Consumer medicine information

Primaxin

Imipenem; Cilastatin

BRAND INFORMATION

Brand name

Primaxin

Active ingredient

Imipenem; Cilastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Primaxin.

SUMMARY CMI

PRIMAXIN®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given PRIMAXIN?

PRIMAXIN contains the active ingredients Imipenem and Cilastatin sodium. PRIMAXIN is an antibiotic which is used to treat serious infections caused by bacteria. These infections may occur in many different parts of the body.

For more information, see Section 1. Why am I being given PRIMAXIN? in the full CMI.

2. What should I know before I am given PRIMAXIN?

Do not use if you have ever had an allergic reaction to PRIMAXIN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given PRIMAXIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PRIMAXIN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given PRIMAXIN?

  • PRIMAXIN will be prepared and given to you by a doctor or nurse. It is given as a slow injection into a vein.
  • Your doctor will decide what dose of PRIMAXIN you will receive, depending upon your condition and the severity of your infection.
  • PRIMAXIN is usually given in divided doses throughout the day.

More instructions can be found in Section 4. How am I given PRIMAXIN? in the full CMI.

5. What should I know while being given PRIMAXIN?

Things you should do

Tell your doctor if:

  • If you feel sick while you are receiving PRIMAXIN.
  • If you develop severe diarrhoea, even if it occurs several weeks after PRIMAXIN has been stopped.
  • If you develop a severe skin reaction such as painful red areas, fluid-filled bumps, large blisters, or peeling of layers of skin whilst being given PRIMAXIN
  • If you have a history of seizures and you are taking anticonvulsant medicines
Driving or using machines
  • PRIMAXIN generally does not cause any problems with your ability to drive a car or operate machinery. However, it may cause dizziness or lightheadedness in some people. Make sure you know how you react to PRIMAXIN before you drive a car or operating machinery.
Looking after your medicine
  • PRIMAXIN will be stored in the pharmacy or on the ward.
  • The powder for injection is kept in a cool dry place where the temperature stays below 25°C

For more information, see Section 5. What should I know while being given PRIMAXIN? in the full CMI.

6. Are there any side effects?

Tell your doctor or nurse if you notice any of the following and they worry you: pain, swelling or red skin where you had the injection, nausea, vomiting, diarrhoea. These are the more common side effects of PRIMAXIN.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

PRIMAXIN®

Active ingredients: Imipenem and Cilastatin sodium

Consumer Medicine Information (CMI)

This leaflet provides important information about PRIMAXIN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about PRIMAXIN.

Where to find information in this leaflet:

1. Why am I being given PRIMAXIN?
2. What should I know before I am given PRIMAXIN?
3. What if I am taking other medicines?
4. How am I given PRIMAXIN?
5. What should I know while being given PRIMAXIN?
6. Are there any side effects?
7. Product details

1. Why am I being given PRIMAXIN?

PRIMAXIN contains the active ingredients Imipenem and Cilastatin sodium. PRIMAXIN is an antibiotic which is used to treat serious infections caused by bacteria. These infections may occur in many different parts of the body.

PRIMAXIN is sometimes given in addition to other antibiotics.

PRIMAXIN works by killing the bacteria causing the infection.

2. What should I know before I am given PRIMAXIN?

Warnings

Do not use PRIMAXIN if:

  • you are allergic to PRIMAXIN, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can be given this medicine.

Check with your doctor if you:

  • are pregnant or are breast-feeding
  • have any medical conditions, especially the following:
    - colitis or any other gastrointestinal disease
    - any central nervous system disorders, such as localised tremors, or seizures (fits)
    - kidney or urinary problems
    - bowel problems
  • you have any allergies to other antibiotics, in particular, penicillins and cephalosporins
If you are allergic to any of these, you may be allergic to PRIMAXIN.
  • if you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you are given PRIMAXIN.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss the possible risks and benefits of being given PRIMAXIN during pregnancy and breast-feeding. PRIMAXIN passes into breast milk and may be passed on to the baby.

Children

PRIMAXIN should not be given to children under 3 months of age or children with kidney problems.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with PRIMAXIN and affect how it works.

Tell your doctor if you are taking:

  • Sodium valproate (medicine used to treat epilepsy, bipolar disorder, migraine or schizophrenia)
  • Ganciclovir (a medicine used to treat some viral infections)
  • Probenecid (a medicine used to treat gout)

Your doctor or pharmacist will be able to tell you what to do when being given PRIMAXIN with other medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect PRIMAXIN.

4. How am I given PRIMAXIN?

How it is given

PRIMAXIN will be prepared and given to you by a doctor or nurse. It is given as a slow injection into a vein.

Your doctor will decide what dose of PRIMAXIN you will receive, depending upon your condition and the severity of your infection.

PRIMAXIN is usually given in divided doses throughout the day.

Your doctor will let you know when you may stop receiving PRIMAXIN.

If you have been given too much PRIMAXIN

If you think that you have been given too much PRIMAXIN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while being given PRIMAXIN?

Things you should do

Call your doctor straight away if you:

  • feel sick while you are receiving PRIMAXIN
Your doctor may need to slow down the rate of the injection.
  • develop severe diarrhoea, even if it occurs several weeks after PRIMAXIN has been stopped
Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any medicine to treat your diarrhoea without first checking with your doctor.
  • develop a severe skin reaction such as painful red areas, fluid-filled bumps, large blisters, or peeling of layers of skin whilst being given PRIMAXIN
You may need urgent medical care.
  • have a history of seizures and you are taking anticonvulsant medicines
You should continue taking these medicines unless your doctor tells you otherwise. Some patients may develop tremors or seizures while receiving PRIMAXIN.

Things you should do after having been given PRIMAXIN

Tell your doctor immediately if you notice any of the following side effects particularly if they occur several weeks after you have been given treatment with PRIMAXIN:

  • severe abdominal cramps or stomach cramps
  • watery and severe diarrhoea, which may also be bloody
  • fever

These are all serious side effects. You may have a serious condition affecting your bowel. You may need urgent medical attention. Do not take any medicine to treat your diarrhoea without first checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PRIMAXIN affects you.

PRIMAXIN generally does not cause any problems with your ability to drive a car or operate machinery. However, it may cause dizziness or lightheadedness in some people. Make sure you know how you react to PRIMAXIN before you drive a car or operating machinery.

Looking after your medicine

  • PRIMAXIN will be stored in the pharmacy or on the ward.
  • The powder for injection is kept in a cool dry place where the temperature stays below 25°C.

6. Are there any side effects?

Tell your doctor, nurse, or pharmacist as soon as possible if you do not feel well while you are being given PRIMAXIN.

PRIMAXIN helps most people with infection, but it may have unwanted side-effects in a few people. All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. PRIMAXIN generally does not cause any problems.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
Tell your doctor or nurse if you notice any of the following and they worry you:
  • pain, swelling or red skin where you had the injection
  • nausea, vomiting
  • diarrhoea

These are the more common side effects of PRIMAXIN.

Speak to your doctor if you have any of these common side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Tell your doctor or nurse immediately if you notice any of the following:
  • high temperature, also called fever
  • seizures or fits
  • tremors, confusion
  • abnormal movements
  • agitation
  • tingling or numbness of the hands and feet
  • fast or irregular heart beat, also called palpitations
  • passing little or no urine (water)
  • bruising more easily than normal
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • yellowing of the skin and eyes, also called jaundice
  • skin problems such as rash or itchiness
  • red or purplish-red patches on the skin
  • severe skin reactions, such as painful red areas, fluid-filled bumps, large blisters, or peeling of layers of skin have been reported for the beta-lactam class of antibiotics
  • hearing loss
  • severe abdominal or stomach cramps
  • watery and severe diarrhoea, which may also be bloody

These are serious side effects of PRIMAXIN. You may need urgent medical attention. Serious side effects are rare.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Allergic Reactions

Allergic ReactionsWhat to do

A few people may be allergic to some medicines. Tell your doctor or nurse immediately if you notice any of the following:

  • dizziness, lightheadedness, fainting
  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • shortness of breath
  • itchy skin rash
  • pinkish, itchy swellings on the skin, also called hives or nettlerash

If you have these, you may have had a serious allergic reaction to PRIMAXIN. You may need urgent medical attention.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these Allergic Reactions.

Also, tell your doctor if you notice:

  • staining of the teeth and/or tongue
  • a change in the colour of your urine

These are other side effects that have been reported with PRIMAXIN.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What PRIMAXIN contains

Active ingredient
(main ingredient)		Imipenem 500 mg and cilastatin 500 mg (as the sodium salt) per vial
Other ingredients
(inactive ingredients)		sodium bicarbonate

Do not take this medicine if you are allergic to any of these ingredients.

What PRIMAXIN looks like

Solutions of PRIMAXIN range from colourless to yellow.

Australian Registration Number:

PRIMAXIN - AUST R 10509

Who distributes PRIMAXIN

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW 2113 Australia

This leaflet was prepared in April 2022.

WPPI-MK0787B-IV-IM-012019

RCN: 000023170

Copyright © (2022) Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Primaxin

Active ingredient

Imipenem; Cilastatin

Schedule

S4

 

1 Name of Medicine

Imipenem and cilastatin sodium.

2 Qualitative and Quantitative Composition

Primaxin (imipinem-cilastatin sodium) is a formulation of imipenem, a thienamycin antibiotic, and cilastatin sodium, the inhibitor of the renal dipeptidase, dehydropeptidase I, with sodium bicarbonate added as a buffer. Primaxin is a potent broad spectrum antibacterial agent for intravenous administration.
Primaxin is supplied as imipenem 500 mg and cilastatin sodium equivalent to cilastatin 500 mg.

Excipient with known effect.

Primaxin contains 37.5 mg of sodium (1.6 mEq).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Primaxin is supplied as a sterile powder mixture in a vial.
Primaxin is buffered to provide solutions in the pH range of 6.5 to 8.5. There is no significant change in pH when solutions are prepared and used as directed. (See Section 4.2 Dose and Method of Administration, Compatibility and stability.) Solutions of Primaxin range from colourless to yellow. Variations of colour within this range do not affect the potency of the product.

4 Clinical Particulars

4.1 Therapeutic Indications

Primaxin is indicated for the treatment of serious infections caused by susceptible strains of microorganisms in the diseases listed below.
1. Lower respiratory tract infections.
2. Intra-abdominal infections.
3. Gynaecological infections.
4. Bacterial septicaemia.
5. Bone and joint infections.
6. Skin and skin structure infections.
7. Endocarditis.
8. Polymicrobial infections. Primaxin is indicated for polymicrobial infections including those in which S. pneumoniae (pneumonia, septicaemia), group A beta-haemolytic Streptococcus (skin and skin structure), or nonpenicillinase producing S. aureus is one of the causative organisms. However, monobacterial infections due to these organisms are usually treated with narrower spectrum antibiotics, such as penicillin G. Efficacy against polymicrobial infection in the immunocompromised host has not yet been established.
Although clinical improvement has been observed in patients with cystic fibrosis, chronic pulmonary disease, and lower respiratory tract infections caused by Pseudomonas aeruginosa, bacterial eradication may not necessarily be achieved.
As with other beta-lactam antibiotics, strains of Pseudomonas aeruginosa may develop resistance rapidly on treatment with Primaxin. When clinically appropriate during therapy of Pseudomonas aeruginosa infections, periodic susceptibility testing should be done.
Infections resistant to other antibiotics, for example, cephalosporins, penicillin and aminoglycosides, may respond to treatment with Primaxin.
Primaxin is not indicated for the treatment of meningitis.

4.2 Dose and Method of Administration

Primaxin is for intravenous use only.
The dosage recommendations for Primaxin represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution.
Initially, the total daily dosage for Primaxin should be based on the type or severity of infection and given in equally divided doses. Subsequent dosing must be based on consideration of severity of infection, degree of susceptibility of the pathogen(s), age and the patient's renal function.

Dosage in adults.

The dosage of Primaxin I.V. in adult patients should be based on suspected or confirmed pathogen susceptibility as shown in Table 1.
These doses should be used for patients with creatinine clearance of greater than or equal to 90 mL/min. A reduction in dose must be made for patients with creatinine clearance of less than or equal to 90 mL/min as shown in Table 2 (see Dosage in adult patients with renal impairment).
Recommended that the maximum total daily dosage not exceed 4 g/day.
Administer 500 mg by intravenous infusion ever 20 to 30 minutes.
Administer 1000 mg by intravenous infusion over 40 to 60 minutes.
In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Dosage in adult patients with renal impairment.

Patients with creatinine clearance less than 90 mL/min require dosage reduction of Primaxin I.V. as indicated in Table 2. The serum creatinine should represent a steady state of renal function. Use the Cockcroft-Gault method described in Equation 1 to calculate the creatinine clearance:
In patients who develop nausea during the infusion, the rate of infusion may be slowed.
In patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min, there may be an increased risk of seizures (see Section 4.4 Special Warnings and Precautions for Use, Central nervous system).
Patients with creatinine clearance less than 15 mL/min should not receive Primaxin I.V unless haemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of Primaxin I.V. for patients undergoing peritoneal dialysis.

Dosage in haemodialysis patients.

When treating patients with creatinine clearance of less than 15 mL/min who are undergoing haemodialysis, use the dosage recommendations for patients with creatinine clearances of less than 30 to greater than or equal to 15 mL/min in Table 2 (see Dosage in adult patients with renal impairment). Both imipenem and cilastatin are cleared from the circulation during haemodialysis. The patient should receive Primaxin I.V. after haemodialysis and at intervals timed from the end of that haemodialysis session. Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on haemodialysis, Primaxin I.V. is recommended only when the benefit outweighs the potential risk of seizures (see Dosage in adult patients with renal impairment).

Dosage in paediatric patients (3 months or older).

Primaxin is not recommended in paediatric patients with CNS infections because of the risk of seizures (see Section 4.4 Special Warnings and Precautions for Use).
For children and infants the following dosage schedule is recommended:
(a) Children ≥ 40 kg body weight should receive adult doses.
(b) Children and infants < 40 kg body weight should receive 15 mg/kg at six hour intervals. The total daily dose should not exceed 2 g.
Clinical data are insufficient to recommend dosing for children under 3 months of age, or paediatric patients with impaired renal function (serum creatinine > 177 micromol/L).
Primaxin is not recommended for the therapy of meningitis. If meningitis is suspected, an appropriate antibiotic should be used.
Primaxin may be used in children with sepsis as long as they are not suspected of having meningitis.

Preparation of Primaxin solution for IV administration.

Primaxin I.V. is supplied as a dry powder in a single dose vial that must be reconstituted and further diluted using aseptic technique prior to IV infusion as outlined below.
Do not use diluents containing benzyl alcohol to reconstitute Primaxin for administration to neonates because it has been associated with toxicity in neonates. While toxicity has not been demonstrated in paediatric patients greater than three months of age, small paediatric patients this age range may also be at risk for benzyl alcohol toxicity.
To prepare the infusion solution, contents of the vial must be reconstituted by adding approximately 10 mL of the appropriate diluent to the vial. List of appropriate diluents are as follows: 0.9% Sodium Chloride Injection; 5% Glucose Injection; 5% Glucose Injection + 0.9% Sodium Chloride Injection; 5% Glucose Injection + 0.45% Sodium Chloride Injection; 5% Glucose Injection + 0.225% Sodium Chloride Injection.
Withdraw 20 mL (10 mL times 2) of diluent from the appropriate infusion bag and constitute the vial with 10 mL of the diluent. The reconstituted suspension must not be administered by direct IV infusion.
After reconstitution, shake vial well and transfer resulting suspension into the remaining 80 mL of the infusion bag.
Add the additional 10 mL of infusion solution to the vial and shake well to ensure complete transfer of vial contents; repeat transfer of the resulting suspension to the infusion solution before administering. Agitate the resulting mixture until clear.
Reconstituted solutions of Primaxin I.V. range from colourless to yellow. Variations of colour within this range do not affect the potency of the product.
For patients with renal insufficiency, a reduced dose of Primaxin I.V. will be administered according to the patient's CrCl, as determined from Table 3. Prepare 100 mL of infusion solution as directed above. Select the volume (mL) of the final infusion solution needed for the appropriate dose of Primaxin I.V. as shown in Table 3.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if discoloration or visible particles are observed.

Storage of reconstituted solutions.

Primaxin, as supplied in single dose vials and reconstituted with the appropriate diluents (see Preparation of Primaxin solution for IV administration), maintains satisfactory potency for 4 hours at room temperature [below 25°C] or for 24 hours under refrigeration [2-8°C]. Do not freeze solutions of Primaxin.
Primaxin should not be mixed with, or physically added to, other antibiotics. However, Primaxin may be administered concomitantly with other antibiotics, such as aminoglycosides.
Primaxin is chemically incompatible with lactate and should not be reconstituted in diluents containing lactate.

4.3 Contraindications

Primaxin is contraindicated in patients who have shown hypersensitivity to any component of this product.

4.4 Special Warnings and Precautions for Use

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more apt to occur in persons with a history of sensitivity to multiple allergens.
There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe hypersensitivity when treated with another beta-lactam. Before initiating therapy with Primaxin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to Primaxin occurs, discontinue the drug. Serious hypersensitivity reactions may require adrenaline and other emergency measures.

Clostridium difficile.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including imipenem. A toxin produced with Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement therapy should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil), may prolong and/or worsen the condition and should not be used.

Central nervous system.

CNS adverse experiences such as myoclonic activity, confusional states or seizures have been reported with Primaxin I.V. formulation, especially when recommended dosages based on renal function and body weight were exceeded. These experiences have occurred most commonly in patients with CNS disorders (e.g. brain lesions or history of seizures) and/or compromised renal function. However, there are rare reports in which there was no recognised or documented underlying CNS disorder. Close adherence to recommended dosage schedules is urged, especially in patients with known factors that predispose to seizures (see Section 4.2 Dose and Method of Administration). Anticonvulsant therapy should be continued in patients with a known seizure disorder.
If focal tremors, myoclonus or seizures occur, patients should be evaluated neurologically and placed on anticonvulsant therapy if not already instituted. If CNS symptoms continue, the dosage of Primaxin should be decreased or discontinued.
Patients with creatinine clearances of < 5 mL/min/1.73 m2 should not receive Primaxin unless haemodialysis is instituted within 48 hours. For patients on haemodialysis, Primaxin is recommended only when the benefit outweighs the potential risk of seizures.
Concentrations of imipenem in the CSF are considerably lower than in the plasma. Its use in the treatment of brain abscess is, therefore, not advised.

Meningitis.

Primaxin is not indicated for the treatment of meningitis.

Development of drug-resistant bacteria.

As with other broad spectrum antibiotics, prolonged use of Primaxin may result in superinfection with non-susceptible organisms. Resistance to Primaxin may develop during therapy (see Section 4.1 Therapeutic Indications). Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
While Primaxin possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system function during prolonged therapy is advisable.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reactions with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, Primaxin should be discontinued immediately and an alternative treatment should be considered.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

Clinical data are insufficient to recommend the use of Primaxin for children under 3 months of age, or paediatric patients with impaired renal function (serum creatinine > 177 micromol/L). (Also see Section 4.2 Dose and Method of Administration, Dosage in paediatric patients (3 months or older)).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Adverse laboratory changes).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Probenecid.

Since concomitant administration of Primaxin and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with Primaxin.

Ganciclovir.

Generalised seizures have been reported in patients who received ganciclovir and Primaxin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Sodium valproate.

Decreased serum levels of sodium valproate with coadministration of carbapenem antibiotics have been reported during postmarketing and in some cases breakthrough seizures have occurred. Careful monitoring of serum levels of sodium valproate should be considered if imipenem is to be coadministered with sodium valproate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction tests in male and female rats were performed with Primaxin at dosage levels up to 320 mg/kg per day. Slight decreases in live fetal body weight were restricted to the highest dosage level. No other adverse effects were observed on fertility, reproductive performance, fetal viability, growth or postnatal development of pups. Similarly, no adverse effects on the fetus or on lactation were observed when Primaxin was administered to rats late in gestation.
(Category B3)
Teratogenicity studies with cilastatin sodium in rabbits and rats at doses up to 300 and 1000 mg/kg, respectively, showed no evidence of adverse effect on the fetus. No evidence of teratogenicity or adverse effect on postnatal growth or behaviour was observed in rats given imipenem at dosage levels up to 870 mg/kg. Similarly, no evidence of adverse effect on the fetus was observed in teratology studies in rabbits with imipenem at dosage levels of 60 mg/kg.
Teratology studies with Primaxin at doses up to 320 mg/kg in pregnant mice and rats during the period of major organogenesis revealed no evidence of teratogenicity.
Data from preliminary studies suggest an apparent intolerance to Primaxin (including emesis, inappetence, body weight loss, diarrhoea and death), at doses equivalent to the average human dose, in pregnant rabbits and cynomolgus monkeys that is not seen in nonpregnant animals in these or higher doses (up to 320 mg/kg) in pregnant rats and mice. Further studies are underway to evaluate these findings.
There are, however, no adequate and well controlled studies in pregnant women. Primaxin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 Imipenem has been detected in human milk. If the use of Primaxin is deemed essential, the patient should stop nursing.

4.7 Effects on Ability to Drive and Use Machines

There are some adverse reactions associated with this product that may affect some patient's ability to drive or operate machinery (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Primaxin is generally well tolerated. Many of the patients treated in clinical trials were severely ill and had multiple background diseases and physiological impairments, making it difficult to determine causal relationship of adverse experiences to therapy with Primaxin.

Local adverse reactions.

Adverse local clinical reactions that were reported as possibly, probably or definitely related to therapy with Primaxin were: phlebitis/ thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%), vein induration (0.2%), infused vein infection (0.1%).

Systemic adverse reactions.

The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably or definitely related to Primaxin were nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%) (see Section 4.4 Special Warnings and Precautions for Use), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%). Drug related nausea/ vomiting occur more frequently in granulocytopenic patients.
Additional adverse systemic clinical reactions reported as possibly, probably or definitely drug related occurring in less than 0.2% of the patients are listed within each body system in order of decreasing severity.

Gastrointestinal.

Pseudomembranous colitis (see Section 4.4 Special Warnings and Precautions for Use), haemorrhagic colitis, gastroenteritis, abdominal pain, glossitis, tongue papilla hypertrophy, heartburn, pharyngeal pain, increased salivation, staining of teeth and/or tongue.

CNS.

Paraesthesia, encephalopathy, agitation, dyskinesia, tremor, psychic disturbances, confusion, myoclonus, vertigo, headache, hallucinations.

Special senses.

Hearing loss, tinnitus, taste perversion.

Respiratory.

Chest discomfort, dyspnoea, hyperventilation, thoracic spine pain.

Cardiovascular.

Palpitations, tachycardia.

Renal.

Oliguria/ anuria, polyuria, acute renal failure (rarely).

Allergic reactions/ skin and other subcutaneous tissue disorders.

Erythema multiforme, angioedema, facial oedema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae, exfoliative dermatitis, drug fever, anaphylactic reactions. Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported with beta-lactam antibiotics.

Body as a whole.

Polyarthralgia, asthenia/ weakness.

Blood.

Haemolytic anaemia, pancytopenia, bone marrow depression.

Liver.

Hepatic failure (rarely), fulminant hepatitis (very rarely), hepatitis (rarely).

Adverse laboratory changes.

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were:

Hepatic.

Increased SGPT (ALT), SGOT (AST), alkaline phosphatase, bilirubin and LDH.

Haemic.

Increased eosinophils, positive Coombs' test, decreased WBC and neutrophils including agranulocytosis, increased WBC, increased platelets, decreased platelets, decreased haemoglobin and haematocrit, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils, prolonged prothrombin time.

Electrolytes.

Decreased serum sodium, increased potassium, increased chloride.

Renal.

Increased BUN, increased creatinine, urine discoloration.

Urinalysis.

Presence of protein, red blood cells, white blood cells, casts, bilirubin and urobilinogen.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific information is available on the treatment of overdosage with Primaxin. Imipenem-cilastatin is haemodialysable. However, usefulness of this procedure in the overdosage setting is unknown (see Section 4.2 Dose and Method of Administration, Dosage in haemodialysis patients).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Microbiology. The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBP) 1A, 1B, 2, 4, 5, and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B. Imipenem has in vitro activity against a wide range of Gram positive and Gram negative organisms.
Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, produced by Gram negative and Gram positive bacteria including those from Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp.
In vitro imipenem is usually active against strains of clinical isolates of the following microorganisms (Gram positive organisms usually have a lower MIC value than Gram negative organisms).
Gram positive: group D streptococci (including enterococci), Streptococcus pyogenes (group A streptococci), Streptococcus agalactiae (group B streptococci), group C streptococci, group G streptococci, Viridans streptococci, Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Staphylococcus aureus including penicillinase producing strains, Staphylococcus epidermidis including penicillinase producing strains, Enterococcus faecalis (formerly Streptococcus faecalis).

Note.

Enterococcus faecium (formerly Streptococcus faecium) and methicillin resistant staphylococci are resistant to imipenem.
Gram negative: Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia stuartii, Citrobacter spp., Klebsiella spp. including K. pneumoniae and K. oxytoca, Enterobacter spp., Serratia marcescens, Serratia spp. including S. proteamaculans (formerly S. liquefaciens), H. influenzae, Acinetobacter spp., Pseudomonas aeruginosa.

Note.

Imipenem is inactive against Stenotrophomonas maltophilia (formerly Xanthomanas maltophilia, formerly Pseudomonas maltophilia) and some strains of Burkholderia cepacia (formerly Pseudomonas cepacia).
Anaerobes: Bacteroides spp. including Bacteroides fragilis, Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Clostridium spp. including C. perfringens, Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Veillonella spp.
In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.
Susceptibility testing. Susceptibility testing interpretation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) is recommended (https//www.eucast.org/).
The prevalence of resistance to antimicrobial agents may vary geographically. Therefore local information on the prevalence and patterns of resistance should be sought when available. Prescribing in the absence of a proven or strongly suspected susceptible infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
The EUCAST has defined S, I and R terms as follows:
S - Susceptible, standard dosing regimen: A microorganism is categorised as "Susceptible, standard dosing regimen", when there is a high likelihood of therapeutic success using a standard dosing regimen of the agent.
I - Susceptible, increased exposure*: A microorganism is categorised as "Susceptible, Increased exposure*" when there is a high likelihood of therapeutic success because exposure to the agent is increased by adjusting the dosing regimen or by its concentration at the site of infection.
R - Resistant: A microorganism is categorised as "Resistant" when there is a high likelihood of therapeutic failure even when there is increased exposure.
* Exposure is a function of how the mode of administration, dose, dosing interval, infusion time, as well as distribution and excretion of the antimicrobial agent will influence the infecting organism at the site of infection.

5.2 Pharmacokinetic Properties

Imipenem.

Absorption.

Intravenous infusion of Primaxin over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 24 microgram/mL for the 250 mg dose, from 21 to 58 microgram/mL for the 500 mg dose and from 41 to 83 microgram/mL for the 1000 mg dose. At these doses, plasma levels of imipenem antimicrobial activity decline to below 4 microgram/mL in 2 to 3 hours and to below 1 microgram/mL or less in 4 to 6 hours.

Distribution.

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

Metabolism.

Imipenem, when administered alone, is metabolised in the kidneys by dehydropeptidase-1 resulting in relatively low levels in urine.
Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that, when imipenem and cilastatin sodium are given concomitantly, fully adequate antibacterial levels of imipenem are achieved in the urine.

Excretion.

The plasma half-life in adults of imipenem was one hour. Approximately 70% of the administered imipenem is recovered in the urine within 10 hours after which no further urinary excretion is detectable. Urine concentrations of imipenem in excess of 10 microgram/mL can be maintained for up to 8 hours with Primaxin at the 500 mg dose.
No accumulation of Primaxin in plasma or urine is observed with regimens administered as frequently as every 6 hours in patients with normal renal function.

Cilastatin.

Absorption.

Peak plasma levels of cilastatin following a 20-minute intravenous infusion of Primaxin, range from 15 to 25 microgram/mL for the 250 mg dose, from 31 to 49 microgram/mL for the 500 mg dose and from 56 to 88 microgram/mL for the 1000 mg dose.

Distribution.

The binding of cilastatin to human serum proteins is approximately 40%.

Metabolism and excretion.

The plasma half-life of cilastatin is approximately 1 hour. Approximately 70% of the cilastatin sodium dose is recovered in the urine within 10 hours of administration of Primaxin.

Pharmacokinetics in special populations.

Paediatric population.

The paediatric plasma half-life resembled those from adults except that children eliminated cilastatin slightly faster - children t½ 38 minutes, adults t½ 60 minutes.

Elderly.

In a small study with six healthy, elderly male volunteers (66 to 75 years of age with renal function consistent with their age), the pharmacokinetics of a single dose of Primaxin (imipenem 500 mg and cilastatin 500 mg) administered intravenously over 20 minutes were consistent with those expected in subjects with slight renal impairment for whom no dose alteration would usually be considered necessary. In this study with very limited data, multiple dosing had no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem or cilastatin was observed.

5.3 Preclinical Safety Data

Genotoxicity.

Gene toxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests were: V79 mammalian cell mutation assay (Primaxin alone and imipenem alone), Ames test (cilastatin sodium alone), unscheduled DNA synthesis assay (Primaxin) and in vivo mouse cytogenicity test (Primaxin). None of these tests showed any evidence of genetic damage.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium bicarbonate.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned, see Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

The dry powder should be stored at a temperature below 25°C.
For storage conditions after reconstitution of the medicinal product, see Section 4.2 Dose and Method of Administration, Storage of reconstituted solutions.

6.5 Nature and Contents of Container

Primaxin is supplied in a single-use 20 mL type 1 glass vial.
Packs of 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Imipenem (N-formimidoyl thienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is [5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-3 -[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1 -azabicyclo[3.2.0]hept-2 -ene-2-carboxylic acid with a molecular weight of 299.37. Its empirical formula is C12H17N3O4S.
Cilastatin sodium is the sodium salt of a derivatised heptenoic acid. Its chemical name is [Z,7(R),2(S)]-7-[(2-amino-2 -carboxyethyl)thio]-2-[[(2,2-dimethyl-cyclopropyl) carbonyl] amino]-2-heptenoic acid monosodium salt with a molecular weight of 380.43. Its empirical formula is C16H25N2O5S.Na.

Chemical structure.


CAS number.

Imipenem.

74431-23-5.

Cilastatin sodium.

81129-83-1.
Imipenem is an off-white, nonhygroscopic crystalline compound. It is sparingly soluble in water, and slightly soluble in methanol.
Cilastatin sodium is an off-white to yellowish-white, hygroscopic, amorphous compound. It is very soluble in water and in methanol.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes