NAME OF THE MEDICINE

Active Ingredient: Ceftriaxone Sodium Chemical Name: disodium(Z)-(6R, 7R)-7-[2-(2-amino-1, 3-thiazol-4-yl)-2-(methoxyimino)acetamido]-8- oxo-3-[(2, 5-dihydro-2-methyl-6-oxido-5-oxo-1, 2, 4-triazin-3-yl)thiomethyl]-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylate hemiheptahydrate. Structural Formula: Molecular Formula: C18H16N8Na2O7S3, 3.5H2O CAS Registry No: 104376-79-6 Molecular weight: 661.59

DESCRIPTION

Ceftriaxone Alphapharm contains ceftriaxone sodium, an almost white to yellowish crystalline powder which is freely soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 12% aqueous solution is approximately 6.0 to 8.0. The colour of ceftriaxone sodium solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. Ceftriaxone sodium contains approximately 83 mg (3.6 mEq) of sodium per g of ceftriaxone activity. Ceftriaxone Alphapharm powder for injection contains ceftriaxone sodium as a single ingredient.

PHARMACOLOGY

Pharmacokinetics

Ceftriaxone is poorly absorbed from the gastrointestinal tract. Average plasma concentrations of ceftriaxone following a single 30 minute intravenous (I.V.) infusion of a 0.5, 1 or 2 g dose and intramuscular (I.M.) administration of a single 0.5 or 1 g dose in healthy subjects are presented in Table 1.

Mean maximum plasma concentrations following I.M. injection occurred between two and three hours post - dosing. Multiple I.V. or I.M. doses ranging from 0.5 to 2 g at 12 to 24 hour intervals resulted in 15 to 36% accumulation of ceftriaxone above single dose values. Accumulation was more with the I.M. doses. Ceftriaxone concentrations in urine are high, as shown in Table 2.

Between 33 to 67 % of a ceftriaxone dose was excreted in the urine as unchanged drug. Substantial amounts are secreted in the bile and ultimately found in the faeces as microbiologically inactive compounds. A small fraction appears in the urine as an unidentified metabolite. Renal excretion of ceftriaxone is not affected by prior administration of probenecid. After a 1 g I.V. dose, average concentrations of ceftriaxone, determined from one to three hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/g in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma. There were, however, wide individual variations in levels. Over a 0.15 to 3 g dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours, apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hr and renal clearance from 0.32 to 0.73 L/hr. Ceftriaxone is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of 25 mcg/mL to a value of 85% bound at 300 mcg/mL. Protein binding is reduced in children and in uremic patients. The in vitro activity of ceftriaxone is decreased 2 to 8 fold by the presence of human serum. The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after 50 mg/kg I.V. doses in paediatric patients suffering from bacterial meningitis are shown in Table 3.

The half-life of ceftriaxone ranges from 7.2 - 19 hours in neonates and from 4.0 - 6.6 hours in infants over six weeks of age. Ceftriaxone crosses the placenta and appears in the milk in low concentrations. Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone were only minimally altered in elderly subjects and in patients with hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with ceftriaxone doses up to 2 g/day. However in some patients with severely impaired renal function the t1/2 of ceftriaxone may be prolonged (37 - 52 hours) and dosage adjustment should be considered. Peak serum levels should be held below 280 mcg/mL. Ceftriaxone was not removed to any significant extent from the plasma by haemodialysis. Plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary.

MICROBIOLOGY

The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone has a high degree of stability in the presence of beta-lactamases, types I, II & III, both penicillinases and cephalosporinases, of gram- negative and gram-positive bacteria. It is susceptible to type IV beta-lactamases at approximately 18% of the rate of cephaloridine. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections (see Indications).

Gram-Negative Aerobes

Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including ampicillin- resistant strains), Klebsiella species (including K. pneumoniae). Neisseria gonorrhoeae (including penicillinase and nonpenicillinase producing strains), Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Morganella morganii and Serratia marcescens.

Note: Strains of the above organisms that are multiply resistant to other antibiotics, eg penicillins, cephalosporins and aminoglycosides, may be susceptible to ceftriaxone sodium. Ceftriaxone is also active against some strains of Pseudomonas aeruginosa. Other pseudomonas species are usually resistant.

Gram-Positive Aerobes

Staphylococcus aureus (including penicillinase producing strains) and Staphylococcus epidermidis (Note: methicillin-resistant staphylococci are resistant to cephalosporins, including ceftriaxone), Streptococcus pyogenes (Group A beta-haemolytic streptococci), Streptococcus agalactiae (Group B streptococci) and Streptococcus pneumoniae, Group G streptococci, Streptococcus viridans and Streptococcus species (Note: Most species of Group D streptococci including Streptococcus faecalis and Streptococcus faecium are resistant).

Susceptibility Testing

Dilution or diffusion techniques - either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. Clinical and Laboratory Standards Institute [CLSI]). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Note: The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Dilution Techniques

A bacterial isolate may be considered susceptible if the MIC value for ceftriaxone is not more than 8 mcg/mL. Organisms are considered resistant to ceftriaxone if the MIC is greater than 32 mcg/mL. Organisms having a MIC value of equal to or less than 32 mcg/mL, but greater than 8 mcg/mL, are expected to be susceptible if a high dosage is used or if the infection is confined to tissues and fluids (e.g. urine), in which high antibiotic levels are attained. E. coli ATCC 25922, S. aureus ATCC 25923 and P. aeruginosa ATCC 27853 are also the recommended reference strains for controlling ceftriaxone dilution tests. Greater than 95% of MICs for the E. coli strain should fall within the range of 0.016 to 0.5 mcg/mL. The range for the S. aureus strain should be 1 to 2 mcg/mL.

CONTRAINDICATIONS

Ceftriaxone is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or a major allergy to penicillin (anaphylaxis, angioneurotic oedema, urticaria). Lignocaine should not be used as a diluent for intramuscular injection in patients who are hypersensitive to lignocaine. Hyperbilirubinaemic neonates, especially prematures, should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients. Because of the risk of precipitation of ceftriaxone-calcium, Ceftriaxone Alphapharm is contraindicated in neonates requiring (or expected to require) treatment with calcium-containing I.V. solutions (including continuous calcium- containing infusions such as parenteral nutrition) (see Interactions with Other Medicines and Precautions - Paediatric Use). A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving ceftriaxone and calcium containing fluids. In some of these cases, the same intravenous infusion line was used for both ceftriaxone and calcium containing fluids and in some precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom ceftriaxone and calcium-containing fluids were administered at different time points via different intravenous lines: no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates (see Adverse Effects - Post-marketing experience).

PRECAUTIONS

Hypersensitivity to Cephalosporins, Penicillins or other Drugs

BEFORE THERAPY WITH CEFTRIAXONE IS INITIATED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. ANAPHYLACTIC REACTIONS WITH FATAL OUTCOME HAVE BEEN REPORTED, EVEN IF A PATIENT IS NOT KNOWN TO BE ALLERGIC OR PREVIOUSLY EXPOSED TO CEFTRIAXONE OR OTHER CEPHALOSPORINS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS ADRENALINE AND OTHER EMERGENCY MEASURES. IF AN ALLERGIC REACTION OCCURS CEFTRIAXONE SHOULD BE DISCONTINUED.

Calcium-containing Solutions

In the available scientific data, there are no reports of intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. However, ceftriaxone should not be mixed or administered to any patient simultaneously with calcium-containing solutions, even via different infusion lines (see Contraindications for information regarding newborns).

Clostridium difficile

Associated Diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibiotics agents, including ceftriaxone and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. Difficile.

C difficile produces toxins A and B which contribute to the development of CDAD. Toxin hyperproducing strains of C difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial agent effective against C. Difficile and surgical evaluation should be instituted as clinically indicated. Drugs which delay peristalsis, for example, opiates and diphenoxylate with atropine (LOMOTIL), may prolong and/or worsen the condition and should not be used. Other causes of colitis should also be considered.

History of Gastrointestinal Disease

Ceftriaxone should be prescribed with caution in individuals with a history of gastrointestinal disease, especially colitis.

Immune mediated Haemolytic Anaemia

Immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including ceftriaxone. Severe cases of haemolytic anaemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin associated anaemia should be considered and ceftriaxone discontinued until the etiology is determined.

Overgrowth of Other Non-Susceptible Organisms

Prolonged use of Ceftriaxone Alphapharm may result in overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pancreatitis and Biliary Precipitation

Cases of pancreatitis (possibly of biliary obstruction aetiology) have been rarely reported in patients treated with Ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of ceftriaxone-related biliary precipitation can therefore not be ruled out.

Gall Bladder Concretions/Precipitates

Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder, usually following doses higher than the standard recommended dose. These shadows are, however, precipitates of calcium ceftriaxone which disappear on completion or discontinuation of ceftriaxone therapy. Rarely have these findings been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended. Discontinuation of ceftriaxone treatment in symptomatic cases should be at the discretion of the physician.

Renal Impairment and Toxicity

Ceftriaxone has shown some evidence of renal toxicity in animals. Clinical studies have shown only transient elevations of serum urea and serum creatinine at the recommended dosages. Ceftriaxone is excreted via both biliary and renal excretion (see Pharmacokinetics). The half life of ceftriaxone may be prolonged in some patients with renal failure, adjustment in dosage may be required. Concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly. Dosage adjustments should not be necessary in patients with hepatic dysfunction. In patients with both hepatic dysfunction and significant renal disease, Ceftriaxone dosage requires close monitoring of serum concentrations.

Alterations in Clotting Time

Alterations in prothrombin times have occurred rarely in patients treated with Ceftriaxone. Patients with impaired vitamin K synthesis or low vitamin K stores (eg chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Use of Lignocaine Hydrochloride in Patients with Impaired Liver Function

Repeated use of lignocaine hydrochloride should be avoided in patients with severe liver disease or decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from decreased metabolism and accumulation).

Carcinogenesis and Mutagenesis

Carcinogenicity studies with ceftriaxone in animals have not been performed. The maximum duration of animal toxicity studies was six months. Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.

Impairment of Fertility

Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses of up to 586 mg/kg/day.

Use in Pregnancy (Category B1)

Teratogenic Effects

: Reproductive studies (Segment II) have been performed in mice and rats at doses up to 586 mg/kg/day and no evidence of embryotoxicity, foetotoxicity or teratogenicity was seen. In primates, at doses up to 84 mg/kg/day no embryotoxicity or teratogenicity was demonstrated.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-Teratogenic Effects

: In rats, in the Segment I (fertility and general reproduction) and Segment III (perinatal and postnatal) studies with intravenously administered ceftriaxone, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behaviour and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.

Use in Lactation

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman.

Paediatric Use

Safety and effectiveness of ceftriaxone in infants and children have been established for the dosages described in the Dosage and Administration section. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Ceftriaxone should not be given to neonates who may be at risk of developing bilirubin encephalopathy (especially premature infants) (see Contraindications). Because of the risk of precipitation of ceftriaxone-calcium (see Interactions with Other Medicines). Ceftriaxone is contraindicated in neonates requiring (or expected to require) treatment with calcium-containing I.V. solutions (including continuous calcium-containing infusions such as parenteral nutrition) (see Contraindications).

INTERACTIONS WITH OTHER MEDICINES

Ceftriaxone does not contain an N-methylthiotetrazole moiety which has been associated with significant impairment of Vitamin-K dependent coagulation by some other cephalosporins. Probenecid does not cause clinically significant changes in the elimination of ceftriaxone. Concomitant use does not confer a therapeutic benefit. In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Ceftriaxone Alphapharm vials or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line. Ceftriaxone Alphapharm must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone calcium (see Dosage and Administrations and Contraindications). No impairment of renal function has so far been observed after concurrent administration of ceftriaxone and diuretics (e.g. frusemide). Healthy adults treated with 3 mg ceftriaxone and 3mg/kg per day of tobramycin for three days did not show any enzymatic evidence of impaired renal function. Based on literature reports ceftriaxone is physically incompatible in admixtures with amsacrine, vancomycin, fluconazole and aminoglycosides.

Laboratory Tests

In patients treated with ceftriaxone the Coombs' test may become false-positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosemia. Likewise, non-enzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically. Haematological changes such as eosinophilia, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia. Isolated cases of agranulocytosis (< 500/mm3) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more. During prolonged treatment the complete blood count should be done at regular intervals.

DOSAGE AND ADMINISTRATION

Dosage

Ceftriaxone Alphapharm may be administered intravenously or intramuscularly. The recommended adult daily dose is 1 to 2 g given once a day or in equally divided doses twice a day depending on the type and severity of the infection. The lower dose would be appropriate for less severe infections. For the treatment of uncomplicated gonococcal infections a single intramuscular dose of 250 mg is recommended. For preoperative use (surgical prophylaxis) in cardiovascular surgery, biliary tract surgery in high risk patients and in vaginal and abdominal hysterectomy a single dose of 1 g administered 1/2 to 2 hours before surgery is recommended. For the treatment of serious miscellaneous infections in children, the recommended total daily dose is 50-75 mg/kg (not to exceed 2 grams), given once per day or in divided doses every 12 hours. In meningitis the dose should be divided and administered every twelve hours. Generally, ceftriaxone therapy should be continued for at least two days after the signs and symptoms of infection have disappeared. The usual duration is 4-14 days. In special conditions eg endocarditis, osteomyelitis, infected joints etc, treatment may be continued for a longer duration. Prolonged therapy results in a higher incidence of adverse effects particularly diarrhoea, rash, eosinophilia, elevated liver enzymes and to a lesser extent neutropenia. When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least ten days. No dosage adjustment is necessary for patients with impairment of hepatic function; however, blood levels should be monitored in patients with severe renal impairment (eg dialysis patients) and in patients with both renal and hepatic dysfunction. Serum levels should not exceed 280 mcg/mL.

Administration

The use of freshly prepared solutions is recommended. These retain their efficacy for at least six hours at room temperature (or 24 hours at 5degC). The solutions are yellowish in colour; this characteristic of the active ingredient is of no significance to the efficacy or tolerance of the drug. A slight opalescence may be seen in the reconstituted solution. Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Ceftriaxone Alphapharm vials or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line. Ceftriaxone Alphapharm must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see Contraindications and Precautions - Paediatric Use). There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (I.V. or oral). Ceftriaxone Alphapharm should also not be mixed with or piggybacked into solutions containing other antimicrobial medicines or into diluent solutions other than those listed below, owing to possible incompatibility. Specifically, the literature reports that ceftriaxone is incompatible with amsacrine, vancomycin and fluconazole and aminoglycosides.

Intramuscular injection: Ceftriaxone Alphapharm 1 g is dissolved in 3.5 mL of 1% lignocaine solution, and administered by deep intragluteal injection. It is recommended that no more than 1 g be injected on either side. The lignocaine solution must never be administered intravenously. Ceftriaxone Alphapharm should be injected well into the body of a relatively large muscle mass. Intramuscular injection of Ceftriaxone Alphapharm without lignocaine solution is painful.

Intravenous injection

: Ceftriaxone Alphapharm 1 g is dissolved in 10 mL of water for injection, and then administered by direct intravenous injection lasting two to four minutes.

Intravenous infusion

: Two grams of Ceftriaxone Alphapharm are dissolved in approximately 40 mL of one of the following infusion solutions:

• Sodium chloride 0.9%

• Sodium chloride 0.45% + glucose 2.5%

• Glucose 5%

• Glucose 10%

• Levulose 5%

• Dextran 70 6% in glucose 5%

The infusion should be given over a period of at least 30 minutes.

OVERDOSAGE

Excessive serum concentrations of ceftriaxone cannot be reduced by haemodialysis or peritoneal dialysis. Treatment of overdosage should be symptomatic and consist of general supportive measures. Contact the Poisons Information Centre on 131126 (Australia) for advice on management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

For intramuscular or intravenous injection:

Vials containing powder equivalent to 250 mg * and 500 mg * ceftriaxone. Packs of 1. Vials containing powder equivalent to 1 g ceftriaxone. Packs of 1 * and 5.

For intravenous infusion:

Vials containing powder equivalent to 2 g ceftriaxone. Packs of 1 * and 5. 250mg (as sodium) powder for injection vial 500mg (as sodium) powder for injection vial 1g (as sodium) powder for injection vial 2g (as sodium) powder for injecton vial *Not marketed in Australia

Storage Conditions

Store below 25degC. Protect from light. Ceftriaxone Alphapharm is sensitive to light. Keep the vial in the outer carton in order to protect from light. Stability: Reconstituted solutions should be used immediately. If necessary, the solutions may be stored for 6 hours below 25C or for 24 hours between 2C to 8C. The product is for single use in one patient only. Discard any residue.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

(ABN 93 002 359 739) Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 www.alphapharm.com.au

POISON SCHEDULE OF THE MEDICINE

S4 - Prescription Only Medicine

DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (the ARTG)

20/01/2012

Date of most recent amendment

1 June 2012