Flumox(oral,inj)

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flumox

Flucloxacillin plus Amoxicillin

 

Description:

Fixed does combination of Amoxicillin and Flucloxacillin is available in both oral and parenteral formulation. Their usage is determined on the basis of severity of infections. Flucloxacillin is an isoxazolyl penicillin of the beta-lactam group of antiboitics, which exerts a bacetericidal effect upon many Gram positive organism including streptococci and beta- lactamase producing staphylococci. It has a relatively narrow spectrum of antibacterial activity.

 

Amoxicillin is a semisynthetic antibiotic, an analog of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S, 5R, 6R) – 6-[[3-(2-chloro-6-fluoropheny)-5-methyl 1,2-oxazole-4-carbonyl] amino]-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane -2- carboxylic acid monohydrate for oral use and as sodium salt for parenteral use.

 

Composition:

Each capsule contains:

Amoxicillin Trihydrate B.P. equivalent to …………………………………. 250 mg Amoxicillin

Flucloxacillin Sodium B.P. equivalent to ……………………………………. 250 mg Flucloxacillin

Each Vial contains

Amoxicillin Sodium B.P. equivalent to ……………………………………… 250 mg Amoxicillin

Flucloxacillin Sodium B.P. equivalent to …………………………………… 250 mg Flucloxacillin

 

Clinical Pharmacology:

Pharmacodynamic properties

i) Properties:

Amoxicillin is similar to ampicillin in its bactericidal action agianst susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. Amoxicillin has been shown to be active against most strains of the following microorganism, both in vitro and in clinical infections.

Flucloxacillin is a narrow spectrum antibiotic of the group of isoxazolylpenicillins: It is not inactivated by staphylococcal beta-lactamases.

Flumox exhibits in vitro and in experimental animals in vivo bactericidal activity against a wide commonly encountered sensitive organism:

(ii) Synergism: Flumox exhibits synergistic bactericidal activity in vitro, and in experimental animals in vivo against some ampicillin resistant organism.

 

           Gram-positive bacteria        Gram-negative bacteria
           Streptococcus pyogens        Neisseria gonorrhoeae
           Strep.faecalis        Neisseria Meningitidis
           Strep.Viridans        Haemophilus influenzae
           Strep.pneumoniae        Escherichia coli
           Staphylococcus aureus        Salmonella typhi
       Salmonella species
           Staphylococcus aureus(penicillinase producing)        Proteus mirabilis
       Bordetella pertussis
           Corynebacterium species        Shigella species
           Clostridium species        Brucella Species
           Bacillus anthracis

(iii) Additive effects: The two components of Flumox i.e. amoxycillin and flucloxacillin generally exhibit an additive effect against sensitive bacteria and bacteria that are sensitive to amoxycillin or to flucloxacillin or remain sensitive to the combinationl, showing that antagonism does not occur when the two components are combined. Flucloxacillin, by its action on the synthesis of the bacterial wall, exerts a bactericidal effect on streptococci, Staphylococci, including the beta-lactamase-producing strains, clostridia and neissieria. It is not active against methicillin-resistant staphylococci.

Strains of the following organisms are generally sensitive to the bactericidal action of flucloxacillin in vitro. (The minimal inhibitory concentration (MIC) of flucloxacillin are quoted below) flucloxacillin is bactericidal with a mode of action similar to that of benzylpenicillin, but is resistant to staphylococcal penicillinase. It is active therefore against penicillinase-producing and non-peniclillinase-producing staphylococci, with minimum inhibitory concentration in range of 0.25 to 0.5mcg per ml. Its activity against streptococci such as Streptococcus pneumoniae and Str. pyogenes is less than that of benzylpenicillin but sufficient to be useful when these organisms are present with penicillin-resistant staphylococci. Flucloxacillin is virtually ineffective against Enterococcus faecalis.

 

Micro-organisms MIC (mg/l)
Streptococcus aureus 0.1-0.25
Streptococcus aureus(beta-lactamase producing) 0.25-0.5
Streptococcus pneumoniae 0.25
Streptococcus pyogens 0.1
Streptococcus viridans group 0.5
Clostridium tetani 0.25
Clostridium welchii 0.25
Neisseria meningitidis 0.1
Neisseria gonorrhoeae 0.1
Neisseria gonorrhoeae(beta-lactamase producing) 2.5

 

The Group A beta-haemolytic streptococci are less sensitive to the isoxazolyl penicillins than to penicillin G or penicillin V.

 

Pharmacokinetic properties

              1. Abosorption:

Orally administered dosage of 250 mg amoxicillin capsules result in average peak blood levels one or two hours after administration in the range of 3.5 mcg/ml to 5.0 mcg/ml respectively. Flucloxicillin is stable in acid media and can therefore be administered either by the oral or parental route. The peak serum of flucloxicillin reached after 1 hour are as follows.

-After 250 mg by the oral route (in fasting subjects): approximately 8.8 mg/l

-After 500 mg by the oral route (in fasting subjects): approximately 14.5 mg/l

Absorption is more efficient when taken on empty stomach. The total quantity absorbed by the oral route represents approximately 79 % of the quantity administered. Flucloxacillin sodium, like dicloxacillin sodium is about twice as well absorbed from the gastro-intestinal tract as cloxacillin sodium, but absorption is also reduced by the presence of food in the stomach. After an oral dose of 250mg to 1g in fasting subjects, peak plasma concentrations in about 1 hour are usually in the range of 5 to 15 mcg per ml. Plasma concentrations following the intramuscular injection of Flucloxacillin sodium are similar, but peak concentrations are achieved in about 30 minutes. Doubling the dose can double the plasma concentration. About 95% of Flucloxacillin in the circulation is bound to plasma proteins. In blood serum, amoxicillin is approximately 20 % protein-bound. Flucloxacillin has been reported to have plasma half-life of approximately 1 hour. The half life of amoxicillin is 61.3 minutes. The half-life is prolonged in neonates.

         2. Distribution:

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluide, except when meninges are inflamed. Most of the amoxicillin is excreted unchanged in the urine.

Its excretion can be delayed by concurrent administration of probenecid. Flucloxicillin diffuses well into most tissues specifically, active concentration of flycloxicillin have been recovered in bones: 11.6mg/I (Compact bone) and 156 mg/I (spongy bone), with a mean serum level of 8.9mg/l. Crossing the meningeal barrier: flucloxicillin diffuses in only small proportion into cerebrospinal fluid of subjects whose meanings are not inflamed. Crossing into mother’s milk: flucloxacillin is excreted in small quantities in mother’s milk. The distribution of flucloxacillin into body tissues and fluids is similar to that of Cloxacillin.

 

        3. Metabolism:

In normal subjects approximately 10% of the flucloxacillin administered is metabolised to penicilloic acid. The elimination half-life of flucloxacillin is 30-60 minutes. Flucloxacillin is metabolised to a limited extent and the unchanged drug and metabolites are excreted in the urine by glomerularfiltration and renal tubular secretion.

     

        4. Excretion:

The drug is rapidly excreted by the kidney, about 50% within 6 hours of administration. A small portion of the dose administered is excreted in the bile. The excretion of flucloxacillin is slowed in cases of renal failure. Metabolites are excreted in the urine by glomerular filtration and renal tubular secretion.

About 50% of a dose by mouth and up to 90% of an intramuscular dose is excreted in the urine within 6 hours. Only small amounts are excreted in the bile. Flucloxacillin is not removed by haemodialysis. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

 

      5. Protein Binding:

The serum protein binding rate is 95% in case of flucloxacillin whereas 20% of amoxicillin is protein bound.

 

Therapeutic indications:

Fixed dose combinations of Amoxicillin and Flucloxacillin is indicated for the treatment of infections due to Gram-positive organisms, including infections caused by -lactamase producing staphylococci. Typical indications include.

 

Skin and Soft Tissue Infections:

Boils, abscesses, carbuncles, furunculosis, cellulitis, infected wounds, infected burns, protection of skin grafts and impetigo.

Infected Skin Conditions: e.g. ulcer, eczema and acne.

 

Respiratory Tract Infections:

Pneumonia, lung abscess, emphysema, sinusitis, pharyngitis tonsillitis, quinsy, otitis media and externa.

Other infections caused by amoxicillin & flucloxacillin-sensitive organisms such as osteomyelitis, enteritis endocarditis, urinary tract infection, meningitis, septicaemia.

Oral proportions of the -lactamase-resistant penicillins(flucloxacillin alone or in combination with amoxicillin) should not be used as initial therapy in serious life threatning infections. Oral therapy with fixed dose combination of amoxicillin and flucloxacillin may be used to follow up the previous use of parenteral amoxicillin plus flucloxacillin combination as soon as the clinical conditions warrants. Parenteral therapy is indicated caused by susceptible pathogens. Empirical therapy for infants with suspected coagulase negative staphylococcal sepsis. Drug may be administered as combination or with netilmicin until culture results available.

Skin and soft tissue infections.

Bone and joint infections

 

Dosage & Method of administration

Oral: Adults (Including elderly patients): 2 capsules initially and then either 1 or 2 capsules 8 -hourly, depending on severity of infection.

Children weighing 20 kg or more should be dosed according to the adult recommendations in severe infections or those caused by less susceptible organisms: 2 capsules every 6 hours for adults and 40mg/kg/ day in divided doses every 6 hours for children may be needed.

Dosage should be administered 1 hour before meals.

 

Parenteral Dose and Administration

25-50mg/kg/dose by slow, IV injection IM or Po.

 

Weeks Postconception<29 Days Postnatal0 to 28
>28
30 to 36 0 to 14
>14
37 to 44 0 to 7
>7
>45 All

 

Flucloxacillin is administered by mouth as the sodium salt, in the form of capsules. Amoxicillin is available as amoxicillin trihydrate. It should be taken at least 30 minutes before meals as the presence of food in the stomach reduce absorption. In severe renal failure a reduction in dosage may be necessary.

 

Contraindications

Amoxicillin & Flucloxacillin are semisynthetic penicillin and should not be given to patients with a history of hypersensitivity to beta-lactam antibiotics (e.g. penicillin cephalosporins) or excipients. Flucloxacillin is contraindicated in patients with a previous history of flucloxacillin-associated jaundice/hepatic function.

 

Special Warnings and Special Precautions for use

Precautions: Dosage should be adjusted in renal impairment with other medicaments and other forms of interactions. Bacteriostatic agents may interfere with the bactericidal actions of amoxicillin and flucloxacillin. Concurrent administration of probenecid delays the renal excretion of amoxicillin and flucloxacillin.

 

Pregnancy and Lactation

 

Pregnancy:

Penicillins are generally considered safe for use in pregnancy. Animal studies with Amoxicillin and Flucloxacillin have shown no teratogenic effects. As limited information is available concerning the results of the use of Amoxicillin and Flucloxacillin in pregnancy. Should only be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Lactation:

Trace quantities of amoxicillin and flucloxicillin are excreted in breast milk. Amoxicillin and Flucloxacillin may be administered during the period of lactation. With the exception of the risk of sensitization there are no detrimental effects for the breastfed infant.

Effect on Ability to Drive and Use Machines.

Adverse effects on the ability to drive or operate machinery have not been observed

 

 

Side Effects:

Hypersensitivity Reactions

Before initiating therapy with amoxicillin and flucloxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactamase. Cross-sensitivity between penicillin and cephalosporins is well documented. If any hypersensitivity reaction occurs, the treatment should be discontinued. Rash, urticaria, purpura, fever, eosinophilia: sometimes angioneurotic oedema, rarely anaphylactic shock (exceptional with oral administration). Certain reactions (fever, arthralgia, myalgia) sometimes develop more than 48 hours after the start of the treatment. Eryhema multiforme has been reported rarely.

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving beta-lactam antibiotic. Although anaphylaxis is more frequently following parenteral therapy, it has occurred in patients on oral therapy. If an allergic reactions occurs, amoxicillin and flucloxacillin should be discontinued and appropriate therapy instituted. Serious anaphylactoid reaction may require immediate emergency treatment with adrenaline, with oxygen, intravenous steroids and airway management including intubation , may also be required. As with other penicillin, it may be expected that untoward reactions will be essentially limited to sensitivity phenomenon. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma hay fever or urticaria. The following adverse reactions have been reported as associated with the use of penicillins: Erythematous maculopapular rashes, erythema multiform, Stevens-Johnson syndrome toxic epidermal necrolysis and urticaria have been reported.

NOTE: These hypersensitivity reaction may be controlled with antihistamine and, if necessary systemic corticosteroids. Whenever such reactions occur, amoxicillin and flucloxacillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin and flucloxacillin therapy.

 

 

Gastrointestinal reactions:

Nausea, vomiting and diarrhea

Minor gastro-intestinal disturbances may occur during treatment. As with other antibiotic, pseudomembranous collitis has been reported rarely. If this condition develops, amoxicillin and flucloxacillin treatment should be discontinued and appropriate therapy, e.g. oral vancomycin should be intiated.

 

Hepatic effects:

Hepatic and cholestatic jaundice have been reported. Hepatic and cholestatic jaundice have been reported occasionally with Flucloxacillin and may be delayed in onset: older patients and those receiving Flucloxacillin for more than two weeks are at greater risk.

These may be delayed for up two months post-treatment. In some cases the course has been protracted and lasted for several months. Very rarely deaths have been reported, almost always in patients with serious underlying disease. Change in liver function test results may occur, but are reversible when treatment is discontinued. A moderated rise in Serum glutamic oxaloacetic transaminase (SCOT) has been noted but the significance of this finding in unknown.

 

Haematological effects:

Neutropenia (including agranulocytosis) and thrombocytopenia may occur but are reversible when treatment is discontinued. Anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported during therapy with penicillin. These reactions are usually, reversible on discontinuation of therapy and are believed to be hypresensitivity reactions.

 

Neurological Effects:

In patients suffering from renal failure, neurological disorders convulsions are possible with high doses (mainly parenteral).

 

Renal Effects:

Intestinal nephritis may occur but is reversible when treatment is discontinued.

 

Interactions:

Like amoxicillin, Flucloxacillin may decrease the efficacy of estrogen-containing oral contraceptives. May reduce absorption of oral contraceptives leading to break through bleeding or pregnancy.

 

Parenteral therapy (Caution & Precautions)

Hypersensitivity to penicillins/cephalosporins

Cautions in preterm infants, especially extreme immaturity

Cautions in infants with liver, renal or gastrointestinal disease.

Venous irritation, soft tissue injury at site IV injection

Pain soft tissue injury at site of IM injection.

Gastrointestinal disturbance (nausea, vomiting, diarrhoea).

Non-specific rashes and skin eruptions.

Fever, Pruritis, urticaria.

Seizures (encephalopathy with high doses greater then 400mg/kg/day.

May be given concurrently with aminoglycoside for synergistic effect. Administer separately as simultaneous administration may cause inactive and precipitation. Adjust dose in suspected renal dysfunction (usually by lengthening in dosing interval)

 

Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically. Flucloxacillin is not removed from the circulation by heaemodialysis.

 

Pharmaceutical Particulars

Incompatibities

As for penicillin. Incompatible with colistina polymyxin B sulphate. Loss of potency after mixing with Streptomycin has been reported.

 

Storage

capsules Store in a cool dry place, protected from light.

Vials (dry powder): Store below 25 , protected from light.

 

Medicine Classification Prescription Medicine Only

Presentation

Flumox Capsules: 2x 10’s, 10×10’s

Flumox injection IM/IV: 1 vial.

Product of:

Zifam Pinnacle Pty.Ltd

The Healthcare Group