Primegard

Uses

Amikacin is used for the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria. It is effective in bacterial septicemia (including neonatal sepsis); in serious infections of the respiratory tract, bones and joints, central nervous system (including meningitis) and skin and soft tissue; intra abdominal infections (including peritonitis); and in bums and post operative infections (including post-vascular surgery). Amikacin is also effective in serious complicated and recurrent urinary tract infections due to susceptible Gram-negative organisms. It may be considered as initial therapy in suspected Gram-negative infections and therapy may be instituted before obtaining the results of susceptibility. Amikacin is also effective in infections caused by Gentamycln and/or TobrAmykin resistant strains of Gram-negative organisms. Amikacin has also been shown to be effective in Staphylococcal infection and may be considered as initial therapy under certain condition in the treatment of known suspected Staphylococcal disease such as, severe infections where the causative organism may either a Gram-negative bacterium or Staphylococcus infection due to susceptible strains of Staphylococcal I Gram-negative infections. In certain severe infections such as neonatal sepsis, concomitant therapy with a penicillin type drug may be used because of the possibility of infections due to Gram positive organism such as streptococci or pneumococci.

Cefepime Hydrochloride is used for the treatment of the following infections:

• Pneumonia (moderate to severe)

• Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis)

• Uncomplicated Skin and Skin Structure Infections

• Complicated Intra-abdominal Infections

• Empiric Therapy for Febrile Neutropenic Patients.

Primegard is also used to associated treatment for these conditions: Bacterial Peritonitis, Bacterial Sepsis, Bone and Joint Infections, Burns, Central Nervous System Infections, Endophthalmitis, Infection caused by staphylococci, Infective pulmonary exacerbation of cystic fibrosis, Intra-Abdominal Infections, Lung Infection, Meningitis, Bacterial, Mycobacterium avium complex infection, Neonatal Sepsis, Nosocomial Pneumonia, Postoperative Infections, Respiratory Tract Infection Bacterial, Skin and Subcutaneous Tissue Bacterial Infections, Tuberculosis (TB), Grade 1, grade 2, grade 3, grade 4 Urinary Tract Infection, Severe Bacterial InfectionsBacterial Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Febrile Neutropenia, Meningitis, Bacterial, Pyelonephritis, Severe Pneumonia, Uncomplicated Urinary Tract Infections, Moderate Pneumonia, Uncomplicated skin and subcutaneous tissue bacterial infections

How Primegard works

The primary mechanism of action of amikacin is the same as that for all aminoglycosides. It binds to bacterial 30S ribosomal subunits and interferes with mRNA binding and tRNA acceptor sites, interfering with bacterial growth. This leads to disruption of normal protein synthesis and production of non-functional or toxic peptides. Other actions have been postulated for drugs of this class. Amikacin, as well as the rest of the aminoglycosides, are generally bacteriocidal against gram-positive and gram-negative bacteria.

Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs).

Dosage

Primegard dosage

Adults and children: 15mg/kg/day in two equally- divided doses (equivalent to 500 mg bid in adults). Use of the 100 mg/2 ml strength is recommended for children for the accurate measurement of the appropriate dose.

Neonates and premature children: An initial loading dose of 10 mg/kg followed by 15 mg/kg/day in two equally divided doses.

Elderly: Doses should be adjusted under impaired renal function in elderly.

Life-threatening infections and/or those caused by pseudomonas: The adult dose may be increased to 500 mg every eight hours but should neither exceed 1.5 gm/day nor be administered for a period longer than 10 days. A maximum total adult dose of 15 gm should not be exceeded.

Urinary tract infections (Other than pseudomonal infections): 7.5 mg/kg/day in two equally divided doses (equivalent to 250 mg bid in adults).

Impaired renal function: In patient with impaired renal function the daily dose should be reduced and/or the intervals between doses increased to avoid accumulation of the drug. Simple doses schedule for renal impairment is given below:

Renal function Dosage schedule

Mild impairment 500 mg every 18 hours

Moderate impairment 500 mg every 24 hours

Severe impairment 250 mg every 24 hours.

Administration:

Intramuscular or intravenous administration: For most infections the intramuscular route is preferred, but in life threatening infections, or in patients in whom intramuscular injection route is not feasible the intravenous route may be used.

Intraperitoneal use: Amikacin may be used as an irrigant after recovery from anesthesia in concentration of 0.25%.

Other routes of administration: Amikacin in concentration of 0.25% may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space, the peritoneum and the cerebral ventricles.

Recommended dosage schedule for adults with normal renal function

Type of Infection Dose Frequency Duration (Days)

Moderate to severe Pneumonia 1-2 g IV q12h 10

Empiric Therapy for Febrile Neutropenic Patients 2 g IV q8h 7

Mild to moderate Uncomplicated or Complicated Urinary 0.5-1 g IV/IM q12h 7-10

Tract Infections (including pyelonephritis)

Severe Uncomplicated or Complicated Urinary 2 g IV q12h 10

Tract Infections (including pyelonephritis)

Moderate to severe Uncomplicated Skin and Skin Structure 2 g IV q12h 10

Infections

Complicated Intra-abdominal Infections 2 g IV q12h 7-10

Pediatric Patients (2 months up to 16 years)

The maximum dose for pediatric patients should not exceed the recommended adult dose.

Type of Infection Pediatric patients up to 40 kg in weight

Dose Frequency Duration

(Days)

Uncomplicated and Complicated Urinary Tract Infections 50 mg/kg q12h 7-10

(including pyelonephritis)

Uncomplicated Skin and Skin Structure Infections 50 mg/kg q12h 10

Pneumonia 50 mg/kg q12h 10

Febrile Neutropenic Patients 50 mg/kg q8h 7

Impaired Hepatic Function - No adjustment is necessary for patients with impaired hepatic function.

Impaired Renal Function - In patients with impaired renal function (creatinine clearance <60 ml/min), the dose of Cefepime should be adjusted. The recommended initial dose of Cefepime should be the same as in patients with normal renal function except in patients undergoing hemodialysis. The recommended doses of Cefepime in patients with renal insufficiency are presented in the following table:

Creatinine Clearance Recommended Maintenance Schedule

(ml/min)

>60 500 mg q12h 1g q12h 2g q12h 2g q8h

Normal recommended

dosing schedule

30-60 500 mg q24h 1g q24h 2g q24h 2g q12h

11-29 500 mg q24h 500 mg q24h 1g q24h 2g q24h

<11 250 mg q24h 250 mg q24h 500 mg q24h 1g q24h

CAPD 500 mg q48h 1g q48h 2g q48h 2g q48h

Hemodialysis 1g on day 1, then 500 mg q24h thereafter 1g q24h

Preparation of Solutions of Cefepime Hydrochloride

Single-dose vial Administration Amount of diluent to be added

500 mg IM 1.3 ml

500 mg IV 5 ml

1 gm IM 2.4 ml

1 gm IV 10 ml

These solutions may be stored up to 24 hours at room temperature or 7 days in a refrigerator.

Cefepime Hydrochloride is compatible at concentrations between 1 and 40 mg/ml with the following IV infusion fluids: (1) 0.9% Sodium chloride, (2) 5% and 10% Dextrose.

Intramuscular or intravenous administration: For most infections the intramuscular route is preferred, but in life threatening infections, or in patients in whom intramuscular injection route is not feasible the intravenous route may be used.

Intraperitoneal use: Amikacin may be used as an irrigant after recovery from anesthesia in concentration of 0.25%.

Other routes of administration: Amikacin in concentration of 0.25% may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space, the peritoneum and the cerebral ventricles.

IV infusion: Add 5 mL, 10 mL, or 10 mL of a compatible IV soln to a vial labeled as containing 500 mg, 1 g, or 2 g, respectively, to provide soln containing approx 100 mg/mL, 100 mg/mL, or 160 mg/mL of the drug, respectively. The appropriate dose of the drug should then be added to a compatible IV soln.

IM inj: Add 1.3 mL or 2.4 mL of an appropriate diluent (e.g. sterile water for inj, NaCl 0.9%) to a vial labeled as containing 500 mg or 1 g respectively, to provide a soln containing approx 280 mg/mL.

Side Effects

When the recommended precautions and dosages are followed the incidence of toxic reactous, such as tinnitus vertigo, and partial reversible or irreversible deafness, skin rash, drug fever, headache, paraesthesia, nausea and vomiting is low. Urinary signs of renal irritation, azotaemia and oliguria have been reported.

Generally Cefepime is well tolerated. However, few side-effects including rash, pruritus, urticaria, fever, headache, nausea, vomiting, diarrhea, dizziness, oral moniliasis may occur.

Toxicity

Oral (LD50): 6000 mg/kg (Mouse) . No antidote for toxicity is currently available. This drug is only 20% dialyzable; however, this is variable based on the type hemodialysis filter used.

Nephrotoxicity

Mild and reversible nephrotoxicity may be observed in 5 - 25% of patients. Amikacin accumulates in the proximal renal tubular cells. Tubular cell regeneration occurs despite continued drug exposure. Toxicity most commonly occurs several days following initiation of therapy. Amikacin may exacerbate pre-existing renal disease.

Ototoxicity

May cause irreversible ototoxicity. Ototoxicity appears to be correlated to cumulative exposure. Drug accumulation in the endolymph and perilymph of the inner ear causes irreversible damage to hair cells of the cochlea or summit of ampullar cristae in the vestibular complex. High- frequency hearing is lost first with progression leading to loss of low-frequency hearing. Further toxicity may lead to retrograde degeneration of the 8th cranial (vestibulocochlear) nerve. Vestibular toxicity may cause vertigo, nausea, vomiting, dizziness, and loss of balance.

Neuromuscular blockade

In addition to the above, amikacin may exacerbate neuromuscular blockade, however, this is less common.

Use in Pregnancy

Category D. Gentamicin and other aminoglycosides are known to cross the placenta. There is evidence of selective uptake of gentamicin by the fetal kidney resulting in damage to immature nephrons. Eighth cranial nerve damage has also been reported after in-utero exposure to some of the aminoglycosides. Because of the chemical similarity, all aminoglycosides should be considered potentially nephrotoxic and ototoxic to the developing fetus. Therapeutic blood amikacin levels in the mother do not equate with safety for the fetus. In reproductive toxicity studies in mice and rats, no effects on fertility or fetal toxicity were observed.

Use in Lactation

It is not known whether amikacin is excreted in breast milk. Since the possible harmful effect on the infant is not known, it is recommended that if nursing mothers must be given amikacin, the infants should not be breastfed during therapy.

Symptoms of overdose include seizures, encephalopathy, and neuromuscular excitability.

Precaution

Since Amikacin is present in high concentrations in the renal excretory system, patients should be well hydrated to minimize chemical irritation of the renal tubules. If azotemia increases, treatment should be stopped. Monitoring of renal function during treatment with aminoglycosides is particularly important.

In patients with impaired renal function (creatinine clearance <60 ml/min), the dose of Cefepime should be adjusted. Cefepime should be prescribed with caution in individuals with a history of gastrointestinal diseases, particularly colitis.

Interaction

Concurrent administration of Amikacin with myorelaxants leads to potentiation of their effects and there is a possibility of cessation of the breathing. The combination with other Aminoglycoside antibiotics should be avoided because of the augmentation of their ototoxic and nephrotoxic effects. Concurrent administration of Amikacin with fast acting diuretics increases the risk of ototoxicity in patients with renal failure. Combination with Cephalosporins or Polymixins increases the risk of nephrotoxicity.

Increased potential for nephrotoxicity and ototoxicity of aminoglycosides. Increased risk of nephrotoxicity with potent diuretics (e.g. furosemide).

Volume of Distribution

• 24 L (28% of body weight healthy adult subjects).

Following administration of usual dosages of amikacin, amikacin has been found in bone, heart, gallbladder, and lung tissue. Amikacin is also distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.

• 18.0 ±2.0 L
• 0.3 ±0.1 L/kg [Pediatric]

Elimination Route

Rapidly absorbed after intramuscular administration. Rapid absorption occurs from the peritoneum and pleura. Poor oral and topical absorption. Poorly absorbed from bladder irrigations and intrathecal administration.

The bioavailability of this drug is expected to vary primarily from individual differences in nebulizer efficiency and airway pathology.

Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17-25 micrograms/mL are attained within 45 minutes to 2 hours.

Following IV infusion of the same dose given over 1 hour peak plasma concentrations of the drug average 38 micrograms/mL immediately following the infusion, 5.5 micrograms/mL at 4 hours, and 1.3 micrograms/mL at 8 hours.

The absolute bioavailability of cefepime after an IM dose of 50 mg/kg was 82.3 (±15)% in eight patients.

Half Life

The plasma elimination half-life of amikacin is usually 2-3 hours in adults with normal renal function and is reported to range from 30-86 hours in adults with severe renal impairment.

2.0 (± 0.3) hours in normal patients. The average half-life in patients requiring hemodialysis was 13.5 (± 2.7) hours and in patients requiring continuous peritoneal dialysis was 19.0 (± 2.0) hours.

Clearance

The mean serum clearance rate is about 100 mL/min and the renal clearance rate is 94 mL/min in subjects with normal renal function.

• 120 mL/min [Healthy adult male receiving a single 30-minute IV infusions of cefepime]
• 3.3 +/-1.0 mL/min/kg [Petriatic patients (2 months – 11 years of age) receiving a single IV dose]

Elimination Route

This drug is eliminated by the kidneys. In adults with normal renal function, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration in the kidney within 24 hours. Amikacin can be completely recovered within approximately 10-20 days in patients with normal, healthy renal function.

In patients with impaired renal function, the clearance of amikacin is found to be decreased; the more severe the impairment, the slower the clearance. The interval between doses of amikacin should be adjusted according to the level of renal impairment. Endogenous creatinine clearance rate and serum creatinine which have a high correlation with serum half-life of amikacin, may be used as a guide for dosing.

Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime is excreted in human milk.

Pregnancy & Breastfeeding use

The safety of Amikacin in pregnancy has not yet been established.

Pregnancy: There are no adequate and well-controlled studies of Cefepime use in pregnant women. Cefepime should be used during pregnancy only if clearly needed.

Lactation: Cefepime is excreted in human breast milk in very low concentrations. Caution should be exercised when Cefepime is administered to a nursing woman.

Contraindication

Amikacin injection is contraindicated in patients with a known history of hypersensitivity to Amikacin.

Hypersensitivity to cefepime or other cephalosporins.

Special Warning

Impaired renal function: In patient with impaired renal function the daily dose should be reduced and/or the intervals between doses increased to avoid accumulation of the drug. Simple doses schedule for renal impairment is given below:

• Mild impairment: 500 mg every 18 hours
• Moderate impairment: 500 mg every 24 hours
• Severe impairment: 250 mg every 24 hours.

Pediatric Use: Safety and effectiveness of Amikacin for injection in children or adolescents under 16 years have not been established

Acute Overdose

In the event of overdose or toxic reaction, peritoneal dialysis or hemodialysis will aid in the removal of Amikacin from the blood.

Patients who receive an overdose should be carefully observed and given supportive treatment. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and neuromuscular excitability.

Storage Condition

Store in a cool dry place protected from light. Keep out of reach of children.

Cefepime Hydrochloride should be stored in a cool & dry place and protected from light.

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