Gentamicin 1mg/ml & 3mg/ml solution for infusion B Braun

Gentamicin Solution for Infusion B.Braun solution for infusion is indicated for the following conditions, when caused by susceptible organisms , when less toxic antimicrobial agents are not effective :

• Acute and chronic urinary tract infections;
• Severe systemic infections, e.g. sepsis, peritonitis, meningitis;
• Bone and soft tissue infections, e.g. acute osteomyelitis, wound and soft tissue infections; infected burns
• Nosocomial lower respiratory tract Infections including severe pneumonia

Gentamicin Solution for Infusion B Braun should be used for all indications, only in combination with other relevant antibiotics (predominantly together with a beta - lactam antibiotic or with an antibiotic effective against anaerobic bacteria), except complicated urinary tract infections. Consideration should be given to South African official guidance on the appropriate use of antibacterial medicines.

Posology

Adults and adolescents

Treatment of bacterial infections. The daily dose recommended in adolescents and adults with normal renal function, is 3 u2013 6 mg/kg body weight per day as one (preferred) up to two divided doses (12 hourly). A maximum daily dose of 6 mg/kg may be needed for the treatment of serious infections and when the susceptibility of the pathogen is relatively poor. Gentamicin has a long-lasting post-antibiotic effect (see section 5.1). Recent in vitro and in vivo studies show that the uptake of aminoglycosides into the renal cortex is limited and hence, with higher peak serum gentamicin levels (after single daily dosing) less aminoglycoside is stored in the kidneys than with conventional multiple dosing.

In the case of combination treatment (e.g. with a beta-lactam antibiotic in the normal dosage) it is also possible to administer the total daily dose as a single dose once a day. Due to the requirement for dose adjustments once daily dosing of gentamicin is not recommended for patients with compromised immunity (e.g. neutropenia), severe renal failure, ascites, bacterial endocarditis, patients with extensive burns (more than 20 % of the skin), and in pregnancy.

Paediatric population

The daily dose in new-borns is 4 u2013 7 mg/kg body weight per day. Due to the longer half-life, new-borns are given the required daily dose in 1 single dose. The daily dose in infants after the first month of life is 4.5 u2013 7.5 mg/kg body weight per day as a single dose (preferred) or divided into 2 single doses. The daily dose recommended in older children with normal renal function is 3 u2013 6 mg/kg body weight per day as a single dose (preferred) or divided into 2 single doses.

One 80 mL bottle of Gentamicin 1 mg/mL Solution for Infusion B Braun contains 80 mg gentamicin and one 80 mL bottle of Gentamicin 3 mg/mL Solution for Infusion B Braun contains 240 mg gentamicin. To avoid overdosing especially in children, the required volume should be calculated according to the posology and should be administered with the required technique. The unused volume shall be discarded (see section 6.6).

Duration of treatment:

In all cases, the general duration of treatment Is 7 to 10 days. When treatment exceeds this period, and in the administration of high dosage levels, it is advisable to monitor renal, auditory and vestibular functions (see section 4.4).

Patients with impaired renal function:

In impaired renal function, the recommended daily dose has to be decreased and adjusted to the renal function. Patients with renal function impairment should be monitored in order to adjust the therapeutic concentrations in plasma, either by decreasing the dose or by increasing the dosage interval (see section 4.4). Dose reduction and interval extension are equivalently suitable solutions. Nonetheless, it should be remembered that doses determined in the way described below are only approximate and that the same dose may lead to different concentrations in the body of different patients. Therefore gentamicin serum levels should be determined in the given patient, so that the dosage can be adapted accordingly.

1) Extension of dosage interval at the normal dose: Since the gentamicin clearance is directly proportional to the creatinine clearance, the following approximate formula may be used: Based on a normal creatinine clearance of 100 mL/min and a creatinine clearance of 30 mL/min in the patient, the application interval with a constant dose would in this case be 26 hours (8 u00d7 100/30 [h]). Normal dose (80 mg) at extended dose interval: Normal dose interval u00d7 creatinine clearance normal creatinine clearance patient = Subsequent dose interval

Blood urea (mmol/L) Creatinine clearance or Glomerular Filtration Rate (GFR) (mL/min) Dose and dosage interval 33.3 > 72 30 u2013 72 12 u2013 30 6 u2013 12 80 mg* every 8 hours 80 mg* every 8 hours 80 mg* every 8 hours 80 mg* every 8 hours *If the patientu2019s weight is < 60 kg the dose should be decreased to 60 mg.

2) Reduction of dose at the normal dose interval: After the usual initial dose, dividing the normal recommended dose by the serum creatinine level may be taken as a rough guide for determination of the reduced dose that should be administered every 8 hours. So e.g. 30 mg may therefore be administered every 8 hours to a patient weighing 60 kg with a serum creatinine level of 2.0 mg/100 mL after an initial dose of 60 mg (1 mg/kg; 60:2).

Reduced dose at normal dose interval (8-hourly) Serum creatinine (mg/100 mL) Approximate creatinine clearance or GFR (mL/min) Percentage of the normal dose u2264 1.0 1.1 u2013 1.3 1.4 - 1.6 1.7 u2013 1.9 2.0 u2013 2.2 2.3 u2013 2.5 2.6 u2013 3.0 3.1 u2013 3.5 > 100 70 u2013 100 55 u2013 70 45 u2013 55 40 u2013 45 35 u2013 40 30 u2013 35 25 u2013 30 100 80 65 55 50 40 35 30 3.6 u2013 4.0 4.1 u2013 5.1 5.2 u2013 6.6 6.7 u2013 8.0 20 u2013 25 15 u2013 20 10 u2013 15 < 10 25 20 15 10

Alternatively, after the usual initial dose, subsequent doses every 8 hours may be calculated according to the formula: Creatinine clearance should be preferred as a parameter especially in the elderly and in patients with fluctuating serum creatinine levels, as is observed in severe infections (e.g. sepsis). It should be emphasised that renal function may change during therapy with gentamicin. It is important to recognise that deteriorating renal function may require a greater reduction of dosage than that specified in the above guidelines for patients with stable renal impairment.

Other special patient populations

Dosage in patients undergoing haemodialysis Gentamicin is dialysable. In the case of a 4 u2013 5-hour haemodialysis, a 50 u2013 60 % reduction in concentration should be expected and in the case of an 8 u2013 12-hour haemodialysis, a 70 u2013 80 % reduction in concentration. The dosage must be individually adjusted after each dialysis session, based on the gentamicin serum concentration at that time. The normal recommended dose after dialysis is 1 u2013 1.7 mg/kg body weight.

Normal dose interval u00d7 creatinine clearance actual creatinine clearance normal (=100mL/ min) = Subsequent dose interval

Elderly patients Elderly patients may require lower maintenance doses than younger adults because of impaired renal function. There is limited experience with once daily dosing of gentamicin in elderly patients. Once daily dosing of gentamicin may not be suitable and therefore, close monitoring is warranted in these patients (see Section 4.5)

Obese patients In obese patients the initial dose should be based on ideal body weight plus 40 % of weight excess.

Critically ill patients Critically ill patients might need higher doses than the maximum daily dose of 6 mg/kg bodyweight to achieve target peak concentration. Monitoring of plasma gentamicin concentration in this patient group is strongly recommended to avoid suboptimal peak concentrations.

Patients with impaired hepatic function No dose adjustment is necessary.

Monitoring advice Serum concentration of gentamicin should be monitored, to ensure efficacy and avoid toxicity especially in elderly, in new-borns, obese patients, in patients with cystic fibrosis, burns, major surgery, spinal cord injury, in patients with impaired renal function and critically ill patients, due to the increased risk of over- or underdosing. Target peak concentration depends on the indication and site of infection. Blood samples are taken before the start of the next dosage interval for trough level. When monitoring gentamicin peak concentration for toxicity, dosage should be adjusted so that prolonged levels above 12mcg/mL are avoided. Trough levels should not exceed 2 u03bcg/mL when administering gentamicin twice daily and 1 u03bcg/mL for a once daily dose. Please refer to section 4.4.

Method of administration Gentamicin 1 mg/mL Solution for Infusion B Braun and Gentamicin 3 mg/mL Solution for Infusion B Braun are administered by intravenous infusion over a period of 30 u2013 60 minutes. Gentamicin 1 mg/mL and 3 mg/mL solutions for infusion are not suitable for intramuscular or slow intravenous injection. Do not add other medicines together with Gentamicin Sulphate solution in the Infusion.

Gentamicin Solution for Infusion B Braun is contraindicated:

• Hypersensitivity to gentamicin or any component listed in section 6.1.
• In patients with a known history of allergy to other aminoglycosides.
• In patients with myasthenia gravis

Prescribers must adhere to the principles of antibiotic stewardship. Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use. In patients with advanced renal impairment or with pre-existing inner ear deafness, gentamicin should be used only if its use is considered essential by the medical practitioner. The frequency or dose of administration should be reduced in patients with impaired renal function (see section 4.2).

Renal impairment Renal impairment such as restriction of glomerular filtration is observed in approximately 10 % of patients treated with gentamicin and is usually reversible. The most important risk factors are high total dose, long duration of therapy, raised serum level (high trough level); in addition, other potential risk factors are age, hypovolaemia and shock. Clinical signs of renal damage are: proteinuria, cylindruria, haematuria, oliguria, raised creatinine and urea concentrations in serum. In isolated cases, acute renal failure may occur. (See section 4.8.).

Renal function should be closely monitored, especially in patients with known or suspected reduced renal function at onset of therapy and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Urine should be examined for decreased specific gravity, increased excretion of protein, and the presence of cells or casts. Blood urea, serum creatinine, or creatinine clearance should be determined periodically. When feasible, (see Section 4.2) Evidence of nephrotoxicity requires dosage adjustment or discontinuance of gentamicin. As with the other aminoglycosides, less frequently changes in renal function may not become manifest until soon after completion of therapy.

Neuromuscular disorders Since gentamicin has neuromuscular blocking properties, particular caution should be exercised in patients with pre- existing neuromuscular diseases (e.g. Parkinsonu2019s disease). Particularly careful monitoring is mandatory. (See section 4.8.) Gentamicin Solution for Infusion B Braun is contraindicated in myasthenia gravis. Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia. These patients should also be monitored very carefully. (See section 4.8.)

Neurotoxicity Neurotoxicity manifested by ototoxicity, both vestibular and auditory (see below), can occur in patients treated with gentamicin sulphate, primarily those with pre-existing renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended. Aminoglycoside- induced ototoxicity is usually irreversible.

Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

Effect on vestibulocochlear nerve Damage to the vestibulocochlear nerve (eighth cranial nerve), whereby both balance and hearing may be affected, is possible. Vestibular damage is the most frequent ototoxic reaction. Hearing loss is manifested initially by diminution of high-tone acuity and is usually irreversible. Important risk factors are pre-existing renal impairment or a history of damage to the eighth cranial nerve; in addition, the risk increases in proportion to the level of the total and daily dose or by association with potentially ototoxic substances. Symptoms of ototoxic effects are: dizziness, ringing/roaring in the ears (tinnitus), vertigo and u2013 less frequently u2013 hearing loss. It is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high- risk patients. Evidence of ototoxicity requires dosage adjustment or discontinuance of gentamicin. Less frequently changes eighth cranial nerve function may not become manifest until soon after completion of therapy. With gentamicin the vestibular mechanism may be affected if trough levels of 2 u03bcg/mL are exceeded. This is usually reversible if observed promptly and the dose adjusted. There have been observed cases of an increased risk of ototoxicity with aminoglycosides administered to patients with mitochondrial mutations, particularly the m.1555A>G mutation, including cases where the patientu2019s aminoglycoside serum levels were within the recommended range. Some cases were associated with a maternal history of deafness and/or mitochondrial mutation. Mitochondrial mutations are rare, and the penetrance of this observed effect is unknown. (See also section 4.8.)

Antibiotic-associated diarrhoea, pseudomembranous colitis Antibiotic-associated diarrhoea and pseudomembranous colitis have been reported with the use of gentamicin.

These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Gentamicin should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted. Medicines that inhibit peristalsis must not be given (see section 4.8).

Treatment with gentamicin may produce excessive growth of drug-resistant microorganisms.

Once daily dosing of gentamicin in elderly patients There is limited experience with once daily dosing of gentamicin in elderly patients. Once daily dosing of gentamicin may not be suitable and therefore, close monitoring is warranted in these patients.

Due to the requirement for dose adjustments, once daily dosing of gentamicin is also not recommended for patients with compromised immunity (e.g. neutropenia), severe renal failure, ascites, bacterial endocarditis, patients with extensive burns (more than 20 % of the skin), and in pregnancy.

Monitoring To avoid adverse events, continuous monitoring (before, during and after treatment) of renal function (serum creatinine, creatinine clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended.

Excipients 80 mL bottle 1mg/mL or 3 mg /mL solution of gentamicin sulphate: This medicinal product contains 283 mg of sodium per 80 mL bottle solution for infusion, equivalent to 14.2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. 120 mL bottle 3 mg/mL solution of gentamicin sulphate: This medicinal product contains 425 mg of sodium per 120 ml bottle solution for infusion, equivalent to 21.3 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Muscle relaxants and ether The neuromuscular blocking activity of aminoglycosides is enhanced by ether and muscle relaxants. If gentamicin is administered during or immediately after surgery, the neuromuscular blockade may be enhanced and prolonged if non-depolarising muscle relaxants are used. These interactions may cause neuromuscular blockage and respiratory paralysis. Because of the increased risk, such patients should be monitored with particular care. Large doses of Gentamicin Solution for Infusion B Braun should not be administered concurrently with neuromuscular blocking medicines.

Injection with calcium chloride may reverse the neuromuscular blockade due to aminoglycosides.

Methoxyflurane anaesthesia Aminoglycosides may increase the kidney damaging effect of methoxyflurane. When used concurrently, extremely severe nephropathies are possible. The anaesthetist should be made aware of the use of aminoglycosides before a surgical procedure.

Potentially nephrotoxic or ototoxic medicines Because of the increased risk of undesired effects, concurrent administration of Gentamicin Solution for Infusion B.Braun with potentially nephrotoxic or ototoxic medicines such as e.g. amphotericin B, colistin, ciclosporin, cisplatin, vancomycin, polymyxin B, streptomycin, neomycin, other aminoglycosides, some cephalosporins (e.g. ceophaloridine), and loop diuretics such as ethacrynic acid and furosemide should be avoided.

In the case of medicines containing cisplatin, it must be noted that the nephrotoxicity of gentamicin can be increased even 3 to 4 weeks after these substances are administered.

Pregnancy Aminoglycosides may cause foetal harm if administered to a pregnant woman, t here are however no adequate data from the use of gentamicin in pregnant women. Studies in animals have shown reproductive toxicity. Gentamicin crosses the placenta. Because of the potential risk of inner e ar and renal damage to the foetus, gentamicin should not be used in pregnancy except in case of a life - threatening indication and if no other treatment options are available. In case of exposure to gentamicin during pregnancy, monitoring of hearing and ren al function of the new - born is recommended.

Breast - feeding Gentamicin is excreted in human breast milk and was detected in low concentrations in serum of breast - fed children. A decision must be made whether to discontinue breast - feeding or to discontinue/abstain from gentamicin therapy. Diarrhoea and fungus infection of the mucous membranes could occur in the breast - fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be borne in mind.

Fertility N o data available.

In the case of administration to outpatients, caution is advised when driving and using machines in view of the possible undesirable effects such as dizziness and vertigo.

Tabulated list of adverse reactions

System Organ Class Frequency Category Infections and infestations Superinfection (with gentamicin - resistant microorganisms), pseudomembranous colitis (see section 4.4) Less Frequent Blood and lymphatic disorders: Dyscrasia, Thrombocytopenia, reticulocytopenia, leukopenia, eosinophilia, granulocytopenia, anaemia, purpura Less frequent Immune system disorders Hypersensitivity reactions of varying severity, ranging from rash and itching, medicine fever to severe acute hypersensitivity reactions (anaphylaxis), up to anaphylactic shock. Hypersensitivity reactions, especially after local use; cross - sensitivity between aminoglycosides may occur; anaphylactic reactions have occurred. Some hypersensitivity rea ctions have been attributed to the presence of sulphites in parenteral formulations Less frequent Metabolism and nutrition disorders Hypokalaemia, hypocalcaemia, hypomagnesaemia, pseudo - Bartter syndrome in patients treated with high doses over a long period (more than 4 weeks), loss of appetite, weight loss. Hypophosphataemia Less frequent Psychiatric disorders Confusion, hallucinations, mental depression Less frequent Nervous system disorders: Polyneuropathies, peripheral paraesthesias Encephalopathy, convulsions, neuromuscular blockage, respiratory depression, muscular paralysis, dizziness, balance disorder, headache, (see also section 4.4) Less frequent Less frequent Eye disorders: Visual disorders Less frequent Subconjunctival injection of gentamicin may lead to pain, hyperaemia and conjunctival oedema, while severe retinal ischaemia has followed intra - ocular injection Frequency unknown Ear and labyrinth disorders Ototoxicity (both vestibular and auditory) Frequent Vestibular damage, hearing loss, Meniu00e9reu2019s disease, tinnitus vertigo Less frequent tinnitus vertigo (see section 4.4) Irreversible hearing loss, deafness Frequency unknown Vascular disorders : Hypotension, hypertension Less frequent Gastrointestinal disorders: Vomiting, nausea, salivation increased, stomatitis Less frequent Hepato - biliary disorders Aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, serum bilirubin increased (all reversible) Less frequent Skin and subcutaneous tissues disorders: Allergic skin exanthema, Skin reddening Toxic epidermal necrolysis, Stevens - Johnson syndrome, erythema multiforme, alopecia Less Frequent Musculoskeletal and connective tissue disorders Muscle pain (myalgia), Amyostasia Less Frequent Renal and urinary disorders Nephrotoxicity, Renal function impairment (see section 4.4) Frequent Blood urea increased (reversible), Acute renal failure, hyperphosphaturia, aminoaciduria, Fanconi - like syndrome in patients treated with a prolonged course of high - dose (see section 4.4) Less frequent General disorders and administration site conditions: Increased body temperature, Pain at injection site, endotoxic shock Less frequent Electrolyte disturbances (notably hypermagnesaemia, but also hypocalcaemia and hypokalaemia) have occurred Frequency unknown

Reporting of suspected adverse reactions 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 to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019. Found under SAHPRAu2019s publications: https://www/sahpra.org.za/Publications/Index/8

Symptoms and treatment

Symptoms Gentamicin has a narrow therapeutic window. In the event of accumulation (e.g. as a result of impaired renal function), renal damage and damage to the vestibulocochlear nerve may occur: In patients with renal impairment, gentamicin serum blood levels in excess of 12 ug/mL may result In ototoxicity. This is reversible if timeously observed and the dose is suitably adjusted. See also Section 4.4).

Treatment in the event of overdose Discontinue medication. There is no specific antidote. Gentamicin can be removed from the blood by haemodialysis (elimination is more slowly and discontinuous with peritoneal dialysis).

Treatment of neuromuscular blockade In the event of neuromuscular blockade (usually caused by interactions, see section 4.5), the administration of calcium chloride is advisable and artificial respiration if required.