Monobact 1.5 gm Injection

Ceftriaxone & Sulbactam for Injection IP

Monobact Kid

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 125 mg

Sulbactam Sodium IP equivalent to Sulbactam 62.5 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 375 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 250 mg

Sulbactam Sodium IP equivalent to Sulbactam 125 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 750 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 500 mg

Sulbactam Sodium IP equivalent to Sulbactam 250 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 1.5 gm

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 1000 mg

Sulbactam Sodium IP equivalent to Sulbactam 500 mg

This pack contains Sterile Water for Injections IP 10 ml.

Powder for solution for injection.

187.5 mg / 375 mg / 750 mg / 1.5 gm

4.1 Therapeutic indication

• Bacterial meningitis
• Infections of bones and joints
• Community acquired pneumonia
• Complicated skin and soft tissue infections
• Hospital acquired pneumonia
• Gonorrhoea
• Acute otitis media
• Syphilis
• Intra-abdominal infections
• Bacterial endocarditis
• Complicated urinary tract infections
• Surgical prophylaxis

4.2 Posology and method of administration

To be administered by deep intramuscular (I.M.) injection, slow intravenous (I.V.) injection, or as a slow I.V. infusion, after reconstitution with sterile water for injection (SWFI).

Dosage recommendations in adults

Usual Recommended Dose : 1.5 g to 3 g of Monobact Injection (1 g / 2 g ceftriaxone + 0.5 g / 1 g sulbactam) per day given once a day or in two equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. Also, the total dose of sulbactam should not exceed 4 grams per day

For Uncomplicated Gonococcal Infections : A single dose of 750 mg of Monobact Injection (500 mg ceftriaxone + 250 mg sulbactam) to be administered by I.M. route. For Preoperative Use (Surgical Prophylaxis): A single dose of 1.5 g of Monobact Injection (1g ceftriaxone + 0.5 g sulbactam) to be administered intravenously 30 minutes to 2 hours before surgery

The usual duration of therapy is 4 to 14 days. In complicated infections, longer therapy may be required. Or, as prescribed by the physician.

Dosage in adult patients with renal impairment and hepatic dysfunction

In patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 grams daily. Dose of sulbactam should be adjusted in patients with marked decrease in renal function (creatinine clearance of < 30 ml/min) and to compensate for reduced clearance less than 15ml/min, maximum dose of sulbactam should not exceed 1 gram per day.

Dosage recommendations in pediatric patients

For children with bodyweight above 50 kg or age over 12 years, the usual adult dosage should be administered. Although, ceftriaxone can be administered in neonates and infants, the safety and efficacy of this combination product (ceftriaxone + sulbactam injection) has not been established in children below 1 year of age. Thus, Monobact Injection is recommended only in pediatric patients 1 year of age or older.

Following doses in children are expressed in terms of ceftriaxone content of the formulation. Usual Recommended Dosage : 50 to 75 mg/kg/day, given in divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 2 grams. Sulbactam dose in children should not exceed 100 mg/kg/day.

Treatment of Meningitis : The initial therapeutic dose should be 100 mg/kg body weight. Thereafter, daily dose of 100 mg/kg may be administered once a day or in equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. The usual duration of therapy is 7 to 14 days depending on the type and severity of infection. Or, as prescribed by the physician

Geriatric patients

Dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment.

Pharmaceutical precautions

Ceftriaxone-containing injection should not be mixed with other drugs in infusion bottle since compatibility has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for reconstitution and dilution for use

Monobact comes in a composite pack containing one vial of dry powder and Sterile Water for Injections IP in ampoule. Each Monobact 1.5 gm pack contains 1 ampoule of 10 ml Sterile Water for Injections IP [SWFI]. Monobact 750 mg contains 1 ampoule of 5 ml Sterile Water for Injections IP, Monobact 375 mg and Monobact Kid packs contain 1 ampoule of 5 ml Sterile Water for Injections IP per pack. SWFI IP from the ampoule should be used to dissolve the dry powder present in the vial, just prior to the use. After adding the SWFI IP into the vial, agitate the vial gently until the powder dissolves completely into the solution.

Though, stability studies have shown that the solution is stable for 24 hrs at 25°C and up to days under 2°C to 8°C. It is advisable to use the solution immediately after reconstitution. Following are the recommendation for diluting the solution

4.3 Contraindications

• In patients with known hypersensitivity to ceftriaxone, cephalosporin class of antibiotics, or to tazobactam or to any component of the formulation.
• In hyperbilirubinemic neonates/preterm newborns : Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
• Premature neonates : Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
• In neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.
• Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.

4.4 Special warnings and precautions

Test dose

Hypersensitivity

Before initiation of therapy, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.

Clostridium difficile-associated diarrhea (CDAD)

CDAD has been reported with use of nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemolytic anemia

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class of antibacterial drugs including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.

Development of drug-resistant bacteria

Prescribing ceftriaxone in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pancreatitis

Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, and total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.

Urolithiasis and post-renal acute renal failure

Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings.

Gallbladder pseudolithiasis

Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings.

Effect on prothrombin time

Alterations in prothrombin times have occurred in patients treated with ceftriaxone. Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Altered laboratory tests

Positive direct Coombs' test and galactosemia test, false-positive test for urinary glucose and elevated lactate dehydrogenase (LDH).

4.5 Drug interactions

Ceftriaxone

Amsacrine, Vancomycin, Fluconazole, and Aminoglycosides : Ceftriaxone is incompatible with these drugs.

Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment. Chloramphenicol : Caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.

Vitamin K Antagonist : Concomitant use of ceftriaxone with vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone.

Sulbactam

Probenecid : Probenecid decreases the renal tubular secretion of sulbactam. Concurrent use of probenecid with sulbactam may result in increased and prolonged blood levels of sulbactam.

4.6 Use in special populations

Pregnancy

Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Monobact Injection should be used during pregnancy only if clearly needed.

Lactation

Although sulbactam is distributed into breast milk in small amounts, no adverse effects have been seen in breast-fed infants and it is usually compatible with breast feeding. Low concentration of ceftriaxone is excreted in human milk. Therefore, caution should be exercised when Monobact Injection is administered to a nursing woman.

Pediatric patients

Safety and effectiveness of ceftriaxone has been established in pediatric patients. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Thus, ceftriaxone-containing preparations should not be administered to hyperbilirubinemic children. Safety and efficacy of Monobact Injection has not been established in children below 1 year of age.

4.7 Effects on the ability to drive and use machines

During treatment undesirable effects such as dizziness, headache, and convulsions may occur, which may influence the ability to drive and use machines. If affected by such events, patients should not drive or operate machinery.

4.8 Undesirable effects

Ceftriaxone-containing preparations are generally well tolerated. In clinical trials, the following adverse reactions were observed (related to ceftriaxone therapy or of uncertain etiology). Local Reactions : Injection site pain, induration, tenderness, phlebitis, warmth, tightness. Hypersensitivity : Rash, pruritus, fever or chills.

Infections and Infestations : Genital fungal infection. Hematologic : Eosinophilia, thrombocytosis, leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

Blood and Lymphatic Disorders : Granulocytopenia, coagulopathy. Gastrointestinal : Diarrhea/loose stools, nausea, vomiting, dysgeusia, pseudomembranous colitis.

Hepatic : Elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin.

Renal : Elevations of the blood urea nitrogen (BUN), creatinine and the presence of casts in the urine.

Central Nervous System : Headache, dizziness.

Dermatologic : Exanthema, allergic dermatitis, urticaria, edema; acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome / toxic epidermal necrolysis) have been reported.

Miscellaneous : Diaphoresis, flushing, increased blood creatinine.

Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

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

4.9 Overdose

In the case of overdose nausea, vomiting, and diarrhea can occur. There is no specific antidote. Treatment should be supportive and symptomatic according the patient's clinical presentation.

5.1 Mechanism of action

Ceftriaxone

Ceftriaxone is a third generation cephalosporin class of beta-lactam antibiotic. Ceftriaxone inhibits bacterial cell wall synthesis and produces bactericidal effect. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gramnegative and Gram-positive bacteria.

Sulbactam

Beta-lactamases are the enzymes produced by certain bacteria to develop resistant to penicillin and cephalosporin class of beta-lactam antibiotics. Sulbactam inhibits action of these enzymes irreversibly. In particular, sulbactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance. The addition of sulbactam effectively extends the antibacterial spectrum of concurrently administered beta-lactam antibiotic (e.g., ceftriaxone) to include many bacteria normally resistant to it.

5.2 Pharmacodynamic properties

The combination of ceftriaxone and sulbactam is active against wide variety of beta-lactamase producing gram-positive and gram-negative bacteria. In addition, it demonstrates synergistic activity (reduction in MICs of combination therapy versus ceftriaxone alone) in a variety of organisms which are sensitive to ceftriaxone.

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

Gram-negative Bacteria

Acinetobacter calcoaceticus       Moraxella catarrhalis

Enterobacter aerogenes             Morganella morganii

Enterobacter cloacae                  Neisseria gonorrhoeae

Escherichia coli                           Neisseria meningitidis

Haemophilus influenzae             Proteus mirabilis

Haemophilus parainfluenzae      Proteus vulgaris

Klebsiella oxytoca                      Pseudomonas aeruginosa 

Klebsiella pneumoniae              Serratia marcescens

Gram-positive Bacteria

Staphylococcus aureus             Streptococcus pyogenes

Staphylococcus epidermidis      Viridans group streptococci

Streptococcus pneumoniae

Anaerobic Bacteria

Bacteroides fragilis Peptostreptococcus species

Clostridium species

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

Gram-negative Bacteria

Citrobacter diversus     Salmonella species (including Citrobacter freundii Salmonella typhi)

Providencia species (including Providencia rettgeri) Shigella species

Gram-positive Bacteria

Streptococcus agalactiae

Anaerobic Bacteria

Porphyromonas (Bacteroides) melaninogenicus Prevotella (Bacteroides) bivius

5.3 Pharmacokinetic properties

Ceftriaxone

Absorption : Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 gram is about 81 mg/l and is reached in 2 to 3 hours after administration. The area under the plasma concentrationtime curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone (Cmax) levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. An 8 to 15 % increase in Cmax is seen on repeated administration; steady state is reached in most cases within 48 to 72 hours depending on the route of administration.

Distribution : The volume of distribution of ceftriaxone is 7 to 12 litre. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l.

Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).

Metabolism : Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora. Elimination : Plasma clearance of total ceftriaxone (bound and unbound) is 10 to 22 ml/min. Renal clearance is 5 to 12 ml/min. 50 to 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 to 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.

Sulbactam

After a 30-minute infusion of 1g of sulbactam, a peak concentration of approximately 43 mcg/ml is obtained. Plasma protein binding is approximately 38%. The mean serum half-life of sulbactam is approximately 1 hour in healthy volunteers. Approximately 75 to 85% of sulbactam is excreted unchanged in the urine during the first 8 hours after administration to individuals with normal renal function.

6.1 Animal toxicology or pharmacology

Ceftriaxone

LD50 values after administration of ceftriaxone by intravenous route were in mice 1840 mg/kg, in rat 2240 mg/kg, and in rabbit 240 mg/kg. LD50 value reported after administration of ceftriaxone by oral route in mice and rats was >10,000 mg/kg. In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1% in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14% in comparison to the control animals. A 50% reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes. 11 Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies. Carcinogenicity studies on ceftriaxone were not conducted. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.

Sulbactam

Relevant data is not available.

Monobact is a combination of Ceftriaxone Sodium and Sulbactam Sodium available as dry powder for reconstitution.

Ceftriaxone

Ceftriaxone is a beta-lactam, third-generation cephalosporin antibiotic with bactericidal activity. Molecular Weight : 554.6g/mol.

Molecular Formula : C18H18N8O7S3.

Chemical Name : (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl] amino]- 3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Sulbactam sodium

Sulbactam is a β-lactamase inhibitor given in combination with β-lactam antibiotics to inhibit β- lactamase, an enzyme produced by bacteria that destroys antibiotic activity. Sulbactam sodium is a derivative of the basic penicillin nucleus. Molecular Weight : 255.22 g/mol.

Molecular Formula : C8H10NNaO5S.

Chemical Name : Sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo [3.2.0] heptane- 2- carboxylate 4,4- dioxide.

8.1 Incompatibilities

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line. Ceftriaxone with sulbactam must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Monobact Kid : A vial of 187.5 mg with SWFI IP 5 ml.

Monobact 375 mg : A vial of 375 mg with SWFI IP 5 ml.

Monobact 750 mg : A vial of 750 mg with SWFI IP 5 ml.

Monobact 1.5 gm : A vial of 1.5 gm with SWFI IP 10 ml.

8.4 Storage and handling instructions

Store below 25°C. Protect from light. Do not freeze.

Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

• Instruct patient to store medication as advised and not to expose the vial to moisture or direct light.
• When ceftriaxone with sulbactam is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of therapy and increase the likelihood that bacteria will develop antimicrobial resistance.
• Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools even as late as two months after the last dose of the antibiotic. If this occurs, instruct patients to contact their physician immediately.
• Instruct patient not to freeze the reconstituted solution and use it immediately after the preparation. Unused portion of solution, if any, should be discarded.

16 August 2024