Linezonix Forte

Uses

- Pharyngitis/tonsillitis caused by Streptococcus pyogenes

- Acute bacterial otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta lactamase-producing strains), Moraxella Catarrhalis (including beta-lactamase-producing strains) or Streptococcus pyogenes.

- Acute bacterial maxillary sinusitis caused by Streptococcus pneumoniae, or Haemophilus influenzae (nonbeta-lactamase-producing strains only)

- Lower respiratory tract infections including pneumoniae, caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta lactamase-producing strains), Klebsiella spp., Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pyogenes, Escherichia coli.

- Acute bacterial exacerbations of chronic bronchitis and secondary bacterial infections of acute bronchitis caused by Streptococcus penumoniae, Haemophilus influenzae (beta-lactamase negative strains), or Haemophilus parainfluenzae (beta-lactamase negative strains).

- Skin and Skin-Structure Infections caused by Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pyogenes, Escherichia coli, Klebsiella spp., and Enterobacter spp.

- Urinary tract infections caused by Escherichia coli or Klebsiella pneumoniae.

- Bone and Joint Infections caused by Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains).

- Gonorrhea : Uncomplicated and disseminated gonococcal infections due to Neiseria gonorrhoeae (penicillinase- and non-penicillinase-producing strains) in both males and females.

- Early Lyme disease (erythema migrans) caused by Borrelia burgdorferi.

- Septicemia caused by Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains), Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae (including ampicillin-resistant strains), and Klebsiella spp.

- Meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae (including ampicillin-resistant strains), Neisseira menintitidis, and Staphylococcus aureus (penicillinase- and non-penicillinase-producing strains).

- Surgical Prophylaxis: Prophylaxis against infections in abdominal, pelvic, orthopedic, cardiac, pulmonary, esophageal and vascular surgery where there is increased risk for infection.

Vancomycin-Resistant Enterococcus faecium infections including cases with concurrent bacteremia.

Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains) or Streptococcus pneumoniae (including multi-drug resistant strains). Combination therapy may be clinically used if the documented or presumptive pathogens include Gram-negative organism.

Complicated skin and skin structure infections, including diabetic foot infections (without concomitant osteomyelitis) caused by Staphylococcus aureus (methicillin-susceptible and ¬resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae.

Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes.

Community-acquired pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains) including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible strains only)

Linezonix Forte is also used to associated treatment for these conditions: Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB), Animal bite, Bacterial Infections, Bloodstream Infections, Bone and Joint Infections, Gonorrhea, Impetigo, Lower Respiratory Tract Infection (LRTI), Lyme Disease, Maxillary Sinusitis, Meningitis, Skin and Subcutaneous Tissue Bacterial Infections, Urinary Tract Infection, Bacterial otitis media, Mild Streptococcal pharyngitis, Mild Streptococcal tonsillitis, Moderate Streptococcal pharyngitis, Moderate Streptococcal tonsillitisCommunity Acquired Pneumonia (CAP) caused by Staphylococcus Aureus Infections, Community acquired pneumonia caused by Susceptible strains of Streptococcus pneumoniae, Complicated Skin and Skin Structure Infection caused by Staphylococcus Aureus Infections, Complicated Skin and Skin Structure Infection caused by Streptococcus Agalactiae Infection, Complicated Skin and Skin Structure Infection caused by Streptococcus Pyogenes Infection, Nosocomial Pneumonia caused by Staphylococcus Aureus Infections, Nosocomial Pneumonia caused by Streptococcus Pneumoniae Infections, Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus Aureus Infections, Uncomplicated Skin and Skin Structure Infections caused by Streptococcus Pyogenes Infection, Vancomycin-resistant Enterococcus faecium infection

How Linezonix Forte works

Cefuroxime, like the penicillins, is a beta-lactam antibiotic. By binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall, it inhibits the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that cefuroxime interferes with an autolysin inhibitor.

Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing.

Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Dosage

Linezonix Forte dosage

Oral :

INFECTIONS DOSAGE DURATION

Tablet

(May be administered without regard to meals)

Adolescents & adults(13 years & above)

Pharyngitis or Tonsillitis 250 mg twice daily 5-10 days

Acute bacterial maxillary sinusitis 250 mg twice daily 10 days

Acute bacterial exacerbation of chronic bronchitis 250-500 mg twice daily 10 days

Secondary bacterial infections of acute bronchitis 250-500 mg twice daily 5-10 days

Uncomplicated skin & skin-structure infections 250-500 mg twice daily 10 days

Uncomplicated urinary tract infection 125-250 mg twice daily 7-10 days

Uncomplicated gonorrhea 1000 mg single dose - - -

Lyme disease 500 mg twice daily 20 days

Paediatric patients (Upto12 years)

(Who can swallow tablets whole)

Pharyngitis or Tonsillitis 125 mg twice daily 5-10 days Acute otitis media 250 mg twice daily 10 days

Acute bacterial maxillary sinusitis 250 mg twice daily 10 days

Suspension

(Must be administered with food. Shake the bottle

well before each use)

Paediatric patients (3 months to 12 years)

Pharyngitis or Tonsillitis 20 mg/kg/day in two divided doses 5-10 days Acute otitis media 30 mg/kg/day in two divided doses 10 days

Acute bacterial maxillary sinusitis 30 mg/kg/day in two divided doses 10 days

Injection :

Adult: 750 mg three times daily by IM or IV injection. In severe infections, dose can be increased upto 1.5 gm three times daily by IV injection. The frequency may be increased to four times daily, if necessary, giving total daily doses of 3 to 6 gms.

Children (above 3 months of age): 30 - 100 mg/kg/day given in 3 or 4 equally divided doses. A dose of 60mg/kg/day is appropriate for most infections.

Neonate: 30 - 100 mg/kg/day given in 2 or 3 equally divided doses.

Surgical prophylaxis: 1.5 gm by IV injection at induction of anaesthesia; up to 3 further doses of 750 mg may be given by IV/IM injection every 8 hours for high risk procedures.

Sequential therapy in adults

Pneumonia: 1.5 gm IV injection twice daily for 2-3 days, followed by 500 mg twice daily (oral) for 7-10 days.

Acute exacerbations of chronic bronchitis: 750 mg twice daily (IM or IV injection) for 2-3 days, followed by 500 mg twice daily (oral) for 5-10 days. (Duration of both parenteral and oral therapy is determined by the severity of the infection and the clinical status of the patient.)

Other recommendations

In Gonorrhoea: Adult: 1.5g as a single dose (as 2 x 750mg injections intramuscularly with different sites, e.g. each buttock).

In Meningitis: Adults: 3gm IV injection three times daily. Children (above 3 months of age): 200-240 mg/kg/day by IV injection in 3 or 4 divided doses reduced to 100 mg/kg/day after 3 days or on clinical improvement. Neonate: 100 mg/kg/day by IV injection reduced to 50 mg /kg/day.

In bone and joint infections: Adult: 1.5 gm IV injection four times daily. Children (above 3 months of age): 150 mg/kg/day (not to exceed the maximum adult dose) in equally divided doses every 8 hours.

In impaired renal function: A reduced dose must be employed when renal function is impaired. Dosage in adults should be determined by the degree of renal impairment and the susceptibility of the causative organism according to the table below -

Creatinine clearance (ml/min) Dose Frequency

> 20 750 mg - 1.5 gm q8h

10-20 750 mg q12h

< 10 750 mg q24h*

* Since Cefuroxime is dialyzable, patients on hemodialysis should be given a further dose at the end of the dialysis.

In paediatric patients with renal insufficiency, the frequency of dosing should be modified consistent with the recommendations for adults.

Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as Linezolid has an oral bioavailability of approximately 100%. The injection should be administered over a period of 30 to 120 minutes. The film coated tablets or oral suspension may be taken with or without food.Adults and Adolescents (12 Years and Older):

• Complicated skin and skin structure infections & Community-acquired pneumonia, including concurrent bacteremia: 600 mg IV or oral b.i.d. for 10 to 14 days.
• Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia: 600 mg IV or oral b.i.d. for 14-28

For Pediatric Patients (Birth through 11 Years of Age):

• Complicated skin and skin structure infections & Community-acquired pneumonia, including concurrent bacteremia: 600 mg IV or oral b.i.d. for 10 to 14 days.
• Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia: 600 mg IV or oral b.i.d.for 14-28.

Neonates <7 days: Most pre-term neonates <7 days of age (gestational age <34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg in every eight hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg t.i.d. by 7 days of life.

Directions for reconstitution:

Shake the bottle well to loosen the powder. Add required amount (with the help of supplied measuring cup) of boiled and cooled water to the dry mixture in the bottle. Shake the bottle vigorously until all the powder is in suspension.

Note: Shake the bottle vigorously before each use. Keep the bottle tightly closed. The reconstituted suspension should be stored in a cool and dry place, preferably in a refrigerator and used within 10 days after reconstitution.

Kilbac 250 IM/IV Injection :

Intramuscular injection : Add 1 ml of supplied water for injection BP to the vial and shake.

Intravenous injection: Add 2 ml of supplied water for injection BP to the vial and shake. The solution should be slowly injected directly into a vein over a 3 to 5 minute period.

Kilbac 750 IM/IV Injection :

Intramuscular injection : Add 3 ml of supplied water for injection BP to the vial and shake.

Intravenous injection: Add 8 ml of supplied water for injection BP to the vial and shake. The solution should be slowly injected directly into a vein over a 3 to 5 minute period.

Kilbac 1.5 IV Injection :

Intravenous injection: Add 16 ml of supplied water for injection BP to the vial and shake. The solution should be slowly injected directly into a vein over a 3 to 5 minute period.

Pharmaceutical precaution

Cefuroxime tablet, powder for suspension and vial (for injection) should be kept in a cool (15° - 30°C) and dry place and protected from light.

Intravenous Administration: Linezolid IV Injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Minute leaks should be checked by firmly squeezing the bag. If leaks are detected, the solution should be discarded, as sterility may be impaired. Linezolid IV Injection should be administered by intravenous infusion over a period of 30 to 120 minutes. The intravenous infusion bag should not be used in series connections. Additives should not be introduced into this solution. The infusion bag should be stored at room temperature and protected from freezing. Linezolid IV Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as Linezolid has an oral bioavailability of approximately 100%.

The injection should be administered over a period of 30 to 120 minutes. The film coated tablets or oral suspension may be taken with or without food.

Reconstitution of Oral Suspension: Shake the bottle to loosen powder. Add 75 ml (with the help of given cup) of boiled & cooled water to the dry mixture in the bottle. For ease of preparation add water to the bottle in two portions. Shake well after each addition until all the powder is in suspension. Shake the suspension well before use. Keep the bottle tightly closed. The reconstituted suspension should be stored in a cool & dry place. Use within 21 days after reconstitution.

Side Effects

Generally Cefuroxime is well tolerated. However, a few side effects like nausea, vomiting, diarrhea, abdominal discomfort or pain may occur. As with other broad-spectrum antibiotics, prolonged administration of Cefuroxime may result in overgrowth of nonsusceptible microorganisms. Rarely (<0.2%) renal dysfunction, anaphylaxis, angioedema, pruritis, rash and serum sickness like urticaria may appear.

Most of the adverse events reported with Linezolid were mild to moderate in intensity. The most common adverse events in patients treated with Linezolid were diarrhea, headache and nausea. Other adverse included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.

Toxicity

Allergic reactions might be expected, including rash, nasal congestion, cough, dry throat, eye irritation, or anaphylactic shock. Overdosage of cephalosporins can cause cerebral irritation leading to convulsions.

Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary.

Precaution

Cefuroxime should be given with care to patients receiving concurrent treatment with potent diuretics & who have history of colitis.

Patients who develop recurrent nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving Linezolid should receive immediate medical evaluation. Where administration of Linezolid and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyper reflexia and incoordination. If signs or symptoms occur physicians should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Convulsions have been reported in patients when treated with Linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

Interaction

No potentially hazardous interactions have been reported.

Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, Linezolid has the potential for interaction with adrenergic and serotonergic agents.

Adrenergic Agents: Some individuals receiving Linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response.

Serotonergic Agents: Physicians should be alert to the possible signs and symptoms of serotonergic syndrome in patients receiving concomitant Linezolid and serotonergic agents.

Volume of Distribution

At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters.

Elimination Route

Absorbed from the gastrointestinal tract. Absorption is greater when taken after food (absolute bioavailability increases from 37% to 52%).

Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (T_max) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing.

The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals.

Half Life

Approximately 80 minutes following intramuscular or intravenous injection.

The elimination half-life is estimated to be between 5 and 7 hours.

Clearance

Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance.

Elimination Route

Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively.

Pregnancy & Breastfeeding use

Pregnancy: While all antibiotics should be avoided in the first trimester if possible. However, Cefuroxime has been safely used in later pregnancy to treat urinary and other infections.

Nursing mothers: Cefuroxime is excreted into the breast milk in small quantities. However, the possibility of sensitizing the infant should be kept in mind

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether Linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Linezolid is administered to a nursing woman.

Contraindication

Cefuroxime is contraindicated in patients with known allergy to Cephalosporins.

Linezolid formulations are contraindicated for use in patients who have known hypersensitivity to Linezolid or any of the other product components. Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product. Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome and/or patients taking directly and indirectly acting sympathomimetic agents (e.g. pseudoephedrine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine or buspirone.

Acute Overdose

Excessively large doses of all Cephalosporins can cause cerebral irritation and may cause convulsions. This complication is unlikely to occur in routine practice unless the patient is in renal failure. Hemodialysis or peritoneal dialysis can remove Cefuroxime.

No cases of overdose have been reported. Symptomatic and supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a Linezolid dose is removed during 3 hours of haemodialysis. No data are available for the removal of Linezolid by peritoneal dialysis or haemoperfusion.

Storage Condition

Tablet: Store below 30° C, protected from light and moisture.

Suspension: Store below 25° C, protected from light and moisture.

Injection: Store below 25° C, protected from light and moisture. Use reconstituted solution immediately. The reconstituted solution is stable for 2 hours at room temperature and for 12 hours when refrigerated at 2° - 8° C.

Should be stored at room temperature 25° C, away from light and moisture.

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