TARGOCID FOR INJECTION; TARGOCID SOLVENT

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

TARGOCID FOR INJECTION
TARGOCID SOLVENT

SCHEDULING STATUS:
S4/S1

PROPRIETARY NAME
(and dosage form):

TARGOCID FOR INJECTION
TARGOCID SOLVENT

COMPOSITION:
TARGOCID FOR INJECTION:
Per vial: Lyophilised Teicoplanin 200 mg
TARGOCID SOLVENT:
Per ampoule: Water for Injection 3 mL
Reconstitute before use. The resultant solution is isotonic.

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1. Broad and medium spectrum antibiotics

PHARMACOLOGICAL ACTION:
TARGOCID (lyophilised teicoplanin) is a bactericidal, glycopeptide antibiotic, produced by fermentation of Actinoplanes teicomyceticus. It is active in vitro against both aerobic and anaerobic Gram-positive bacteria.
Species usually sensitive:
Staphylococcus aureus, coagulase negative staphylococci (sensitive or resistant to methicillin), streptococci, enterococci, Listeria monocytogenes, micrococci, group JK Corynebacteria, Gram-positive anaerobes including Clostridium difficile and peptococci.
Species usually resistant:
Nocardia asteroides, lactobacillus spp., Leuconostoc and all Gram-negative bacteria.
Bactericidal synergy has been demonstrated in vitro, in combination with aminoglycosides, against group D streptococci and staphylococci. In vitro combinations of TARGOCID with rifampicin or fluorinated quinolones show primarily additive effects and sometimes synergy. One-step resistance to TARGOCID could not be obtained in vitro, and multi-step resistance was only reached in vitro after 11 to 14 passages. TARGOCID does not show cross-resistance with other classes of antibiotics. Following intravenous and intramuscular administration, TARGOCID is widely distributed in body tissues. It is slowly eliminated with a plasma half-life of 70 to 100 hours; the excretory route is renal. TARGOCID is not absorbed when administered orally. TARGOCID does not penetrate through the blood-brain barrier.

INDICATIONS:
TARGOCID is indicated in potentially serious Gram-positive infections, including those which cannot be treated with other antimicrobial drugs. The effectiveness of TARGOCID has been documented in the following infections caused by organisms sensitive to TARGOCID:
endocarditis, septicaemia and osteomyelitis, respiratory infections, skin and soft tissue infections, urinary tract infections and peritonitis associated with chronic ambulatory peritoneal dialysis (CAPD).

CONTRA-INDICATIONS:
Hypersensitivity to teicoplanin.
Safety and efficacy has not been established in children under three years of age.
TARGOCID should not be used during pregnancy and lactation, as safety has not been established. It is not known whether TARGOCID passes into breast milk.
TARGOCID must not be injected into the subarachnoid space.

WARNINGS:
TARGOCID should be administered with caution in patients known to be hypersensitive to vancomycin since cross hypersensitivity may occur. However, a history of "Red Man Syndrome" which can occur with vancomycin, is not a contra-indication to TARGOCID. Thrombocytopenia has been reported with TARGOCID, especially at doses higher than those usually recommended. It is advisable for periodic haematological studies to be performed during treatment. Liver and renal function tests are recommended during treatment.
Serial renal and auditory function tests should be undertaken in the following circumstances:

•	prolonged treatment in patients with renal insufficiency.
•	concurrent and sequential use of other drugs which may have neurotoxic and/or nephrotoxic properties. These include aminoglycosides, colistin, amphotericin B, cyclosporin, cisplatin, furosemide and ethacrynic acid. However, there is no evidence of synergistic toxicity when TARGOCID is used in combination with the above drugs.

DOSAGE AND DIRECTIONS FOR USE:
The reconstituted TARGOCID injection may be administered either intravenously or intramuscularly. The intravenous injection may be administered either as a bolus or as a 30 minute infusion. Dosage is usually once daily but, in cases of severe infection, a second injection should be administered on the first day in order to reach the required serum concentrations more rapidly.
The majority of patients, with infections caused by organisms sensitive to the antibiotic, show a therapeutic response within 48 to 72 hours. The duration of therapy is determined by the type and severity of the infection, and the clinical response of the patient. In endocarditis and osteomyelitis, treatment for three weeks or longer is recommended.
Determination of teicoplanin serum concentrations may optimise therapy. In severe infections, trough serum concentrations should not be less than 10 mg per litre. Peak concentrations measured one hour after a 400 mg intravenous dose are usually in the range of 20 to 50 mg per litre; peak serum concentrations of up to 250 mg per litre have been reported after intravenous doses of 25 mg per kg. A relationship between serum concentration and toxicity has not been established.

THERAPEUTIC DOSAGE:
Adults and elderly patients with normal renal function:
Moderate infections:
Skin and soft tissue infections, urinary tract infections, lower respiratory tract infections.
Loading dose:
One single i.v. injection of 400 mg (two vials) on the first day.
Maintenance dose:
A single i.v. or i.m. injection of 200 mg daily.

Severe infections:
Joint and bone infections, septicaemia, endocarditis.
Loading dose:
400 mg i.v. injection every 12 hours for the first three doses.
Maintenance dose:
A single i.v. or i.m. injection of 400 mg daily.
In some clinical situations, such as infected, severely burned patients or Staphylococcus aureus endocarditis, unit maintenance doses of up to 12 mg per kg may be required.
Note:
Standard doses of 200 and 400 mg are equivalent to mean doses of 3 mg per kg and 6 mg per kg respectively. In overweight patients it is recommended that the dose be adapted to the weight of the patient as follows: moderate infections 3 mg per kg; severe infections 6 mg per kg.
Children:
TARGOCID can be used to treat Gram positive infections in children from the age of three years. For severe infections and neutropenic patients the recommended dose is 10 mg per kg every 12 hours, by intravenous injection, for the first three doses. Thereafter a dose of 10 mg per kg should be administered by either intravenous or intramuscular injection as a single dose each day. For moderate infections the recommended dose is 10 mg per kg. by intravenous injection, every twelve hours for the first three doses. Thereafter a dose of 6 mg per kg should be administered by either intravenous or intramuscular injection as a single dose each day.
Adults and elderly patients with renal insufficiency:
For patients with impaired renal function, reduction of the dose is not required until the fourth day of treatment.
From the fourth day of treatment:

•	In mild renal insufficiency: Creatinine clearance between 40 and 60 mL per minute: the dose of TARGOCID should be halved; either by administering the initial unit dose every two days, or by administering half the initial unit dose once a day.
•	In severe renal insufficiency: Creatinine clearance less than 40 mL per minute and in haemodialysed patients: the dose of TARGOCID should be one third of the normal dose; either by administering the initial unit dose every third day, or by administering one third of the unit dose once a day. TARGOCID is not removed by dialysis.
•	In continuous ambulatory peritoneal dialysis: After a single intravenous loading dose of 400 mg, if the patient is febrile, the recommended dosage is 20 mg per litre, per bag, in the first week; 20 mg per litre in alternate bags in the second week; and 20 mg per litre in the overnight dwell bag only, in the third week.

TARGOCID is stable in peritoneal dialysis solutions (1,36% or 3,86% dextrose).

Do not keep mixed solutions for longer than 24 hours.

Monitoring the Plasma Concentrations:
If checks are carried out on the teicoplanin serum level in patients with severe infections, then the minimum serum level should not be below 10 mg per litre. (measured just before the following dose).

TYPE OF ADMINISTRATION AND DURATION OF USE:
1. Type of Administration
In order to produce the ready-to-use solution, all the TARGOCID SOLVENT (water for injection) in the accompanying ampoule is injected slowly into the vial with the dry substance. The vial is then shaken until the dry substance is completely dissolved. Care must be taken to avoid the formation of foam. If foam does develop during the preparation of the injection solution, it is recommended that the solution be left to stand for approximately 15 minutes until the foam has disappeared. TARGOCID may be administered by either intravenous or intramuscular injection. The intravenous dose may be given by rapid injection over one minute or by short infusion.
Following preparation of the ready-to-use solution, TARGOCID is injected directly intravenously; or into the proximal end of a dripline after clamping the line. TARGOCID can be injected quickly, i.e. within one minute. TARGOCID can also be injected intramuscularly.
For the purposes of infusion, TARGOCID is dissolved in 20 to 50 mL of infusion solution and administered over 20 to 30 minutes. The following infusion solutions are suitable for mixing with TARGOCID:
Isotonic saline solution 0,95%
Ringer's solution
Ringer's lactate solution
5% glucose solution
Solutions containing 0,18% sodium chloride and 4% glucose
Reconstituted solutions of TARGOCID should be used as soon as possible, otherwise they may be stored for 24 hours at 2 to 8°C.
Solutions of TARGOCID and aminoglycosides are incompatible and should not be mixed before injection.

2. Duration of Use
With infections caused by Teicoplanin-sensitive pathogens, a therapeutic result is shown in the majority of cases within 48 to 72 hours.
The duration of treatment is based upon the severity of the infection as well as upon the clinical and bacteriological progress. The treatment should be continued for at least three days after the patient has become afebrile and after the disappearance of clinical symptoms.
In cases of endocarditis or osteomyelitis at least three weeks treatment is recommended.
TARGOCID should not be administered for longer than four months.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects
The following side-effects have been observed in clinical studies: occasional hypersensitivity reactions, exanthema, erythema, pruritus, fever, bronchospasm and anaphylactic reactions. Pain at the injection site and phlebitis or the formation of an abscess have been observed occasionally.
In some cases a rise in the transaminase and/or alkaline phosphatase has been observed. A rise in serum creatinine may also occur.
Eosinophilia, thrombocytopenia or leucopenia have been described.
TARGOCID can, on rare occasions, lead to nausea and vomiting, headaches or dizziness.
Loss of hearing, tinnitus or vestibular disturbances have been observed in patients treated with TARGOCID in combination with a potentially ototoxic drug such as an aminoglycoside.
Special Precautions
In patients with restricted kidney function the therapy should be monitored carefully. Where treatment in such patients is continued for longer than three weeks, regular checks are recommended on the serum level as well as on kidney, liver and auditory function.
Such tests are also recommended in cases of concurrent and sequential use of other drugs which may have neurotoxic and/or nephrotoxic properties e.g. aminoglycosides, colistin, amphotericin, cyclosporin, cisplatin, furosemide and ethacrynic acid.
Unless measurement of the serum concentrations can be guaranteed to accompany the therapy, patients with a creatinine clearance lower than or equal to 20 mL per minute must be excluded from therapy with TARGOCID.
TARGOCID may not be administered into the subarachnoid space.
Periodic haematological studies plus liver and renal function tests, are advisable during prolonged treatment. Administer with caution to patients known to be vancomycin-sensitive since cross hypersensitivity may occur. There is no record of any adverse interaction with other medication.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
General symptomatic measures are recommended for the management of an overdose. Available information on two children with agranulocytosis to whom several doses of 100 mg per kg per day were administered in error, shows that despite very high serum concentrations of 300 mg per litre, no intoxication phenomena appeared.
TARGOCID is not removed by haemodialysis or peritoneal dialysis.

IDENTIFICATION:

Lyophilised product	: Spongy, ivory-coloured, homogenous mass.
Solvent	: Clear, colourless, odourless liquid.
Reconstituted solution	: Clear, yellowish solution.

PRESENTATION:
Pack of 1 x 10 mL injection vial containing 200 mg of lyophilised Teicoplanin substance and 1 x 3 mL ampoule of Water for Injection.

STORAGE INSTRUCTIONS:

Lyophilised product	: Store below 25°C.
Reconstituted product	: May be retained for 24 hours if stored at 2 to 8°C.

KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBERS:

TARGOCID FOR INJECTION	: Z/20.1.1/61
TARGOCID SOLVENT	: Z/34/159

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
ROUSSEL LABORATORIES (PTY) LTD.
5th Street, Marlboro Ext. 1,
Sandton

DATE OF PUBLICATION OF THIS PACKAGE INSERT:

TARGOCID FOR INJECTION	: 11 July 1994
TARGOCID SOLVENT	: 1 April 1992