans based on repeated dose toxicity and genotoxicity studies.

Animal studies have shown that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Co-administration of cilastatin with imipenem in the ratio of 1: 1 prevented the development of nephrotoxicity in rabbits and monkeys. Available data suggest that cilastatin prevents nephrotoxicity by preventing the entry of imipenem into tubular cells.

A teratology study performed on pregnant cynomolgus monkeys treated with imipenem-cilastatin sodium at doses of 40/40 mg / kg / day (intravenous bolus) revealed maternal toxicity including emesis, inappetence, weight loss, diarrhea, abortion, and in some death cases. When doses of imipenem-cilastatin sodium (approximately 100/100 mg / kg / day or approximately 3 times the usual recommended human daily intravenous dose) were administered to pregnant cynomolgus monkeys with an intravenous infusion rate similar to that used in the clinic in "man, c" was minimal maternal intolerance (occasional emesis), there were no maternal deaths, no evidence of teratogenicity, but c "there was an increase in embryo loss relative to the control group (see section 4.6 ).

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of imipenem / cilastatin.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Sodium bicarbonate.


06.2 Incompatibility

This medicinal product is chemically incompatible with lactate and must not be reconstituted with lactate-containing diluents. It can be administered, however, into an intravenous infusion system through which a lactate solution has been administered.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.


06.3 Period of validity

2 years.

After reconstitution:

Diluted solutions should be used immediately. The time interval between the start of reconstitution and the end of the intravenous infusion should not exceed two hours.


06.4 Special precautions for storage

Do not store above 25 ° C.

Do not freeze the reconstituted solution.

For storage conditions after reconstitution of the medicinal product, see section 6.3.


06.5 Nature of the immediate packaging and contents of the package

20 ml Type I glass vials.

This medicine is supplied in packs of 1 vial, 10 vials and 25 vials.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

Each vial is for single use only.

Reconstitution:

The contents of each vial should be transferred to 100 ml of an appropriate infusion solution (see sections 6.2 and 6.3): 0.9% sodium chloride. In exceptional circumstances in which 0.9% sodium chloride cannot be used for clinical reasons, 5% glucose should be used instead.

A recommended procedure is to add approximately 10 ml of the appropriate infusion solution to the vial. Shake well and transfer the resulting mixture into the solution for infusion container.

WARNING: THE MIXTURE MUST NOT BE USED FOR DIRECT INFUSION.

Repeat with an additional 10 ml of solution for infusion to ensure complete transfer of the contents of the vial into the solution for infusion. The resulting mixture must be stirred until it becomes clear.

The concentration of the solution reconstituted following the procedures mentioned above is approximately 5 mg / ml for both imipenem and cilastatin.

Changes in color, from colorless to yellow, do not affect the potency of the medicine.

Unused medicine or waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

MSD Italia S.r.l.

Via Vitorchiano, 151 - 00189 Rome

08.0 MARKETING AUTHORIZATION NUMBER

AIC n. 025887062

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 04 June 2011

10.0 DATE OF REVISION OF THE TEXT

January 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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