Forplus 400 Injection

Teicoplanin for Injection IP 400 mg

Each Combi - pack contains:

1. Teicoplanin Injection IP 400 mg
   1. Each vial contains: Teicoplanin IP……… 400 mg
   2. Excipients…………… q.s.
2. Sterile Water for Injections IP 5 ml

Lyophilized Powder for solution for injection/infusion 400 mg

4.1. Therapeutic indication

Glycopeptide antibiotic-use in serious gram +ve infection, staphylococcal infection in patients sensitive or unresponsive to penicillin and cephalosporins CAPD related peritonitis, prophylaxis in orthopaedic surgery at risk of gram +ve infections.

4.2. Posology and method of administration

Posology

The dose and duration of treatment should be adjusted according to the underlying type and severity of infection and clinical response of the patient, and patient factors such as age and renal function.

Adults and elderly patients with normal renal function

¹ Measured by FPIA- Fluorescence Polarization Immunoassay

Duration of treatment

The duration of treatment should be decided based on the clinical response. For infective endocarditis a minimum of 21 days is usually considered appropriate. Treatment should not exceed 4 months.

Combination therapy

Teicoplanin has a limited spectrum of antibacterial activity (Gram positive). It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a high suspicion that the most likely pathogen(s) would be suitable for treatment with teicoplanin.

Clostridium difficile infection-associated diarrhoea and colitis

The recommended dose is 100-200 mg administered orally twice a day for 7 to 14 days.

Elderly population

No dose adjustment is required, unless there is renal impairment.

Adults and elderly patients with impaired renal function

Dose adjustment is not required until the fourth day of treatment, at which time dosing should be adjusted to maintain a serum trough concentration of at least 10 mg/L.

After the fourth day of treatment:

• In mild and moderate renal insufficiency (creatinine clearance 30-80 mL/min) : maintenance dose should be halved, either by administering the dose every two days or by administering half of this dose once a day.
• In severe renal insufficiency (creatinine clearance less than 30 mL/min) and in haemodialysed patients: dose should be one-third the usual dose, either by administering the initial unit dose every third day or by administering one-third of this dose once a day. Teicoplanin is not removed by haemodialysis.

Patients on continuous ambulatory peritoneal dialysis (CAPD)

After a single intravenous loading dose of 6 mg/kg bodyweight, 20 mg/L is administered in the bag of the dialysis solution in the first week, 20 mg/L in different bags the second week and then 20 mg/L in the overnight bag in the third week.

Paediatric population

The dose recommendations are the same in adults and children above 12 years of age.

Neonates and infants up to the age of 2 months

Loading dose

One single dose of 16 mg/kg body weight, administered intravenously by infusion on the first day.

Maintenance dose

One single dose of 8 mg/kg body weight administered intravenously by infusion once a day

Children (2 months to 12 years)

Loading dose: One single dose of 10 mg/kg body weight administered intravenously every 12 hours, repeated 3 times.

Maintenance dose: One single dose of 6-10 mg/kg body weight administered intravenously once a day

METHOD OF ADMINISTRATION

Teicoplanin should be administered by the intravenous or intramuscular route. The intravenous injection may be administered either as a bolus over 3 to 5 minutes or as a 30-minute infusion. Only the infusion method should be used in neonates.

Preparation of Injection:

The powder should be reconstituted strictly in accordance with the instructions below. Errors in reconstitution may result in the formation of a stable foam and delivery of smaller doses.

The entire contents of the accompanying diluent water ampoule should be added slowly down the side wall of the vial of Forplus-400. The vial should be rolled gently between the palms until the powder is completely dissolved, taking care to avoid foam formation. DO NOT SHAKE. If the solution does become foamy, allow to stand for 15 minutes for the foam to subside. Withdraw the entire contents from the vial slowly into a syringe, trying to recover most of the solution by placing the needle in the central part of the stopper.

The reconstituted solution contains :

For a 400 mg vial : 400 mg/3.0 ml of Teicoplanin.

The reconstituted solution may be injected directly, or alternatively diluted with any of the following diluents.

• 0.9% Sodium Chloride Solution
• Compound Sodium Lactate Solution
• 5% Dextrose Solution
• 0.18% Sodium Chloride & 4% Dextrose Solution

In keeping with good clinical pharmaceutical practice reconstituted vials of Forplus-400 should be used immediately and any unused portion discarded. In case if not used immediately, the reconstituted solution should be kept at 2°C to 8°C and used within 24 hours.

Solutions kept longer than 24 hours should be discarded

4.3. Contraindications

Teicoplanin is contraindicated in patients with known hypersensitivity to the drug.

4.4. Special warnings and precautions for use

Teicoplanin should not be administered by intraventricular use.

Hypersensitivity reactions

Serious, life-threatening hypersensitivity reactions, sometimes fatal, have been reported with teicoplanin (e.g. anaphylactic shock). If an allergic reaction to teicoplanin occurs, treatment should be discontinued immediately and appropriate emergency measures should be initiated. Teicoplanin must be administered with caution in patients with known hypersensitivity to vancomycin, as crossed hypersensitivity reactions, including fatal anaphylactic shock, may occur. However, a prior history of "red man syndrome" with vancomycin is not a contraindication to the use of teicoplanin.

Infusion related reactions

In rare cases (even at the first dose), red man syndrome (a complex of symptoms including pruritus, urticaria, erythema, angioneurotic oedema, tachycardia, hypotension, dyspnoea) has been observed. Stopping or slowing the infusion may result in cessation of these reactions. Infusion related reactions can be limited if the daily dose is not given via bolus injection but infused over a 30-minute period.

Severe bullous reactions

Life-threatening or even fatal cutaneous reactions Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with the use of teicoplanin. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present teicoplanin treatment should be discontinued immediately.

Spectrum of antibacterial activity

Teicoplanin has a limited spectrum of antibacterial activity (Gram-positive). It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a high suspicion that the most likely pathogen(s) would be suitable for treatment with teicoplanin. The rational use of teicoplanin should take into account the bacterial spectrum of activity, the safety profile and the suitability of standard antibacterial therapy to treat the individual patient. On this basis it is expected that in most instances teicoplanin will be used to treat severe infections in patients for whom standard antibacterial activity is considered to be unsuitable.

Loading dose regimen

Since data on safety are limited, patients should be carefully monitored for adverse reactions when teicoplanin doses of 12 mg/kg body weight twice a day are administered. Under this regimen blood creatinine values should be monitored in addition to the recommended periodic haematological examination. Teicoplanin should not be administered by intraventricular use.

Thrombocytopenia

Thrombocytopenia has been reported with teicoplanin. Periodic haematological examinations are recommended during treatment, including complete blood cell count.

Nephrotoxicity

Renal failure has been reported in patients treated with teicoplanin. Patients with renal insufficiency, and/or in those receiving teicoplanin in conjunction with or sequentially with other medicinal products with known nephrotoxic potential (aminoglycosides, colistin, amphotericin B, ciclosporin, and cisplatin) should be carefully monitored, and should include auditory tests. Since teicoplanin is mainly excreted by the kidney, the dose of teicoplanin must be adapted in patients with renal impairment.

Ototoxicity

As with other glycopeptides, ototoxicity (deafness and tinnitus) has been reported in patients treated with teicoplanin. Patients who develop signs and symptoms of impaired hearing or disorders of the inner ear during treatment with teicoplanin should be carefully evaluated and monitored, especially in case of prolonged treatment and in patients with renal insufficiency. Patients receiving teicoplanin in conjunction with or sequentially with other medicinal products with known neurotoxic/ototoxic potential (aminoglycosides, ciclosporin, cisplatin, furosemide and ethacrynic acid) should be carefully monitored and the benefit of teicoplanin evaluated if hearing deteriorates. Special precautions must be taken when administering teicoplanin in patients who require concomitant treatment with ototoxic and/or nephrotoxic medicinal products for which it is recommended that regular haematology, liver and kidney function tests are carried out.

Superinfection

As with other antibiotics, the use of teicoplanin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

4.5. Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed.

Teicoplanin and aminoglycoside solutions are incompatible and must not be mixed for injection; however, they are compatible in dialysis fluid and may be freely used in the treatment of CAPD-related peritonitis. Teicoplanin should be used with care in conjunction with or sequentially with other medicinal products with known nephrotoxic or ototoxic potential. These include aminoglycosides, colistin, amphotericin B, ciclosporin, cisplatin, furosemide, and ethacrynic acid. However, there is no evidence of synergistic toxicity in combinations with teicoplanin. In clinical studies, teicoplanin has been administered to many patients already receiving various medications including other antibiotics, antihypertensives, anaesthetic agents, cardiac medicinal products and antidiabetic agents without evidence of adverse interaction.

Paediatric population- Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are a limited amount of data from the use of teicoplanin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. In rats there was an increased incidence of stillbirths and neonatal mortality. The potential risk for humans is unknown. Therefore, teicoplanin should not be used during pregnancy unless clearly necessary. A potential risk of inner ear and renal damage to the foetus cannot be excluded.

Breast-feeding

It is unknown whether teicoplanin is excreted in human milk. There is no information on the excretion of teicoplanin in animal milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with teicoplanin should be made taking into account the benefit of breast-feeding to the child and the benefit of teicoplanin therapy to the mother.

Fertility

Animal reproduction studies have not shown evidence of impairment of fertility.

4.7. Effects on ability to drive and use machines

Teicoplanin has minor influence on the ability to drive and use machines. Teicoplanin can cause dizziness and headache. The ability to drive or use machines may be affected. Patients experiencing these undesirable effects should not drive or use machines.

4.8. Undesirable effects

In the table below all the adverse reactions, which occurred at an incidence greater than placebo and more than one patient are listed using the following convention : Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to < 1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions should be monitored when teicoplanin doses of 12 mg/kg body weight twice a day are administered

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 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 Symptoms

Cases of accidental administration of excessive doses to paediatric patients have been reported. In one case agitation occurred in a 29-day-old newborn who had been administered 400 mg intravenously (95 mg/kg). Management Treatment of teicoplanin overdose should be symptomatic. Teicoplanin is not removed by haemodialysis and only slowly by peritoneal dialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Glycopeptide Antibacterials, ATC code : J01XA 02

Mechanism of action

Teicoplanin inhibits the growth of susceptible organisms by interfering with cell-wall biosynthesis at a site different from that affected by beta-lactams. Peptidoglycan synthesis is blocked by specific binding to D-alanyl-D-alanine residues.

Mechanism of resistance

Resistance to teicoplanin can be based on the following mechanisms:

• Modified target structure: This form of resistance has occurred particularly in Enterococcus faecium. The modification is based on exchange of the terminal D-alanine- D-alanine function of the amino-acid chain in a murein precursor with D-Ala-D-lactate, thus reducing the affinity to vancomycin. The responsible enzymes are a newly synthesised D-lactate dehydrogenase or ligase.
• The reduced sensitivity or resistance of staphylococci to teicoplanin is based on the overproduction of murein precursors to which teicoplanin is bound. Cross-resistance between teicoplanin and the glycoprotein vancomycin may occur. A number of vancomycinresistant enterococci are sensitive to teicoplanin (Van-B phenotype).

Pharmacokinetic/Pharmacodynamic relationship

Teicoplanin antimicrobial activity depends essentially on the duration of time during which the substance level is higher than the minimum inhibitory concentration (MIC) of the pathogen.

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

^a No current data were available when the tables were published. The primary literature, standard volumes and treatment recommendations assume sensitivity.

^b Collective term for a heterogeneous group of streptococcus species. Resistance rate can vary depending on the actual streptococcus species.

5.2 Pharmacokinetic properties

Absorption

Teicoplanin is administered by parenteral route (intravenously or intramuscularly). After intramuscular administration, the bioavailability of teicoplanin (as compared to intravenous administration) is almost complete (90%). After six daily intramuscular administrations of 200 mg the mean (SD) maximum teicoplanin concentration (Cmax) amounts to 12.1 (0.9) mg/L and occurs at 2 hours after administration. After a loading dose of 6 mg/kg administered intravenously every 12 hours for 3 to 5 administrations, Cmax values range from 60 to 70 mg/L and C are usually above 10 mg/L. After an intravenous loading dose of 12 mg/kg administered every 12 hours for trough 3 administrations, mean values of Cmax and C are estimated to be around 100 mg/L and 20 mg/L, respectively. After a maintenance dose of 6 mg/kg administered once daily Cmax and C values are approximately 70 mg/L and 15 mg/L, trough respectively. After a maintenance dose of 12 mg/kg once daily Ctrough values range from 18 to 30 mg/L.

Distribution

The binding to human serum proteins ranges from 87.6 to 90.8% without any variation in function of the Teicoplanin concentrations. Teicoplanin is mainly bound to human serum albumin. Teicoplanin is not distributed in red cells. The volume of distribution at steady-state (Vss) varies from 0.7 to 1.4 mL/kg. The highest values of Vss are observed in the recent studies where the sampling period was superior to 8 days. Teicoplanin distributed mainly in lung, myocardium and bone tissues with tissue/serum ratios superior to 1. In blister fluids, synovial fluid and peritoneal fluid the tissue/serum ratios ranged from 0.5 to 1.

Elimination of Teicoplanin from peritoneal fluid occurs at the same rate as from serum. In pleural fluid and subcutaneous fat tissue the tissue/serum ratios are comprised between 0.2 and 0.5. Teicoplanin does not readily penetrate into the cerebrospinal fluid (CSF).

Biotransformation

Unchanged form of Teicoplanin is the main compound identified in plasma and urine, indicating minimal metabolism. Two metabolites are formed probably by hydroxylation and represents 2 to 3% of the administered dose.

Elimination

Unchanged Teicoplanin is mainly excreted by urinary route (80% within 16 days) while 2.7% of the administered dose is recovered in feces (via bile excretion) within 8 days following administration. Elimination half-life of Teicoplanin varies from 100 to 170 hours in the most recent studies where blood sampling duration is about 8 to 35 days. Teicoplanin has a low total clearance in the range of 10 to 14 mL/h/kg and a renal clearance in the range of 8 to 12 mL/h/kg indicating that Teicoplanin is mainly excreted by renal mechanisms.

Linearity

Teicoplanin exhibited linear pharmacokinetics at dose range of 2 to 25 mg/kg.

Special populations 

• Renal impairment: As teicoplanin is eliminated by renal route, Teicoplanin elimination decreases according to the degree of renal impairment. The total and renal clearances of Teicoplanin depends on the creatinine clearance.
• Elderly patients: In the elderly population the Teicoplanin pharmacokinetics is not modified unless in case of renal impairment.
• Paediatric population: A higher total clearance (15.8 mL/h/kg for neonates, 14.8 mL/h/kg for a mean age 8 years) and a shorter elimination half-life (40 hours neonates; 58 hours for 8 years) are observed compared to adult patients.

Following repeated parenteral administration to the rat and dog, effects on the kidney were observed and were shown to be dose-dependent and reversible. Studies to investigate the potential to cause ototoxicity in the guinea-pig indicate that a mild impairment of cochlear and vestibular function is possible, in the absence of morphological damage.

Subcutaneous administration of teicoplanin at up to 40 mg/kg/day did not affect male and female fertility in the rat. In embryofetal development studies, no malformations were observed following subcutaneous administration of up to 200 mg/kg/day in the rat and intramuscular administration up to 15 mg/kg/day in the rabbit. However, in the rat, there was an increased incidence of stillbirths at doses of 100 mg/kg/day and above and neonatal mortality at 200 mg/kg/day. This effect was not reported at 50 mg/kg/day. A peri and postnatal study in rats showed no effects on the fertility of the F1 generation or on the survival and development of the F2 generation following subcutaneous administration of up to 40 mg/kg/day.

Teicoplanin did not show any potential to cause antigenicity (in mice, guinea-pigs or rabbits), genotoxicity or local irritancy

Teicoplanin is a novel bactericidal, glycopeptide antibiotic, produced by fermentation of Actinoplanes teichomyceticus. It acts by inhibition of peptidoglycan synthesis in the cell wall of gram positive bacteria.

IUPAC Name : Ristomycin A 34-O-[2-(acetylamino)-2-deoxy-beta-Dglucopyranosyl]-22, 31-dichloro-7-demethyl-64-O-demethyl-19-deoxy-56-O-[2- deoxy-2-[(8-methyl-1-oxononyl) amino]-beta-D-glucopyranosyl]-42-O-alpha-Dmannopyranosyl

Molecular Formula : C77H77N9O31Cl2·R

Molecular Weight : 1709.39

1. Incompatibilities Teicoplanin and aminoglycoside are incompatible when mixed directly and must not be mixed before injection. If teicoplanin is administered in combination therapy with other antibiotics, the preparation must be administered separately. This medicinal product must not be mixed with other medicinal products except those mentioned in method of administration section.
2. Shelf-life Refer on the pack.
3. Packaging information A vial of 400 mg with SWFI IP 5 ml.
4. Storage and handing instructions Store below 25°C. Protect from light & moisture. Keep out of reach of children. It is advisable to use reconstituted vial of Forplus-400 immediately. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

• Finish the prescribed course of Forplus®-400, even if you start to feel better. Stopping it early may cause the infection to return and become more difficult to treat. It is given by an injection or drip into a vein or into a muscle.
• Lactation It is unknown whether teicoplanin is excreted in human milk. There is no information on the excretion of teicoplanin in animal milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with teicoplanin should be made taking into account the benefit of breast-feeding to the child and the benefit of teicoplanin therapy to the mother.
• Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including Forplus^®-400. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, advise patients to contact his or her healthcare provider.
• Development of Resistance Patients should be counseled that antibacterial drugs including Forplus®-400 should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Forplus®-400 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 (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Forplus®-400 or other antibacterial drugs in the future.

1st June 2024