INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ORPIC 2 mg/mL IV (intravenous infusion)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ORPIC 2 mg/mL IV (intravenous infusion)

COMPOSITION:
Each 50 mL vial contains:
127 mg Ciprofloxacin Lactate equivalent to 100 mg Ciprofloxacin
Each 100 mL vial contains:
254 mg Ciprofloxacin Lactate equivalent to 200 mg Ciprofloxacin
Each 200 mL vial contains:
508 mg Ciprofloxacin Lactate equivalent to 400 mg Ciprofloxacin

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1. Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION:
Ciprofloxacin is a synthetic fluoroquinolone antibiotic. It is bactericidal and acts by inhibiting the A subunit of DNA-gyrase which is essential in the reproduction of bacterial DNA.
Pharmacokinetics:
After oral administration, ciprofloxacin plasma levels are dose-related and peak at 0,5-2 hours.
The absolute bioavailability is approximately 70%. Protein binding is 40%. Forty to fifty percent is excreted in urine as unchanged ciprofloxacin. Approximately 15% of a single dose is eliminated as metabolites. Elimination is primarily renal and mainly during the first 12 hours after dosing. Renal clearance is approximately 300 mL/ minute. The elimination half-life of unchanged ciprofloxacin is 3-5 hours. The elimination kinetics is linear.
Micro-organisms resistant to ciprofloxacin:
Enterococcus faecium; Norcardia asteroids; Ureaplasma urealyticum; Peptostreptococcus species; Peptococcus species; Bacteroides; Treponema pallidum.

INDICATIONS:
ORPIC 2 mg/mL IV is indicated for the treatment of the following infections, when caused by susceptible organisms:
Lower Respiratory Tract Infections caused by:
Enterobacter cloacae, Escherichia coli, Haemophilus parainfluenzae, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.
Urinary tract infections caused by:
Citrobacter diversus, Citrobacter freunndii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus epidermidis, Streptococcus faecalis.
Skin and soft tissue infections caused by:
Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyrogenes.
Gastro-intestinal infections:
Infective diarrhoea caused by Campylobacter jejuni, Escherichia coli, Shigella flexneri and Shigella sonnei.
Bone infections:
Osteomyelitis due to susceptible Gram-negative organisms.
Gonorrhoea.

CONTRA-INDICATIONS:
ORPIC 2 mg/mL IV is contra-indicated in patients with a history of hypersensitivity to ciprofloxacin, any other quinolones, or any of the inactive ingredients.
Pregnancy and lactation.

ORPIC 2 mg/mL IV is contra-indicated in children under the age of 18 years. Experimental evidence indicates lesions of the cartilage of weight-bearing joints in immature members of certain animal species.

WARNINGS:
ORPIC 2 mg/mL IV should be used with caution in patients with a history of convulsive disorders.
Crystalluria related to the use of ORPIC 2 mg/mL IV has been observed. Patients receiving ORPIC 2 mg/mL IV should be well hydrated and excessive alkalinity of the urine should be avoided.
In the treatment of infections caused by Pseudemonas aeruginosa, an aminoglycoside must be administered concomitantly (see DOSAGE AND DIRECTIONS FOR USE).

INTERACTIONS:
Concurrent administration of ORPIC 2 mg/mL IV with theophylline may lead to elevated plasma concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related toxicity. If concomitant use cannot be avoided, plasma levels of theophylline should be monitored and dosage adjustments made as appropriate.
ORPIC 2 mg/mL IV should be administered 1-2 hours before, or at least 4 hours after taking iron preparations, antacids containing magnesium, aluminium, calcium or sucralfate, as interference with absorption may occur. This restriction does not apply to antacids belonging to the class of H2-receptor blockers.
Concomitant administration of the nonsteroidal anti-inflammatory medicine fenbufen with quinolones may increase the risk of central nervous system stimulation and seizures.
Monitoring of serum creatinine concentrations is advised in patients on concomitant cyclosporin therapy, as transient increases in serum creatinine concentrations have been observed.
The simultaneous administration of ORPIC 2 mg/mL IV and warfarin may lead to warfarin toxicity; therefore the INR should be closely monitored.
Concurrent administration of ORPIC 2 mg/mL IV and glibenclamide can potentiate the action of glibenclamide, leading to hypoglycaemia.
Probencid interferes with renal secretion of ORPIC 2 mg/mL IV Co-administration of probencid and ORPIC 2 mg/mL IV increases the ORPIC 2 mg/mL IV serum concentrations.
Metoclopramide accelerates the absorption of ORPIC 2 mg/mL IV, resulting in shorter time to reach maximum plasma concentrations.

PREGNANCY AND LACTATION:
Safety in pregnancy and lactation has not been established (see CONTRA-INDICATIONS).

DOSAGE AND DIRECTIONS FOR USE:
In the treatment of infections caused by Pseudomonas aeruginosa, an aminoglycoside must be administered concomitantly.
Dosage and duration of treatment:
The dosage of ORPIC 2 mg/mL IV is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, mass and renal function of the patient.
Adults: The usual dose is 100 mg-200 mg IV every 12 hours.
For severe and/or complicated infections 400 mg may be administered every 12 hours.
Intravenous therapy should be discontinued as soon as oral ORPIC therapy can be substituted. The normal duration of intravenous therapy is up to 7 days.
In cystic fibrosis patients, the normal dose is 200 mg IV every 12 hours. The low body mass of these patients should however, be taken into consideration when determining dosage (5-10 mg/kg/day).
Directions of Intravenous Administration:
ORPIC 2 mg/mL IV should be administered by intravenous infusion over a period of 60 minutes. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation. The infusion solution can be infused either directly or after mixing with the other compatible infusion solutions.
THIS PREPARATION MUST BE DILUTED BEFORE USE.
The aqueous concentrate should be aseptically withdrawn from the ORPIC 2 mg/mL IV ampoule or vial. This should be diluted with a suitable compatible intravenous solution to a final concentration of 1-2 mg/mL (see COMPATIBILITY AND STABILITY). The resulting solution should be infused over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set that may already be in place.
Compatibility and stability:
ORPIC 2 mg/mL IV is compatible with various intravenous solutions, including sterile water for injection, 0,9% sodium chloride solution, 5% and 10% dextrose solutions, 5% dextrose with 0,225% or 0,45% sodium chloride solutions, Ringer's solution and Ringer's Lactate solution. If ORPIC 2 mg/mL IV has been mixed with one of the above compatible solutions, for microbiological reasons and light sensitivity, these solutions should be administered shortly after admixture.
Important incompatibilities:
Unless compatibility with other infusion solutions or medicines has been confirmed, they should always be administered separately. Signs of incompatibility include precipitation, clouding and discoloration.
Incompatibility will present with all infusion solutions and medicines that are physically or chemically unstable at the pH of the ciprofloxacin infusion solutions (3,9-4,5), e.g. penicillin's and heparin solutions, especially on combination with solutions adjusted to an alkaline pH.
ANY REMAINING SOLUTION MUST BE DISCARDED.
Impaired Renal or Liver Function:
In patients with reduced renal function, the half-life of ciprofloxacin may be prolonged. The dosage needs to be adjusted as shown below.
For patients with renal impairment and hepatic insufficiency, monitoring of medicine serum levels provides the most reliable basis for dose adjustment.
Dose adjustment of ciprofloxacin for patients with renal or hepatic impairment:

1.	Kidney insufficiency:
	1.1		Clcr>31 mL/min/1,73 m2 Max 800 mg/day intravenously
	1.2		Clcr<30 mL/min/1,73 m2 Max 400 mg/day intravenously
	1.3		Impaired renal function and haemodialysis - As in 1.2 above; after dialysis on dialysis days.
2.	Renal impairment and CAPD (chronic ambulatory peritoneal dialysis):
	2.1		Addition of ORPIC 2 mg/mL IV solution to the dialysate (intraperitoneal): 50 mg ciprofloxacin per litre of dialysate administered 4 times a day.
	2.2		Oral administration of either ORPIC tablet as 500 mg tablet or 2 x 250 mg tablets.
	2.3		For CAPD patients with peritonitis, the recommended daily oral dose is 500 mg four times a day.
3.		Hepatic impairment: No dose adjustment.
4.		Hepatic and renal impairment: As in 1.1 and 1.2 above.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Side effects:
Gastro-intestinal system:
Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain. The development of severe and persistent diarrhoea may indicate pseudomembranous colitis, requiring immediate treatment. In such cases ORPIC 2 mg/mL IV must be discontinued and appropriate therapy initiated (e.g. vancomycin, orally 4 x 250 mg/day).
Vision:
Visual disturbances (e.g. diplopia, colour vision).
Hearing and vestibular disorders:
Tinnitus, transient impairment of hearing - especially at high frequencies.
Haematological system:
Eosinophilia, leucocytopenia, granulocytopenia, anaemia, thrombocytopenia, leucocytosis, thrombocytosis, haemolytic anaemia, altered prothrombin values.
Skin:
Rashes:
Less frequent: Urticaria and photosensitivity (blisters, sensation of skin burning), erythema nodosum and erythema exsudativum multiforme (minor) have been reported. The following have been reported: Stevens-Johnson syndrome, Leyll's syndrome, punctate skin haemorrhages (petechiae), haemorrhagic bullae and papules with signs of vascular involvement (vasculitis).
Central Nervous system:
Frequency unknown: Dizziness, headache, tiredness, nervousness, agitation, and trembling.
Less frequent: Insomnia, peripheral paralgesia, sweating, unsteady gait, convulsions, increase in intracranial pressure, anxiety states, nightmares, confusion, hallucinations, increase in intracranial pressure, psychotic reactions (even progressing to self-endangering behavior), depression. In some instances, these reactions occurred after the first administration of ciprofloxacin. In these cases ORPIC 2 mg/mL IV must be discontinued and the medical practitioner informed immediately.
Musculoskeletal disorders:
Rare: Joint pain, joint swelling.
Less frequent: general feeling of weakness, and myalgia (which may be of special importance in patients with myasthenia gravis) and tendosynovitis have been observed. Cases of achillotendinitis have been observed. Partial or complete rupture of the Achilles tendon occurred in predominantly elderly patients on treatment with systemic glucocorticoids. At any sign of an achillotendinitis (or any tendonitis) (e.g. painful swelling) the administration of ORPIC 2 mg/mL IV should be discontinued and a medical practitioner should be consulted.
Cardiovascular system:
Rare: Tachycardia, flushing, migraine, syncope.
Genitourinary system:
Crystalluria related to the use of ciprofloxacin has been observed. Patients receiving ORPIC 2 mg/mL IV should be well hydrated and excessive alkalinity of the urine should be avoided.
Frequency unknown: Interstitial nephritis, transient renal impairment including transient renal failure, and haematuria, have been reported.
Hypersensitivity reactions:
Frequency unknown: Anaphylactic/anaphylactoid reactions can occur (e.g. facial, vascular and laryngeal oedema, dyspnoea progressing to life-threatening shock), in some instances after the first administration. In these cases ORPIC 2 mg/mL IV has to be discontinued and appropriate medical treatment instituted.
Local Reactions:
Phlebitis or thrombophlebitis, local irritation and pain at the site of injection. Intravenous infusion should be administered by slow infusion over a period of 60 minutes. These reactions are more frequent if the infusion time is 30 minutes or less, or if small veins of the hand are used. These may appear as local skin reactions, which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.
Influence on laboratory parameters/urinary sediment:
There can be temporary elevations of transaminases, alkaline phosphatase of cholestatic jaundice, (especially in patients with liver damage, temporary increase in urea, creatinine or hyperbilirubinaemia).
Other:
Impaired taste and smell, hyperglycaemia. Hepatic necrosis, very seldom progressing to hepatic failure, has been reported.
The ability to drive a motor vehicle or operate machinery may be impaired by ORPIC 2 mg/mL IV This applies particularly in combination with alcohol.
Long-term or repeated administration of ORPIC 2 mg/mL IV can lead to superinfections with resistant bacteria or fungi.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
In the event of acute, excessive oral over-dosage, reversible renal toxicity has been reported.
Apart from routine emergency measures, it is recommended to monitor renal function and to administer magnesium- or calcium-containing antacids which reduce the absorption of oral ORPIC 2 mg/mL IV.
Only a small amount of ciprofloxacin (< 10%) is removed from the body after haemodialysis or peritoneal dialysis.
Treatment is symptomatic and supportive.

IDENTIFICATION:
A clear yellowish to slightly yellow, odourless solution free from foreign bodies and visible particulate matter.

PRESENTATION:
ORPIC 2 mg/mL IV solution for intravenous infusion are presented in transparent, colourless, Type I glass vials, sealed with an orange bromobutyl rubber stopper and aluminium cap and are available in the following pack sizes:

•	50 mL Type I glass vials containing Ciprofloxacin 100 mg/50 mL
•	100 mL Type I glass vials containing Ciprofloxacin 200 mg/100 mL
•	200 mL Type I glass vials containing Ciprofloxacin 400 mg/200 mL

Each vial is individually packed and available in 1's.

STORAGE INSTRUCTIONS:
Store below 25°C, protected from light.
Store in outer carton until required for use.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER:
A 40/20.1.1/0454

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
PHARMACARE LIMITED
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF PACKAGE INSERT:
15 March 2006

28.ORN.1AS31LE

New addition to this site: February 2008
Source: Pharmaceutical Industry

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