Cravit

Cravit

levofloxacin

Manufacturer:

Daiichi-Sankyo

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Levofloxacin.
Description
Levofloxacin is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate. It has a molecular formula of C18H20FN3O4·½H2O, molecular weight of 370.38 and a melting point of 222-230°C (decomposition).
Levofloxacin is a light yellowish-white to yellowish-white crystals or crystalline powder, odorless and has a bitter taste. It is freely soluble in glacial acetic acid, sparingly soluble in water and methanol, slightly soluble in ethanol and practically insoluble in ether. It is light sensitive.
Excipients/Inactive Ingredients: Solution for infusion: Sodium chloride, sodium hydroxide, hydrochloric acid (q.s. pH 4.8) and water for injection.
Action
Antibacterial.
Pharmacology: Cravit is a broad-spectrum quinolone antibacterial agent containing levofloxacin, optically active (-)-S-form of racemate ofloxacin synthesized by Daiichi Pharmaceutical Co., Ltd. It shows broad and potent antibacterial activities against gram-positive bacteria eg, Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis and gram-negative bacteria eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Enterobacter cloacae, Moraxella catarrhalis, Legionella pneumophila and other microorganisms eg, Chlamydia pneumoniae and Mycoplasma pneumoniae. Cravit, which is transferred rapidly to each tissue in high concentrations without being accumulated there, is mostly excreted in the urine as unchanged form. Cravit shows clinical efficacy on respiratory and genitourinary tract, skin and skin structure infections.
Pharmacokinetics: Absorption and Serum Concentration: Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1-2 hrs after oral dosing. The absolute bioavailability of a 500-mg tablet is approximately 99%, demonstrating complete oral absorption of levofloxacin. Levofloxacin pharmacokinetics is linear and predictable after single and multiple oral dosing regimens. The mean±SD peak and trough plasma concentrations attained following multiple oral regimens were approximately 5.7±1.4 and 0.5±0.2 mcg/mL after the 500-mg doses and 8.6±1.9 and 1.1±0.4 mcg/mL after 750-mg doses, respectively.
Distribution: The mean volume of distribution of levofloxacin generally ranges from 74-112 L after single and multiple 500- and 750-mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissue and blister fluid of healthy subjects at approximately 3 hrs after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple oral administration of 750 mg and 500 mg levofloxacin, respectively to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and range from approximately 2.4-11.3 mcg/g over 24 hr period after a single 500-mg oral dose.
In vitro, over a clinically relevant range (1-10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24-38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism: Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. It undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hrs, whereas <4% of the dose was recovered in feces in 72 hrs. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion: Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life (t½) of levofloxacin ranges from approximately 6-8 hrs following single or multiple doses of levofloxacin given orally. The mean apparent total body clearance and renal clearance range from approximately 144-226 mL/min and 96-142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.
Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It is 2-fold stronger than that of ofloxacin.
The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.
Levofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. It is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics including penicillins. Fluoroquinolones may therefore be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (Range: 10-9 to 10-10). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications: Aerobic Gram-Positive Microorganisms: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains) and Streptococcus pyogenes.
Aerobic Gram-Negative Microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis and Pseudomonas aeruginosa.
Others: Chlamydia pneumoniae and Mycoplasma pneumoniae.
The following in vitro data are available, but their clinical significance is unknown.
Aerobic Gram-Positive Microorganisms: Staphylococcus epidermidis, Streptococcus (Group C/F), Streptococcus (Group G), Streptococcus agalactiae, Streptococcus milleri and Viridans group streptococci.
Aerobic Gram-Negative Microorganisms: Acinetobacter baumannii, Acinetobacter lwoffii, Bordetella pertussis, Citrobacter (diversus) koseri, Citrobacter freundii, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella oxytoca, Morganella morganii, Pantoea (Enterobacter) agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas fluorescens and Serratia marcescens.
Anaerobic Gram-Positive Microorganisms: Clostridium perfringens.
Indications/Uses
Treatment of adults (≥16 years) with mild, moderate and severe infections caused by susceptible strains of the designated microorganisms in the following conditions: Acute sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis.
Acute exacerbation of chronic bronchitis due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae or Moraxella catarrhalis.
Community-acquired pneumonia due to Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumophila or Mycoplasma pneumoniae.
Nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an antipseudomonal β-lactam is recommended.
Uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma and wound infections due to Staphylococcus aureus and Streptococcus pyogenes.
Complicated skin and skin structure infections (mild to moderate) due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes or Proteus mirabilis.
Urinary tract infection (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa or Staphylococcus saprophyticus.
Chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis and Staphylococcus epidermidis.
Pyelonephritis (mild to moderate) caused by Escherichia coli.
Empirical treatment for community-acquired pneumonia most likely caused by organisms susceptible to levofloxacin.
Third-line therapy for Helicobacter pylori infection.
Levofloxacin-Based Triple Therapy: Levofloxacin, in combination with other antimicrobial agents and proton-pump inhibitor as triple therapy is indicated for the treatment of patients with gastric ulcer caused by H. pylori infection and duodenal ulcer disease.
Dosage/Direction for Use
Empirical Treatment for Community-Acquired Pneumonia: 500 or 750 mg is administered once daily.
Patients with Normal Renal Function: See Table 1.

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Patients with Impaired Renal Function: See Table 2.

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When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance: See equation.

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The serum creatinine should represent a steady state of renal function.
Patients with Impaired Liver Function: No adjustment of dosage is required since levofloxacin is not metabolized to any relevant extent by liver and is mainly excreted by kidneys.
Elderly: No adjustment is required in the elderly, other than that imposed by consideration of renal function.
Overdosage
According to toxicity studies in animals, the most important signs to be expected following acute overdosage of Cravit 500 or 750 mg are central nervous system symptoms eg, confusion, dizziness, impairment of consciousness and convulsive seizures, as well as gastrointestinal reactions eg, nausea and mucosal erosions.
In the event of an acute overdosage, the stomach should be emptied. Antacid may be used for protection of gastric mucosa. No specific antidote exists. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
Contraindications
Patients with a history of hypersensitivity to levofloxacin, ofloxacin or to any excipients of Cravit.
Patients with epilepsy and those with history of tendon disorder related to fluoroquinolone administration.
Use in Pregnancy: Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day. It was not teratogenic in rats at oral doses as high as 810 mg/kg/day or at IV dose up to 160 mg/kg/day. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day.
In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Cravit must not be used in pregnant women or women suspected of being pregnant.
Use in Lactation: In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Cravit must not be used in breastfeeding women.
Use in Children: Safety and effectiveness in pediatric patients and adolescents <16 years have not been established. Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species.
Warnings
Levofloxacin is more soluble than other quinolones, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine.
Acute renal failure or interstitial nephritis.
Excessive exposure to sunlight should be avoided. However, phototoxicity has been observed very rare incidence <0.01%. Therapy should be discontinued if phototoxicity (eg, a skin eruption) occurs.
Dysglycemia: During post-marketing surveillance, hypoglycemia and hyperglycemia have been reported in patients taking levofloxacin. Serious symptoms eg, hypoglycemic coma have been reported in patients receiving levofloxacin. Hypoglycemia may be prone to develop in patients with diabetes mellitus (especially those receiving sulfonylureas or insulin preparations), patients with impaired renal function and elderly patients. Serious colitis with bloody stool eg, pseudomembranous colitis. If such symptoms as abdominal pain and frequent diarrhea are noted, treatment with levofloxacin should be discontinued immediately and appropriate therapeutic measures taken.
Rhabdomyolysis characterized by myalgia, weakness, elevated CK (CPK) and increased myoglobin in plasma and urine, and accompanied with acute exacerbation of renal function.
Tendon disorder eg, Achilles tendonitis or tendon rupture. If symptoms eg, pain and edema in the peritendinous region are observed, treatment with levofloxacin should be discontinued immediately and appropriate therapeutic measures taken. The risk of tendonitis and tendon rupture is increased in patients >60 yrs, in those on concomitant corticosteroid therapy, and transplant recipients.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, and therefore may give false-negative results in the bacteriological diagnosis of tuberculosis.
Some undesirable effects (see Adverse Reactions) may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situation where these abilities are of special importance (eg, driving a car or operating machinery).
Shock or anaphylactoid reaction (initial symptoms erythema, rigor, dyspnea); toxic epidermal necrolysis or oculomucocutaneous syndrome (Stevens-Johnson syndrome); convulsion.
Prolonged QT and Ventricular Tachycardia (Including Torsades De Pointes): During post-marketing surveillance, prolonged QT which may sometimes lead to the occurrence of ventricular tachycardia including Torsades de pointes have been reported spontaneously in patients taking levofloxacin. The risk of the events may be increased in patients with serious heart diseases (eg, arrhythmia and ischemic heart disease), patients with uncorrected hypokalemia, patients receiving class 1A (quinidine sulfate, procainamide hydrochloride) and class III (amiodarone hydrochloride, sotalol hydrochloride) antiarrhythmic agents and in elderly patients.
Fulminant hepatitis, hepatic function disorder or jaundice (Initial Symptoms: Nausea, vomiting, anorexia, malaise, pruritus).
Pancytopenia, agranulocytosis (Initial Symptoms: Pyrexia, pharynx pain, malaise), hemolytic anemia with hemoglobinuria or thrombocytopenia.
Interstitial pneumonia or eosinophilic pneumonia accompanied with pyrexia, cough, dyspnea, abnormal chest X-ray or eosinophilia.
Psychiatric symptoms eg, confusion, delirium and depression.
Hypersensitivity Vasculitis: If symptoms eg, pyrexia, abdominal pain, arthralgia, purpura or maculopapules and skin biopsy evidence of leukocytoclastic vasculitis are observed, treatment with levofloxacin should be discontinued immediately and appropriate therapeutic measures taken.
Exacerbation of myasthenia gravis.
Patients receiving levofloxacin 750 mg may develop some adverse reactions eg, dizziness, headache, nausea or vomiting more than levofloxacin 500 mg.
Special Precautions
Cravit Should be Administered with Caution in The Following Patients: Patients with impaired renal function; those exposed to direct sunlight; with known or suspected central nervous system disorder that may predispose to seizures or lower the seizure threshold; diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (especially, sulfonylureas or with insulin preparations).
Patients with a history of hypersensitivity to quinolone antibiotics.
Patients with serious heart diseases eg, arrhythmia and ischemic heart disease (prolonged QT may occur); patients with uncorrected electrolyte imbalance (eg, hypokalemia, hypomagnesemia) and patients receiving class 1A and III antiarrhythmic agents.
Patients with myasthenia gravis (symptoms may be exacerbated).
Effects on the Ability to Drive or Operate Machinery: Neurologic adverse effects eg, dizziness, vertigo and somnolence may occur. Therefore, patients should be instructed that such neurologic adverse effects may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situation where these abilities are of special importance (eg, activities at high place, driving a car or operating machinery).
Use in the Elderly: The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since Cravit is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
Use In Pregnancy & Lactation
Use in Pregnancy: Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as high as 360 mg/kg/day. It was not teratogenic in rats at oral doses as high as 810 mg/kg/day or at IV dose up to 160 mg/kg/day. No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day.
In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Cravit must not be used in pregnant women or women suspected of being pregnant.
Use in Lactation: In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Cravit must not be used in breastfeeding women.
Adverse Reactions
The following adverse reactions have been reported in clinical studies and post-marketing experience. The incidence identified as follows reflects exposure to levofloxacin 500 mg in total of 1,930 patients in pooled phase 3 and 4 clinical trials [eg, 1,582 patients from phase 3 clinical trials conducted in Japan (337 patients) and China (1,245 patients) and 348 patients from phase 4 clinical trials] or 29,880 patients in a post-marketing studies conducted in Japan. If the incidence category of an adverse reaction is different between each source (ie, the incidence from the pooled clinical trials and the incidence from the post-marketing study), the higher frequency is represented.
The following Council of International Organizations of Medical Sciences (CIOMS) frequency rating is used: Very common: 10%≤ incidence; common: 1%≤ incidence <10%; uncommon: 0.1%≤ incidence <1%; rare: 0.01%≤ incidence <0.1%; very rare: Incidence <0.01%.
Blood and Lymphatic System Disorders: Uncommon: Anemia. Very Rare: Thrombocytopenia*. Incidence Unknown: Pancytopenia*, agranulocytosis*, hemolytic anemia with hemoglobinuria*.
Immune System Disorder: Incidence Unknown: Anaphylactoid reaction*.
Metabolism and Nutrition Disorder: Uncommon: Anorexia. Incidence Unknown: Hypoglycemia (hypoglycemic coma may occur)*, hyperglycemia*.
Psychiatric Disorders: Common: Sleep loss. Incidence Unknown: Psychiatric symptoms eg, confusion*, delirium*, depression*, hallucination.
Nervous System Disorders: Common: Dizziness, headache. Uncommon: Somnolence, numbness, tremor, mental dullness, dysgeusia. Rare: Disturbed consciousness. Very Rare: Convulsion*, ageusia. Incidence Unknown: Peripheral nerve disorder, extrapyramidal disorder, anosmia, parosmia.
Eye Disorders: Rare: Abnormal vision.
Ear and Labyrinth Disorders: Uncommon: Tinnitus. Incidence Unknown: Hearing losses.
Cardiac Disorders: Uncommon: Palpitations. Incidence Unknown: Ventricular tachycardia (including Torsades de pointes)*, prolonged QT*, tachycardia.
Vascular Disorders: Very Rare: Shock*. Incidence Unknown: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dry throat. Incidence Unknown: Interstitial and eosinophilic pneumonia*.
Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea, abdominal discomfort. Uncommon: Abdominal pain and distension, dyspepsia, constipation. Rare: Stomatitis. Very Rare: Glossitis. Incidence Unknown: Colitis with bloody stool eg, pseudomembranous colitis*.
Hepatobiliary Disorders: Uncommon: Abnormal hepatic function. Incidence Unknown: Fulminant hepatitis*, jaundice*.
Skin and Subcutaneous Tissue Disorders: Uncommon: Pruritus, rash. Rare: Hyperhidrosis, urticaria. Very Rare: Photosensitivity. Incidence Unknown: Toxic epidermal necrolysis (TEN)*, oculomucocutaneous syndrome (Stevens-Johnson syndrome)*, hypersensitivity vasculitis*.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthralgia, pain in extremity, back pain, weakness. Rare: Arthropathy, myalgia. Incidence Unknown: Rhabdomyolysis*, tendon disorders eg, Achilles tendonitis or tendon rupture*, myasthenia gravis exacerbation*, muscle rupture.
Renal and Urinary Disorders: Uncommon: Hematuria. Rare: Pollakiuria, oliguria, acute renal failure*. Incidence Unknown: Interstitial nephritis*, anuria, dysuria, urinary retention.
General Disorders and Administration Site Conditions: Uncommon: Thirst, chest discomfort, malaise, feeling hot, edema. Very Rare: Pyrexia. Incidence Unknown: Chest pain.
Investigations: Common: Increased AST, ALT, LDH and eosinophil count, decreased white blood cell count. Uncommon: Increased creatinine, alkaline phosphatase, γ-GTP, blood bilirubin and CPK, positive urinary protein, decreased lymphocyte, neutrophil and platelet count, and blood glucose, present glucose urine. Rare: Increased BUN, decreased urine output. Very Rare: Increased blood glucose.
*See Warnings.
Drug Interactions
Antacid, Sucralfate, Metal Cations and Multivitamins: While the chelation by divalent cations is less marked than with other quinolones, concurrent administration of Cravit with antacids containing magnesium or aluminum, as well as sucralfate, metal cations eg, iron and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin resulting in systemic levels considerably lower than desired. These agents should be taken at least 2 hrs before or 2 hrs after levofloxacin administration.
Theophylline, Fenbufen, or Similar Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) (Phenylacetic Acid/Propionic Acid Derivatives): No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However, there are indications of a pronounced lowering of the cerebral seizure threshold when quinolones are given concurrently with other drugs that lower seizure threshold (eg, theophylline) or with fenbufen or similar NSAIDs.
Antidiabetic Agents: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered.
Anticoagulants (Warfarin and its Derivatives): Co-administration of warfarin and its derivatives has been reported that the effect of warfarin was potentiated (hepatic metabolism of warfarin may be inhibited, or free warfarin may be increased by competitive displacement from the protein-binding site) and therefore, prothrombin time prolonged.
Class IA and Class III Antiarrhythmics: Levofloxacin should be used with caution in patients receiving class IA antiarrhythmics (eg, quinidine sulfate and procainamide hydrochloride) and class III antiarrhythmics (eg, amiodarone HCl and sotalol HCl). Prolonged QT may occur.
Storage
Store below 30°C.
MIMS Class
Quinolones
ATC Classification
J01MA12 - levofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.
Presentation/Packing
FC tab 250 mg (pale yellowish-white to reddish-white, oblong, biconvex) x 5's. 500 mg (pale yellowish-white to reddish-white, oblong, biconvex) x 5's. 750 mg x 5's. Soln for infusion (clear yellow to a greenish-yellow solution) 5 mg/mL x 50 mL x 1's, 100 mL x 1's. 150 mL x 1's.
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