Levofloxacin

Cravox^®: Tablet (film-coated) 250 mg x 10’s.
             Tablet (Film coated) 500 mg x 10’s.

Cravox^® Infusion: Vial

Levofloxacin is the optical S-(-) isomer of ofloxacin. It has a wide-spectrum antibacterial effect. Levofloxacin is active against gram-positive and gram-negative bacteria including anaerobes. Moreover, levofloxacin has shown antibacterial activity against Chlamydia pneumoniae and Mycoplasma pneumoniua. Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentration.
The main mechanism of action of levofloxacin is through the inhibition of DNA gyrase, a type II topoisomerase, resulting in inhibition of bacterial DNA replication and transcription.

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1-2 hours after oral dosing. The absolute bioavailability of a 500-mg oral dose of levofloxacin is approximately 99%. Food has little effect on the absorption of levofloxacin. The peak and through plasma concentrations attained following multiple once-daily IV 500-mg regimens were approximately 6.4 and 0.6 mcg/mL, respectively. Levofloxacin is widely distributed throughout the body in high concentration.
Levofloxacin also penetrates well into lung tissue. Lung tissue concentrations were generally 2-to 5-fold higher than plasma concentrations and ranged from  approximately 2.4-11.3 mcg/g over a 24-hr period after a single 500-mg oral dose. Levofloxacin penetrates rapidly into bronchial mucosa and epithelia lung fluid (ELF with maximum concentration in bronchial mucosa and ELF of 8.3 mcg/g and 10.8 mcg/mL, respectively after 500 mg per oral administration. These were reached approximately 1 hour after administration. Levofloxacin is metabolized  to a very small extend, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for <5% of the dose excreted to urine. Following oral and IV administration of levofloxacin, it is eliminated relatively slowly from the plasma (t1/2-6-8 hrs). Excretion is primarily by the renal route (>85% of the administered dose).
Clearance of levofloxacin is reduced and plasma elimination half-life is prolonged in patients with impaired renal function (creatinine clearance <80 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Majority of levofloxacin is not metabolized in the body. About 85% of the administered dose is excreted in urine as an unchanged form.

Administration:
Cravox^® IV is ready for use and should only be administered by slow IV infusion. The infusion time for 500 mg (100 mL) should not be <60 min (1 hour). Protection from light is not necessary during infusion time. Once the vial has been opened (rubber stopper perforated) the solution should be used immediately (within 3 hours) in order to prevent any bacterial contamination.

Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: Ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents. In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not effieciently removed by hemodialysis or peritoneal dialysis.

Hypersensitivity to levofloxacin, quinolone antimicrobial agents or any other components of Cravox^®/Cravox^® IV. Patients with epilepsy. Patients with history of tendon disorder related to fluoroquinolone administration. Children or growing adolescent. Pregnancy and lactation (see Precautions).

In immature rats and dogs, the oral and IV administration of levofloxacin increased the incidence and severity of osteochondrosis. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species.
Convulsions and toxic psychoses have been reported in patients receiving quinolones, including levofloxacin. Quinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness, anxiety, light-headedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and rarely, suicidal thoughts or acts. These reactions may occur following the 1st dose. If these reactions occur in patients receiving levofloxacin, the drug should be discontinued and appropriate measures instituted. As with other quinolones, levofloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (eg, certain drug therapy, renal dysfunction).
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones.
These reactions often occur following the 1st dose.
Some reactions have been accompanied by cardiovascular collapse, hypotension/shock seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial oedema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnoea, urticaria, itching and other serious skin reactions. Levofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, IV fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.
Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain aetiology, have been reported rarely in patients receiving therapy with quinolones. 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 (eg, 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; thrombocytopenia, including thrombotic thrombocytopenic purpura; leucopenia; agranulocytosis; pancytopenia; and/or other haematologic abnormalities. Cravox^® IV should be discontinued immediately at the first appearance of a skin rash or any other signof hypersensitivity and supportive measures instituted. Pseudomembraneous colitis has been reported with nearly all antibacterial agents, including levofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.
Treatment with antibacterial agent alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis”.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measure should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
Ruptures of the shoulder, hand and Achilles tendon that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Levofloxacin should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including levofloxacin.

General: Although levofloxacin is more soluble than other quinolones, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine.
Administer levofloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxation may be reduced. In patients with impaired renal function (creatinine clearance <80 mL/min), adjustment of the dosageregimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance.
Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving drugs in this class. Excessive exposure to sunlight should be avoided. However, in clinical trials with levofloxacin, phototoxicity has been observed in <0.1% of patients. Therapy should be discontinued if phototoxicity (eg, skin eruption) occurs.
As with other quinolones, levofloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizures or lower the seizure threshold (eg, certain drug therapy, renal dysfunction).
As with other quinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycaemia, have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (eg, glyburide/glibenclamide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycaemic reaction occurs in a patient being treated with levofloxacin, levofloxacin should be discontinued and appropriate therapy should be initiated immediately.
As with any potent antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic and haematopoetic is advisable during therapy.
Information for Patients: Patients should be advised to drink fluid liberally; that antacids containing magnesium, or aluminium, as well as sucralfate, metal cations eg, iron, and multivitamin preparations with zinc should be taken at least 2 hours before or 2 hours after levofloxacin administration; that levofloxacin can be taken without regard to meals; that levofloxacin can be taken without regard to meals; that levofloxacin may cause neurologic adverse effects (eg, dizziness, lightheadedness); to discontinue treatment and inform their physician if they experience pain, the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (eg, swelling of the lips, tongue, face, tightness of the throat, hoarseness) or other symptoms of an allergic reaction; to avoid excessive sunlight or artificial ultraviolet light while receiving levofloxacin and to discontinue therapy if phototoxicity (ie, skin eruption) occurs; that if they are diabetic and are being treated with insulin or an oral hypoglycaemic reaction occurs, they should discontinue levofloxacin and consult a physician.
Effects on the Ability to Drive or Operate Machinery: Patients should know how they react to levofloxacin before they operate automobile or machinery or engage in other activities requiring mental alertness and coordination.

The safety and efficacy of Cravox^®/Cravox^® IV in pregnant and nursing women have not been established.

The safety and efficacy of Cravox^®/Cravox^® IV in children, adolescents (<18 years) have not been established.

The incidence of drug-related adverse reactions in patients during phase 2 and 3 clinical trials conducted in North America was 6.2%. Among patients receiving multipledose therapy, 3.7% discontinued therapy with levofloxacin due to adverse experience.
In clinical trials, the following events were considered likely to be drug-related in patients receiving multiple doses of levofloxacin: Diarrhoea 1.2%, nausea 1.2%, vaginitis 0.8%, flatulence 0.5%, pruritus 0.5%, rash 0.3%, abdominal pain 0.3%, taste per version 0.2%, vomiting 0.2%, anorexia 0.1%, anxiety 0.1%, constipation 0.1%, oedema 0.1%, fatique 0.1%, headache 0.1%, increased sweating 0.1%, leucorrhea 0.1%, malaise 0.1%, nervousness 0.1%, sleep disorders 0.1%, tremor 0.1%, and urticaria 0.1%.
In clinical trials, the most frequently reported adverse events occurring in >3% of the study population regardless of drug relationship, were: Nausea 6.6%, diarrhoea 5.4%, headache 5.4% and constipation 3.1%.
In clinical trials, the following events occurred in 1-3% of patients, regardless of drug relationship: Insomnia 2.9%, dizziness 2.5%, vomiting 2.1%, abdominal pain 2%, dyspepsia 2%, rash 1.7%, vaginitis 1.8%, flatulence 1.6%, pruritus 1.6%, pain 1.4%, chest pain 1.1% and back pain 1%.
The following adverse events occurred in clinical trials at a rate of 0.5% to <1% regardless of drug relationship: Agitation, anorexia, anxiety, arthralgia, dry mouth, dyspnoea, oedema, fatigue, fever, genital pruritus, increased sweating, nervousness, pharyngitis, rhinitis, skin disorder, somnolence and taste perversion.
Aditional adverse events occurring in clinical trials at a rate of 0.3% to <0.5% regardless of drug relationship include: Cardiac failure, hypertension,leucorrhea, myocardial infarction, myalgia, purpura, tinnitus, tremor and urticaria.
Events occurring at a frequency <0.3% regardless of drug relationship but considered medically important include: Cardiac failure, hypertension, leucorrhea, myocardial infarction, myalgia, purpura, tinnitus, tremor and urticaria.
Events occurring in clinical trials at a rate of 0.3% to <0.5% regardless of drug relationship include: Abnormal coordination, abnormal dreaming, abnormal hepatic function, abnormal platelets, abnormal renal function, abnormal vision, acute renal failure, aggravated diabetes mellitus, aggressive reaction, anaemia, angina pectoris, acute respiratory distress syndrome (ARDS), arrhythmia, arthritis, asthma, bradycardia, cardiac arrest, cerebrovascular disorder, circulatory failure, coma, confusion, convulsions (seizures), coronary thrombosis, delirium, depression, diplopia, embolism-blood clot, emotional lability, erythema nodosum, GI haemorrhage, granulocytopenia, hallucination, heart block, hepatic coma, hypoglycaemia, hypotension, impaired concentration, increased lactate dehydrogenase (LDH), jaundice, leukocytosis, leucopenia, lymphadenopathy, manic reaction, mental deficiency, muscle weakness, pancreatitis, paralysis, paranoia, postural hypertension, pseudomembranous colitis, rhabdomyolysis, sleep disorder, stupor, syncope, tachycardia, tendonitis, thrombocytopenia, vertigo, decreased weight, abnormal WBC not otherwise specified.
In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctuate lenticular opacities, have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.
Crystalluria and clyndruria have been reported with other quinolones.
The following laboratory abnormalities appeared in 1.9% of patients receiving multiple doses of levofloxacin. It is not known whether these abnormalities were caused by the drug or the underling condition being treated.
Blood Chemistry: Decreased glucose, decreased lymphocytes.
Post Marketing Adverse Reactions: Additional serious adverse reactions reported from the marketing experience with levofloxacin outside of the United States regardless of drug relationship include:
Allergic pneumonitis, anaphylactic shock, anaphylactoid reaction, dysphonia, abnormal EEG, encephalopathy, eosinophilia, erythema multiforme, haemolytic anaemia, multi-system organ failure, palpitation, paresthesia, Steven-Johnson syndrome, tendon rupture and vasodilation.

Levofloxacin has potential to form stable coordination compounds with many metal ions. This is vitro chelation potential has the following formation with Aluminium, copper, zinc, magnesium and calcium. Antacids containing aluminium or magnesiumand drugs containing iron decrease absorption of Cravox^®.
The administration of these drugs are recommended at least 2 hours before or after Cravox^® administration.
The concomitant administration of a nonsteroidal anti-infammatory drug with a quinolone, including Cravox^®, may increase the risk of CNS stimulation and convulsive seizures.
Antidiabetic Agents: Disturbances of blood glucose, including hyperglycaemia and hypoglycaemia. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and therefore, may give false negative results in the bacteriological diagnosis of tuberculosis.
Cravox^® IV should not be mixed with heparin or alkaline solution (eg, sodium hydrogen carbonate).

Cravox^® IV should not be mixed with heparin or alkaline solution (eg, sodium hydrogen carbonate). It should be administered alone unless compatibility with other infusion fluids has been demonstrated. Compatible infusion solutions include the following: Sodium chloride solution 0.9% USP, dextrose injection 5% USP, dextrose in Ringer solution 5% USP, dextrose in Ringer 2.5% USP, combination solution for parenteral nutrition (amino acids, carbohydrates, electrolytes).