Description:
Amplus is a broad spectrum formulation of (ampicillin + cloxacillin). Amplus exhibits bactericidal activity against a wide range of Gram-negative organisms.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties:
AMPLUS is a combination of ampicillin and cloxacillin. Cloxacillin is a narrowspectrum antibiotic of the isoxazolyl penicillin group; it is not inactivated by staphylococcal beta-lactamases. Ampicillin is a broad-spectrum antibiotic of the aminopenicillin group; it is not resistant to beta-lactamases.

Both ampicillin and cloxacillin are bactericidal antibiotics and act by interfering with the formation of new bacterial cell wall by dividing organisms. The prevalence of acquired resistance is geographically variable and for select species may be very high. Local information on resistance is desirable, particularly when treating severe infections.

AMPLUS susceptibility rates are higher than ampicillin rates due to the cloxacillin activity against β-lactamase producing staphylococci. Methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-susceptible coagulase-negative staphylococcus (MSCoNS) are commonly susceptible to AMPLUS. MRSA and MRCoNS are resistant to AMPLUS. For all other indicated bacterial species, the susceptibility of AMPLUS is similar to ampicillin including limited
activity against Gram-negative organisms.

Pharmacokinetic properties:
Absorption:
Both ampicillin and cloxacillin are stable in the gastric environment resulting in good absorption. Neither component of the combination of ampicillin and cloxacillin interferes with the absorption or excretion of the other. The total quantity absorbed by the oral route represents 50% (cloxacillin) and 40% (ampicillin) of the quantity administered. The presence of food in the stomach may depress oral absorption and AMPLUS should therefore be taken 0.5 to 1 hour before meals.

Distribution:
AMPLUS diffuses well into most tissues and body fluids including, among others, bronchial secretions, sinuses, saliva, cerebrospinal fluid (variable percentage depending on the degree of meningeal inflammation), bile, serous membranes and middle ear.

Crossing the meningeal barrier: AMPLUS diffuses in only small proportion into the cerebrospinal fluid of subjects whose meninges are not inflamed.

Crossing into breast milk: AMPLUS is excreted in small quantities in breast milk.

Plasma half-life for cloxacillin is 0.5 to 1 hour and 1 to 1.5 hours for ampicillin.

Protein binding: the serum protein binding proportion is approximately 94% for cloxacillin and 18% for ampicillin.

Metabolism:
In normal subjects approximately 20% (cloxacillin) and 40% (ampicillin) of the dose administered is metabolised.

Excretion:
AMPLUS is eliminated mainly through the kidney. Approximately 30% of the dose administered orally and over 60% of the ampicillin dose administered parenterally is eliminated in active form in the urine within 24 hours. The equivalent percentages for cloxacillin are approximately 20% and 30% respectively. A small proportion (10%) of the dose administered is excreted in bile.

Renal impairment
Renal impairment In cases of renal failure, the dosage should be adapted in accordance with the following: Creatinine clearance greater than 50 ml/minute: normal dose according to indication.

Creatinine clearance between 50 and 10 ml/minute:

• Dosage (oral or parenteral administration) initial dose: normal dose (according to indication).
• Dosage (oral or parenteral administration) maintenance dose: the normal unit dose (AMPLUS 500 mg orally, up to 1 g i.m. or i.v) three times daily.

Creatinine clearance below 10 ml/minute:

• Dosage (oral or parenteral administration) initial dose: normal dose (according to indication).
• Dosage (oral or parenteral administration) maintenance dose: the
  normal unit dose twice or once daily.

In cases of dialysis, an additional normal unit dose (AMPLUS 500 mg orally, up to 1 g i.m. or i.v) is to be administered after the procedure.

Hepatic impairment
Hepatic impairment Reduce frequency of administration depending on the severity of the condition.

CLINICAL PARTICULARS:
Therapeutic Indications
AMPLUS is indicated for the treatment of the following infections including mixed Gram-positive (except methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant
coagulase-negative staphylococcus (MRCoNS)) and Gram-negative infections:

Surgery: post-operative wound infections, post-operative pulmonary infections
Respiratory infections: bronchopneumonia, acute exacerbations of chronic bronchitis.
Obstetrics: puerperal fever.
Other infections such as septicaemia, bone infections e.g. osteomyelitis, ear, nose and throat infections.

AMPLUS neonatal suspension and injection are indicated for the prophylaxis or treatment of bacterial infections in premature babies or neonates, caused by known susceptibile strains of bacteria.

DOSAGE AND ADMINISTRATION

Adults and Elderly

Children 2 to 12 years

Neonates to 2 years

METHOD OF ADMINISTRATION

Oral route:
AMPLUS should be administered 0.5 to 1 hour before meals.

Parenteral route:
Administer by slow i.v. injection (3 to 4 minutes). AMPLUS may also be added to infusion fluids (except for aminoglycosides, amino acid solutions, fat emulsions and blood), and can, therefore, be administered simultaneously with these forms of treatment or injected, suitably
diluted, into the drug tube over a period of 3 to 4 minutes.

CONTRAINDICATION:
AMPLUS should not be given to patients with a history of hypersensitivity to betalactam antibiotics (e.g. penicillins, cephalosporins) or excipients. AMPLUS is contraindicated for ocular administration.

WARNINGS AND PRECAUTIONS
Caution should be observed when administering AMPLUS neonatal suspension to babies whose mothers are hypersensitive to penicillin. Before initiating therapy with AMPLUS, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactams. Cross-sensitivity between penicillins and cephalosporins is well documented.
Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving beta-lactam antibiotics.

Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity. If an allergic reaction occurs, AMPLUS should be discontinued and the appropriate alternative therapy instituted. All adverse reactions
should be treated symptomatically.

AMPLUS should be avoided if infectious mononucleosis and/or acute or chronic leukaemia of lymphoid origin are suspected. The occurrence of a skin rash has been associated with these conditions following the administration of ampicillin. Prolonged use may occasionally result in overgrowth of non-susceptible organisms. Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.

Dosage should be adjusted in patients with renal impairment. Cloxacillin can displace bilirubin from protein-binding sites. Normal caution should therefore be exercised in the treatment of jaundiced neonates. AMPLUS neonatal suspension and syrup contain sodium benzoate which is a mild irritant to the skin, eyes and mucous membrane. It may increase
the risk of jaundice in newborn babies.

DRUG INTERACTIONS:
Probenecid decreases the renal tubular excretion of AMPLUS. Concurrent use with AMPLUS may result in increased and prolonged blood levels of AMPLUS.
In common with other antibiotics, AMPLUS may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Sulphonamides and acetylsalicylic acid inhibit serum protein binding of cloxacillin in vitro. This may result in increased levels of free cloxacillin in serum in vivo.

Bacteriostatic drugs may interfere with the bactericidal action of AMPLUS. Concurrent administration of allopurinol during treatment with AMPLUS can increase the likelihood of allergic skin reactions.

USE IN PREGNANCY AND LACTATION:
Adequate studies with Ampicillin + cloxacillin for use in pregnancy and lactation are not available Hence this should be used if benefit outweighs risk under guidance from physicians.

ADVERSE EFFECTS:
Common: Diarrhoea , nausea. Skin rash , urticaria and pruritus. Uncommon: Vomiting,
Very Rare: Haemolytic anaemia, leucopenia, thrombocytopenia, agranulocytosis, Anaphylaxis, other hypersensitivity reactions, Myoclonus, convulsions, Pseudomembranous colitis, hemorrhagic colitis, Hepatitis and cholestasis jaundice. A moderate and transient
increase in transaminases , Bullous reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), exfoliative dermatitis, purpura, Interstitial nephritis.

OVERDOSAGE:
Overdosage with oral AMPLUS is unlikely to cause serious reactions if renal function is normal. Very high dosage of i.v. administered ampicillin and/or high dosage of cloxacillin in renal failure may provoke neurotoxic reactions similar to those seen with benzylpenicillin in excess.
Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident. These symptoms should be treated symptomatically.

PHARMACEUTICAL PARTICULARS

INCOMPATIBILITIES
AMPLUS must not be dissolved in either protein or protein hydrolysate solutions or in lipid solutions, or in blood or plasma. When AMPLUS is prescribed together with an aminoglycoside, the two antibiotics should not be mixed in the same container as the one containing the infusion solution because a loss of activity may occur.

STABILITY & COMPATIBILITY
Amplus is stable with commonly used intravenous fluids at 23ºC if infused over a period of 6 hours. Solutions should be changed after 2 hours if it is administered in fluids containing dextrose or other carbohydrates or within 4 hours for solutions containing sodium bicarbonate. Amplus Should not be mixed with blood products or protienaceous fluids such as protein hydrolysates nor with lipid emulsions.

SYRUP
Once dispensed the syrup should be used within 7 days.

STORAGE
Should be kept tightly closed and stored in cool, dry place below 25 ºC.

AVAILABILITY
250mg CAPSULES:
250mg capsules contains: Ampicillin Trihydrate eq. to Ampicillin base…125mg
Cloxacillin Sodium eq. to Cloxacillin base…125mg

500mg CAPSULES:
500mg capsules contains: Ampicillin Trihydrate eq. to Ampicillin base…250mg
Cloxacillin Sodium eq. to Cloxacillin base…250mg

250mg SYRUP:
250mg powder for preparing orange-flavoured syrup. When dispensed, each 5ml contains: Ampicillin Trihydrate eq. to Ampicillin base…125mg
Cloxacillin Sodium eq. to Cloxacillin base…125mg

250mg VIAL:
250mg vial containing 125mg Ampicillin plus 125mg Cloxacillin

500mg VIAL:
500mg vial containing 250mg Ampicillin plus 250mg Cloxacillin

DIRECTION

• Protect from heat, sunlight & moisture, store below 25ºC.
• The expiration date refer to the product correctly stored at the required condition.
• Keep out of the reach of children.
• For suspected adverse drug reaction for BOSCH products, report at ade@bosch-pharma.com
• To be sold on the prescription of registered medical practitioner only