Product Index

WARNING: 

SERIOUS ADVERSE REACTIONS, INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM (CNS) EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Composition

CIPLOX-OZ Tablets

Each film-coated tablet contains:

Ciprofloxacin Hydrochloride, IP

Equivalent to Ciprofloxacin……500 mg

Ornidazole, IP…………………………500 mg

Dosage Form

Oral tablet

Pharmacology

Pharmacodynamics

Ciprofloxacin

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

Mechanism of Resistance

The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <10-9 to 1x10-6.

Cross-Resistance

There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.

Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections:

Gram-positive Bacteria

Bacillus anthracis

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates only)

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Bacteria

Campylobacter jejuni

Citrobacter koseri

Citrobacter freundii

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas aeruginosa

Salmonella typhi

Serratia marcescens

Shigella boydii

Shigella dysenteriae

Shigella flexneri

Shigella sonnei

Yersinia pestis

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus haemolyticus (methicillin-susceptible isolates only)

Staphylococcus hominis (methicillin-susceptible isolates only)

Gram-negative Bacteria

Acinetobacter lwoffi

Aeromonas hydrophila

Edwardsiella tarda

Enterobacter aerogenes

Klebsiella oxytoca

Legionella pneumophila

Pasteurella multocida

Salmonella enteritidis

Vibrio cholerae

Vibrio parahaemolyticus

Vibrio vulnificus

Yersinia enterocolitica

Ornidazole

Ornidazole is a 5-nitroimidazole derivative active against protozoa and anaerobic bacteria. It is converted to reduction products that interact with DNA to cause destruction of the helical DNA structure and strand, leading to protein synthesis inhibition and cell death in susceptible organisms.

Ornidazole is effective against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia (Giardia intestinalis), and also against certain anaerobic bacteria such as Bacteroides and Clostridium spp.,  Fusobacterium spp., and anaerobic cocci.

Pharmacokinetics

Ciprofloxacin

Absorption

The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve (AUC) are shown in the chart for the 250 mg to 1,000 mg dose range.

Dose (mg)	Maximum Serum Concentration (mcg/mL)	Area Under Curve (AUC) (mcg•hr/mL)
250	1.2	4.8
500	2.4	11.6
750	4.3	20.2
1,000	5.4	30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500 or 750 mg are 0.1, 0.2 and 0.4 μg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1,000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an AUC equivalent to that produced by an intravenous (IV) infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at the steady state equivalent to that produced by an IV infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C_max similar to that observed with a 400 mg IV dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.

Steady-state Pharmacokinetic Parameters Following Multiple Oral and IV Doses
Parameters	500 mg	400 mg	750 mg	400 mg
AUC (mcg•hr/mL)	q12h, PO 13.7a	q12h, IV 12.7a	q12h, PO 31.6b	q8h, IV 32.9c
Cmax (mcg/mL)	2.97	4.56	3.59	4.07

^{PO= oral}

^aAUC_0–12h

^bAUC_24h=AUC_0–12h × 2

^cAUC_24h=AUC_0–8h × 3

Food

When ciprofloxacin tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of ciprofloxacin tablet, however, is not substantially affected. Avoid concomitant administration of ciprofloxacin with dairy products (like milk or yoghurt) or calcium-fortified juices alone since decreased absorption is possible; however, ciprofloxacin may be taken with a meal that contains these products

Distribution

The binding of ciprofloxacin to serum proteins is 20 to 40%, which is not likely to be high enough to cause significant protein binding interactions with other drugs.

After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue, including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in the lungs, skin, fat, muscle, cartilage and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humours of the eye.

Metabolism

Four metabolites have been identified in human urine, which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome (CY) P450 1A2 (CYP1A2)-mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolised by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug.

Excretion

The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 μg/mL during the first 2 hours, and are approximately 30 μg/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several-fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose is recovered from the faeces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Drug–Drug Interactions

Antacids

Concurrent administration of antacids containing magnesium hydroxide or aluminium hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%.

Histamine H2-receptor Antagonists

Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.

Metronidazole

The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

Tizanidine

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C_max 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg twice a day for 3 days). Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine.

Ropinirole

In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with twice-daily 500 mg ciprofloxacin, the mean C_max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine-associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin is advised.

Sildenafil

Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean C_max and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with ciprofloxacin due to the expected two-fold increase in the exposure of sildenafil upon co-administration of ciprofloxacin.

Duloxetine

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean C_max of duloxetine.

Lidocaine

In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with ciprofloxacin 500 mg twice daily resulted in an increase of lidocaine C_max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with ciprofloxacin and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.

Metoclopramide

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.

Omeprazole

When ciprofloxacin was administered as a single 1,000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and C_max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined.

Special Populations

Elderly

Pharmacokinetic studies of the oral (single dose) and IV (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (older than 65 years) as compared with young adults. Although the C_max is increased by 16 to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant.

Renal Impairment

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required.

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency has not been fully studied.

Ornidazole

Following oral administration, ornidazole is rapidly absorbed. Mean absorption is 90%. Peak plasma concentrations are reached within 3 hours. The mean volume of distribution after IV administration is 1 litre per kg. Plasma protein-binding of ornidazole is about 13%. The active ingredient of ornidazole penetrates the cerebrospinal fluid, the body fluids and the tissues very effectively. Plasma concentrations are within the range considered to be optimal for the various indications (6 to 36 mg/l).

After repeated administration of 500 mg or 1,000 mg every 12 hours to healthy volunteers, an accumulation factor of 1.5 to 2.5 was calculated.

Ornidazole is mainly metabolised to 2-hydroxymethyl and a-hydroxymethyl metabolites in the liver. Both main metabolites are less active against Trichomonas vaginalis and anaerobic bacteria than the unchanged ornidazole. The half-life is about 13 hours. Of a single dose, 85% is eliminated within the first 5 days, most of this being metabolised. Also, 4% of the dose is excreted as unaltered substance in the urine.

Patients with Hepatic Impairment

In patients with liver cirrhosis the elimination half-life is longer (22 versus 14 hours) and clearance lower (35 versus 51 ml/min) than in healthy subjects. The dosing interval should be doubled in patients with severe hepatic impairment.

Patients with Renal Impairment

The pharmacokinetics of ornidazole is unaltered in renal impairment. Dose adjustment is, therefore, unnecessary in patients with impaired renal function.  Ornidazole is removed by haemodialysis. An additional dose of 500 mg of ornidazole should be administered if the daily dose is 2 g/d, or an additional dose of 250 mg ornidazole if the daily dose is 1 g/d, should, therefore, be administered before the start of haemodialysis.

Neonates and Children

The pharmacokinetics or ornidazole in neonates and young children is similar to those in adults.

Indications

CIPLOX-OZ Tablets are indicated for the treatment of diarrhoea of mixed infection in adult patients only.

Dosage and Administration

One tablet of CIPLOX-OZ is recommended as twice-daily therapy.

Contraindications

CIPLOX-OZ Tablets are contraindicated in persons with a history of hypersensitivity associated with the use of ofloxacin, ornidazole or any member of the quinolone or nitroimidazole group of antimicrobial agents.

Concomitant administration with tizanidine is contraindicated.

Warnings and Precautions

Ciprofloxacin

Disabling and Potentially Irreversible Serious Adverse Reactions, Including Tendinitis and Tendon Rupture, Peripheral Neuropathy and CNS Effects

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and CNS effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion).These reactions can occur within hours to weeks after starting ciprofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions 

Discontinue ciprofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinitis and Tendon Rupture

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting ciprofloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue ciprofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

Peripheral Neuropathy

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons, resulting in paraesthesia, hypoesthesia, dysaesthesia and weakness, have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible in some patients.

Discontinue ciprofloxacin immediately if the patient experiences symptoms of peripheral neuropathy, including pain, burning, tingling, numbness, and/or weakness or other alterations in sensations, including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimise the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy.

CNS Effects

Psychiatric Adverse Reactions

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behaviour such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; and memory impairment. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care.

CNS Adverse Reactions

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pscudotumour cerebri), dizziness, and tremors. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). If seizures occur, discontinue ciprofloxacin and institute appropriate care.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including ciprofloxacin, have neuromuscular-blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis.

Other Serious, and Sometimes Fatal, Adverse Reactions

Other serious, and sometimes fatal, adverse reactions, some due to hypersensitivity, and some due to uncertain aetiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• Fever, rash, or severe dermatologic reactions (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome)
• Vasculitis; arthralgia; myalgia; serum sickness
• Allergic pneumonitis
• Interstitial nephritis; acute renal insufficiency or failure
• Hepatitis; jaundice; acute hepatic necrosis or failure
• Anaemia, including haemolytic and aplastic; thrombocytopaenia, including thrombotic thrombocytopaenic purpura; leucopaenia; agranulocytosis; pancytopaenia; and/or other haematologic abnormalities

Discontinue ciprofloxacin immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and ensure that supportive measures are instituted. 

Hypersensitivity Reactions

Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including ciprofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial oedema, dyspnoea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, IV fluids, IV antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated.

Hepatotoxicity

Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range, 1 to 39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment immediately.

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin.

Serious Adverse Reactions with Concomitant Theophylline

Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred.

Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate

Clostridium difficile-associated Diarrhoea

Clostridium difficile (C. difficile)-associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including ciprofloxacin, 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. Hypertoxin-producing isolates 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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Prolongation of the QT Interval

Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram (ECG) and cases of arrhythmia. Cases of torsades de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin.

Avoid ciprofloxacin in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsades de pointes (e.g. congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalaemia or hypomagnesaemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA anti-arrhythmic agents (quinidine, procainamide), or Class III anti-arrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.

Musculoskeletal Disorders in Paediatric Patients and Arthropathic Effects in Animals

Ciprofloxacin is indicated in paediatric patients (less than 18 years of age) only for cUTI, prevention of inhalational anthrax (post-exposure), and plague  with cefuroxime axetil (250 to 500 mg BID) and with clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse reaction profile comparable with the control drugs.

Paediatric Patients

Short- (6 weeks) and long-term (1 year) musculoskeletal and neurological safety of oral/IV ciprofloxacin, was compared with a cephalosporin for treatment of cUTI or pyelonephritis in paediatric patients, 1 to 17 years of age (mean age of 6 ± 4 years), in an international multicentre trial. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). A total of 335 ciprofloxacin- and 349 comparator-treated patients were enrolled.

An Independent Paediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse reactions, including abnormal gait or abnormal joint exam (baseline or treatment-emergent). Within 6 weeks of treatment initiation, the rates of musculoskeletal adverse reactions were 9.3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. All musculoskeletal adverse reactions occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the adverse reactions. Ciprofloxacin-treated patients were more likely to report more than one adverse reaction and on more than one occasion compared with control patients. The rate of musculoskeletal adverse reactions was consistently higher in the ciprofloxacin group compared with the control group across all age subgroups. At the end of 1 year, the rate of these adverse reactions reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) in the comparator-treated patients (Table 7).

	Ciprofloxacin	Comparator
All Patients (within 6 weeks)	31/335 (9.3%)	21/349 (6%)
95% Confidence Interval2	(–0.8%, +7.2%)
Age Group
12 months to <24 months	1/36 (2.8%)	0/41
2 years to <6 years	5/124 (4%)	3/118 (2.5%)
6 years to <12 years	18/143 (12.6%)	12/153 (7.8%)
12 years to 17 years	7/32 (21.9%)	6/37 (16.2 %)
All Patients (within 1 year)	46/335 (13.7%)	33/349 (9.5%)
95% Confidence Interval1	(–0.6%, + 9.1%)

The incidence rates of neurological adverse reactions within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.

In this trial, the overall incidence rates of adverse reactions within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent adverse reactions were gastrointestinal in 15% (50/335) of ciprofloxacin patients compared with 9% (31/349) of comparator patients. Serious adverse reactions were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared with 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse reaction was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse reactions that occurred in at least 1% of ciprofloxacin patients were diarrhoea (4.8%), vomiting (4.8%), abdominal pain (3.3%), dyspepsia (2.7%), nausea (2.7%), fever (2.1%), asthma (1.8%), and rash (1.8%).

Short-term safety data for ciprofloxacin was also collected in a randomised, double-blind, clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years). A total of 67 patients received ciprofloxacin IV 10 mg/kg/dose every 8 hours for 1 week followed by ciprofloxacin tablets 20 mg/kg/dose every 12 hours to complete 10 to 21 days of treatment and 62 patients received the combination of ceftazidime IV 50 mg/kg/dose every 8 hours and tobramycin IV 3 mg/kg/dose every 8 hours for a total of 10 to 21 days. Periodic musculoskeletal assessments were conducted by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range, 0 to 93 days). Musculoskeletal adverse reactions were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse reactions were similar in nature and frequency between treatment arms. The efficacy of ciprofloxacin for the treatment of acute pulmonary exacerbations in paediatric cystic fibrosis patients has not been established.

In addition to the adverse reactions reported in paediatric patients in clinical trials, it should be expected that adverse reactions reported in adults during clinical trials or postmarketing experience may also occur in paediatric patients.

Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

System Organ Class	Adverse Reactions
Cardiovascular	QT prolongation Torsades de pointes Vasculitis and ventricular arrhythmia
CNS	Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching
Eye Disorders	Nystagmus
Gastrointestinal	Pseudomembranous colitis
Haemic/Lymphatic	Pancytopenia (life threatening or fatal outcome) Methemoglobinaemia
Hepatobiliary	Hepatic failure (including fatal cases)
Infections and Infestations	Candidiasis (oral, gastrointestinal, vaginal)
Investigations	Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum)
Musculoskeletal	Myalgia Myoclonus Tendinitis Tendon rupture
Psychiatric Disorders	Agitation Confusion Delirium
Skin/Hypersensitivity	Acute generalised exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction
Special Senses	Anosmia Hyperesthesia Hypoesthesia Taste loss

Adverse Laboratory Changes

Changes in laboratory parameters while on ciprofloxacin are listed below:

Hepatic: elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin.

Haematologic: eosinophilia, leucopaenia, decreased blood platelets, elevated blood platelets, pancytopaenia.

Renal: elevations of serum creatinine, BUN, crystalluria, cylindruria, and haematuria have been reported.

Other changes occurring were elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in haemoglobin, anaemia, bleeding diathesis, increase in blood monocytes, and leucocytosis.

The drug may cause low blood sugar and mental health-related side effects. Low blood sugar levels, also called hypoglycaemia, can lead to coma. The mental health side effects more prominent and more consistent across the systemic fluoroquinolone drug class are as mentioned below:

• Disturbances in attention
• Disorientation
• Agitation
• Nervousness
• Memory impairment
• Serious disturbances in mental abilities called delirium

Ornidazole

Mild side effects such as somnolence, headache and gastrointestinal disturbances such as nausea and vomiting may occur.

Disturbances of the CNS such as dizziness, tremor, rigidity, poor coordination, seizures, tiredness, vertigo, temporary loss of consciousness and signs of sensory or mixed peripheral neuropathy have been observed in isolated cases. Taste disturbances, abnormal liver function tests and skin reactions have been observed.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Ciprofloxacin

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminium or calcium-containing antacids, which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after haemodialysis or peritoneal dialysis.

Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post-treatment observation period at the highest oral doses tested; up to 5,000 mg/kg in either rodent species, or up to 2,500 mg/kg in the dog. Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin >2,500 mg/kg. Mortality was delayed in these animals, occurring 10 to 14 days after dosing.

In mice, rats, rabbits and dogs, significant toxicity, including tonic/clonic convulsions, was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.

Ornidazole

In cases of overdosage, the symptoms mentioned under UNDESIRABLE EFFECTS occur in a more severe form.  No specific antidote is known. The administration of diazepam is recommended if cramps occur.

Storage and Handling Instructions

Protect from light. Store in a cool, dry and dark place.

Packaging Information

CIPLOX-OZ Tablets: Blister pack of 10 tablets

Last Updated: Apr 2019

Last Reviewed: Apr 2019