Cravit Tablet, I.V.

CRAVIT^®
CRAVIT^® I.V.
Levofloxacin

Composition
Each film coated tablet contains:
Levofloxacin hemihydrate equivalent to Levofloxacin anhydrate 250 mg or 500 mg

Each ml of infusion contains:
Levofloxacin hemihydrate equivalent to Levofloxacin anhydrate 5 mg

Pharmacology
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 pneumoniae. 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. It is 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 one to two 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 trough plasma concentration attained following multiple once-daily oral 500 mg regimens were approximately 5.7 and 0.5 ug/ml, respectively. The peak and trough concentration attained following multiple once - daily i.v. 500 mg regimens were approximately 6.4 and 0.6 ug/ml, respectively, after the 750 mg doses were 12.1 and 1.3 mg/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 to 11.3 ug/g over a 24 hours period after a single 500 mg oral dose. Levofloxacin penetrates rapidly into bronchial mucosa and epithelial lung fluid (ELF) with maximum concentration in bronchial mucosa and epithelial lining fluid after 500 mg per oral were 8.3 ug/g and were reached approximately one hour after administration. Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for ‹ 5 % of the dose excreted to urine. Following oral and intravenous administration of Levofloxacin, it is eliminated relatively slowly from the plasma (T½ = 6-8 hours). 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. The majority of the drug is not metabolized in the body. About 85% of the administered dose is excreted in urine as an unchanged form.

Indications
CRAVIT^® is indicated in infections with susceptible microorganism, such as acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, communityacquired pneumoniae (including penicillin-resistant streptococcus pneumoniae strains), complicated skin and skin structure infections, complicated urinary tract infection, including acute pyelonephritis. CRAVIT^® i.v. only given to the patients who are unable to use the oral dosage form.

Contraindications
CRAVIT^® must not be used :

• In patients hypersensitive to Levofloxacin, quinolone antimicrobial agents or any other components of this product.
• In patients with epilepsy.
• In patients with history of tendon disorder related to Fluoroquinolone administration.
• Children or growing adolescent.
• During pregnancy.
• In breast feeding women.

Warnings and precautions
Warnings

• The safety and efficacy of CRAVIT^® in children, adolescents (under the age of 18 years), pregnant women, and nursing women have not been established. (See Contraindications).
• In immature rats and dogs, the oral and intravenous 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, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia and rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving Levofloxacin, the drug should be discontinued and appropriate measured instituted. As with other quinolones, Levofloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy) 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).
• Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones. These reactions often occur following the first dose. Some reactions have been accompanied by cardio­ vascular collapse, hypotension/ shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, 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, intravenous 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 etiology, 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 (e.g. toxic epidermal necrolysis, Stevens­ Johnsons Syndrome) ; vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted.
• Pseudomembranous 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 agents 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 againts C. diffile colitis.
• Ruptures of the shoulder, hand and achilles tendons 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 tendenitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including Levofloxacin.

Precautions

• 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.
• Administered 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 Levofloxacin may be reduced. In patients with impaired renal function (creatinin clearance = 80 ml/min), adjustment of the dosage regimen 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 of sunlight should be avoided. However in clinical trials with Levofloxacin, phototoxicity has been observed in less than 0.1 % of patients.Therapy should be discontinued if phototoxicity (e.g. skin eruption) occurs.
• As with other quinolones, Levofloxacin should be used with caution in any· patient with a known of or suscepted CNS disorder that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy) 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).
• As with other quinolones, disturbances of blood glucose, including symptomatic hyper and hypoglicemia, have been reported, usually in diabetic patients concomitant treatment with an oral hypoglycemic agent (e.g. or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with Levofloxacin, Levofloxacin should be discontinued immediately and appropriate therapy should be initiated immediately.
• As with any potent antimicrobial drug, periodic assessment of organ system functions, including renal, hepatic and hematopoietic, 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 such as iron and multi-vitamin preparations with zinc should be taken at least two hours before or two hours after Levofloxacin administration.
• That Levofloxacin can be taken without regard to meals.
• That Levofloxacin may cause neurologic adverse effects (e.g. dizziness, lightheadedness) and that patients should know how they react to Levofloxacin before they operate automobile or machinery or engage in other activities requiring mental alertness and coordination.
• To discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded.
• That Levofloxacin may be associated with hypersensitivity reactions, even following the first dose, and to discontinue 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 (e.g. 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 (i.e. skin eruption) occurs.
• That if they are diabetic and are being treated with insulin or an oral hypoglicemic agent and hypoglicemic reaction occurs, they should discontinue Levofloxacin and consult a physician.

Adverse reactions
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 multiple-dose 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; diarrhea 1.2 %, nausea 1.2 %, vaginitis 0.8%, flatulence 0.5 %, pruritis 0.5 %, rash 0.3 %, abdominal pain 0.3 %, genital moniliasis 0.3 %, dizziness 0.3 %, dyspepsia 0.3 %, insomnia 0.3 %, taste perversion 0.2 %, vomiting 0.2 %, anorexia 0.1 %, anxiety 0.1 %, constipation 0.1 %, edema 0.1 %, fatigue 0.1 %, headache 0.1 %, increased sweating 0.1 %, leukorrhea 0.1 %, malaise 0.1 %, nervousness 0.1 %, sleep disorder 0.1 %, tremor 0.1 %, 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%, diarrhea 5.4%, headache 5.4%, constipation 3.1%. In clinical trials, the following events occured in 1 to 3% of patients, regardless of drug relationship: insomnia 2.9%, dizziness 2.5%, vomiting 2.1% abdominal pain 2.0%, dyspepsia 2.0%, rash 1.7%, vaginitis 1.8%, flatulence 1.6%, pruritis 1.6%, pain 1.4%, chest pain 1.1%, back pain 1.0%. The following adverse events occured in clinical trials at a rate of 0.5 to less than 1% regardless of drug relation ship : agitation, anorexia, anxiety, arthralgia, dry mouth, dyspnea, edema, fatigue, fever, genital pruritis, increased sweating, nervousness, pharyngitis, rhinitis, skin disorder, somnolence, taste perversion.
Additional adverse events occurring in clinical trials at a rate of 0.3% to less than 0.5% regardless of drug relationship include: cardiac failure, hypertension, leukorrhea, myocardial infarction, myalgia, purpura, tinnitus, tremor, urticaria.
Events occurring at a frequency lower than 0.3 % regardless of drug relationship but considered medically important include : abnormal coordination, abnormal dreaming, abnormal hepatic function, abnormal platelets, abnormal renal function, abnormal vision, acute renal failure, aggravated diabetes mellitus, aggressive reaction, anemia, angina pectoris, ARDS, arrythmia, arthritis, asthma, bradycardia, cardiac arrest, cerebrosvascular disorder, circulatory failure, coma, confusion, convulsions (seizures), coronary thrombosis, delirium, depression, diplopia, embolism-blood clot, emotional lability, erythema nodosum, G.I. hemorrhage, granulocytopenia, hallucination, heart block, hepatic coma, hypoglycemia, hypotension, impaired concentration, increased LDH, jaundice, leukocytosis, leukopenia, lymphadenopathy, manic reaction, mental deficiency, muscle weakness, pancreatitis, paralysis,paranoaia, postural hypertension, pseudomembranous colitis, rhabdomyolisis, sleep disorder, stupor, syncope, tachycardia, tendinitis, thrombocytopenia, vertigo, weight decrease, WBC abnormal not otherwise specified. In clinical trials using multiple-dose therapy, opthalmologic abnormalities, including cataracts and multiple punctate 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 underlying condition being treated.
Blood chemistry :decreased glucose, decreased lymphocytes.
Post-marketing adverse reactions :
Additional serious adverse reported from the marketing experience with Levofloxacin outside of the United States regardless of drug relationship include: allergic pneumonitis, anaphylactic shock, anaphylactoid reaction, dysphonia, abnonnal EEG, enchephalopathy, eosinophilia, erythema multiforme, hemolytic anemia, multi-system organ failure, palpitation, paresthesia, Stevens-Johnson Syndrome, tendon rupture, vasodilation.

Overdosage
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 i.v. 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 efficiently removed by hemodialysis or peritoneal dialysis.

Drug interactions

• Levofloxacin has potential to form stable coordination compounds with many metal ions. This invitro chelation potential has the following formation with Al⁺³ › Cu⁺² › Zn⁺² › Mg⁺² › Ca⁺². Antacids containing aluminium or magnesium and drugs containing iron decrease absorption of CRAVIT^®. The administration of these drugs are recommended at least 2 hours before or after CRAVIT^® administration.
• The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including CRAVIT^®, may increase the risk of CNS stimulation and convulsive seizures.
• Anti-diabetic agents: Disturbances of blood glucose, including hyperglycemia and hypoglycemia. Therefore, careful monitoring of blood glucose is recommended when these agent are coadministered.
• Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, and therefore, may give false negative results in the bacteriological diagnosis of tuberculosis.
• CRAVIT^® i.v. should not be mixed with heparin or alkaline solution (e.g. sodium hydrogen carbonate).

Dosage and administration
Dosage
Given the bioequivalence of the parenteral and oral forms, the same dosage can be used, usually for 7 - 14 days depending on the severity of the disease.
Usual dose in patients with normal renal function : 250 mg-750 mg once daily depends on the type and severity of the infection and the sensitivity of the presumed causative pathogen.
CRAVIT^® i.v. is administration by slow intravenous infusion.
It is usually possible to switch from initial intravenous treatment to the oral route after a few days, according to the condition of the patient.
Elderly patients and patients with impaired liver function (but normal kidney function)
should receive the same dosage as normal adult.

Dosage in patients with renal insufficiency (creatinin clearance ≤ 50 ml/min):

Creatinine clearance		Dosage regimen
› 50 ml/min	1 x 250 mg/24 h (no dose adaption)	1 x 500 mg/24 h (no dose adaption)
50 - 20 ml/min	initial dose: 250 mg then : 125 mg/24 h	initial dose: 500 mg then: 250 mg/24 h
19 - 10 ml/min	initial dose: 250 mg then: 125 mg/48 h	initial dose: 500 mg then: 125 mg/24 h
‹ 10 ml/min  (including hemodialysis and CAPD)1	initial dose: 250 mg then: 125 mg/48 h	initial dose: 500 mg then: 125 mg/24 h

¹  No. additional doses are required after hemodialysis or continuous ambulatory peritoneal dialysis
(CAPD).


Administration

• CRAVIT^® i.v. is ready for use and should only be administered by slow intravenous infusion. The infusion time for 500 mg (100 ml) and 750 mg (150 ml) should not be less than 60 minutes (1 hour) and 90 minutes (1.5 hour), respectively. 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.
• CRAVIT^® i.v. should not be mixed with heparin or alkaline solution (e.g. sodium hydrogen carbonate ).
• CRAVIT^® i.v. should be administered alone unless compatibility with other infusion fluids has been demostrated.

Compatible infusion solutions include the following :

• 0.9 % sodium chloride solution, USP. 
• 5 % dextrose injection, USP.
• 2.5 % dextrose in ringer solution.
• combination solution for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Presentations

Tablet 250 mg	:	Box of 1 strip x 10 tablets	Reg. No. DKL9711628317A1
Tablet 500 mg	:	Box of 1 strip x 10 tablets	Reg. No. DKL9711628317B1
Vial 500 mg/ 100 ml	:	Box of 1 vial	Reg. No. DKL0111632749A1
Vial 250 mg/ 150 ml	:	Box of 1 vial	Reg. No. DKL0111632749A1
Vial 750 mg/ 150 ml	:	Box of 1 vial	Reg. No. DKL0111632749A1

Store below 30°C.
Protect from light.
Keep in well - closed containers.

ON MEDICAL PRESCRIPTION ONLY.

Manufactured by:
PT KALBE FARMA Tbk., Bekasi - Indonesia

Under license of:
Daiichi Sankyo Co. Ltd., Japan

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