Tovid

Uses

Higher concentrations of Benzalkonium chloride is used as an antiseptic and disinfectant. This is also widely used as a preservative in eye-drops.

Tobramycin Respirator Solution is used for the management of cystic fibrosis patients with Pseudomonas aeruginosa. Also used for severe COPD patients colonized with Pseudomonas aeruginosa. Safety and efficacy have not been demonstrated in patients below the age of 6 years, patients with a forced expiratory volume <25% or >75% predicted, or patients colonized with Burkholderia cepacia.

For the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany its use.

Tovid is also used to associated treatment for these conditions: Diaper Dermatitis, Dry Eye Syndrome (DES), Eye and eyelid infections, Gingivitis, Hemorrhoids, Infantile Eczema, Mouth irritation, Pruritus Ani, Tonsillitis, Throat inflammation, Antisepsis, Disinfection therapy, Eye disinfection, Eye lubrication, Hand Hygiene, Skin disinfection, Wound treatmentBacterial Peritonitis, Bone Infection, Cystic fibrosis, Pseudomonas aeruginosa infection, Eye Infections, Inflammation of the External Auditory Canal, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Meningitis, Bacterial, Ocular Inflammation, Septicemia gram-negative, Skin and Subcutaneous Tissue Bacterial Infections, Corticosteroid-responsive Disorder of the Ophthalmic, Ear infection-not otherwise specified caused by susceptible bacteria, Ocular bacterial infections, Recurrent Complicated Urinary Tract Infection, Steroid-responsive inflammation

How Tovid works

Although not entirely elucidated, the bactericidal action of benzalkonium chloride is believed to be due to the disruption of intermolecular interactions. Such disruption can cause the dissociation of cellular membrane lipid bilayers of bacteria, resulting in compromised cellular permeability control and the leakage of important cellular contents. Additionally, other important molecular complexes like enzymes which control the maintenance of a great range of respiratory and metabolic cellular activities, are also susceptible to such deactivation. Consequently, a variety of critical intermolecular interactions and tertiary structures in very highly specific biochemical systems that allow bacterial agents to function normally can be readily disrupted or deactivated by cationic surfactants like benzalkonium chloride. .

Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below.

Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model.

Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.

Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria.

Dosage

Tovid dosage

• Tincture of benzalkonium chloride 1:750 is used for the preoperative disinfection of unbroken skin or treatment of superficial injuries.
• For preoperative disinfection of mucous membranes and denuded skin, benzalkonium chloride solution in concentrations of 1:10000 to 1:2000 is used.
• For irrigation of the eye, a solution of 1:10000 to 1:5000 is used.
• For urinary bladder and urethral irrigation, a solution 1:5000 to 1:20000 is used.
• For vaginal douche and irrigation, benzalkonium chloride solution 1:5000 to 1:20000.

Tobramycin (Respirator Solution) The recommended dosage for, both adult and paediatric patients, 6 years of age and older, is one single-use ampoule (300 mg) administered b.i.d for 28 days. Dosage is not adjusted by weight.

The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

If you are taking several medications, the recommended order is as follows: bronchodilator first, followed by chest physiotherapy, then other inhaled medications and finally Tobramycin.

You should take Tobramycin in repeated cycles of 28 days on drug, followed by 28 days off drug. You should take Tobramycin twice a day during the 28 day period on drug.

Tobramycin Eye Drops: In mild to moderate disease, 1 drop into the affected eye(s) every 4 hours. In severe infections, 1 drop into the affected eye(s) hourly until improvement, following which dosage should be reduced prior to discontinuation.

Tobramycin Eye Ointment: In mild to moderate disease it should be applied thinly and evenly into the conjunctival sac of the affected eyes 2 to 3 times per day. For severe cases it should be applied thinly and evenly into the conjunctival sac of the affected eyes 3 to 4 times per day. Following improvement, treatment should be reduced prior to discontinuation.

Side Effects

Repeated application may cause hypersensitivity reactions. May cause nausea and vomiting if ingested.

Inhaled Tobramycin is generally well-tolerated. Voice alterations and tinnitus are more common in the on-drug periods. However all the episodes are transient and resolved without discontinuation of the regimen. Others like dizziness and increase in serum creatinine were similar to those occurring with placebo.

The most frequent adverse reactions to Tobramycin are localized ocular toxicity and hypersensitivity, including lid itching and swelling and conjunctival erythema. These reactions occur in less than 3% of patients treated.

Toxicity

An oral dose of 100-400 mg/kg or a parenteral dose of 5-15 mg/kg is believed to be fatal in humans .

A potential concern for larger concentrations of benzalkonium chloride to possibly cause corneal damage when implemented as an excipient ingredient in aqueous eye products is an issue that should be discussed between potential patents and their health care providers . Since decreased regular blinking and tear generation in patients experiencing dry eyes due to any number of eye conditions can result in reduced dilution of applied eye drops containing the benzalkonium chloride preservative , alternative options including benzalkonium chloride-free products should be considered.

Additionally, benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. In addition, benzalkonium chloride may cause eye irritation and is known to discolour soft contact lenses . There may also be the possibility of benzalkonium chloride containing eye drops to cause some stinging and pain .

There is the possibility of ototoxicity occurring when benzalkonium chloride containing ear drops are applied to the ear .

Benzalkonium chloride used as a preservative in nebulised solutions of anti-asthma drugs has been reported to cause dose-related bronchoconstriction especially in asthmatic patients and has been associated with the precipitation of respiratory arrest .

Despite the fairly widespread cutaneous use of benzalkonium chloride, only limited human evidence of sensitization in relatively small populations of individuals have been reported . Nevertheless, the main adverse effect for topical formulations of benzalkonium chloride is usually the warning 'may cause local irritation' .

Toxicity information regarding tobramycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nephrotoxicity, ototoxicity, neuromuscular blockade, and respiratory failure/paralysis. Symptomatic and supportive measures are recommended; hemodialysis may help clear excess tobramycin. Accidental ingestion of tobramycin is unlikely to result in an overdose, as aminoglycosides are poorly absorbed in the gastrointestinal tract.

Poor gastrointestinal absorption is reflected in animal studies. When administered by the intraperitoneal or subcutaneous route, the LD50 for mice and rats ranges from 367-1030 mg/kg while the oral LD50 values are more than 7500 mg/kg.

Precaution

As with other anti-infective, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

Warning: Do not touch the dropper or tube opening to any surface, including eyes or hands. The dropper or tube opening is sterile. If it becomes contaminated, it could cause an infection in the eye. Use caution when driving, operating machinery, or performing other hazardous activities. Tobramycin ophthalmic may cause blurred vision. If blurred vision is experienced, avoid these activities. Caution should be taken to wear the contact lenses. After applying the medication, wait at least 15 minutes before inserting contact lenses, unless otherwise directed by doctor. Do not use other eye drops or medications during treatment with tobramycin ophthalmic unless otherwise directed by doctor

Interaction

Disinfectants containing quaternary ammonium salts should not be used for skin preparation before injections of viscoelastic solutions. Hyaluronic acid will precipitate in the presence of these salts.

Patients taking Tobramycin concomitantly with beta agonists, inhaled corticosteroids, other anti pseudomonal antibiotics or parenteral aminoglycosides demonstrated adverse experience profiles.

Specific drug interaction studies on Tobramycin ophthalmic preparation have not been established

Volume of Distribution

When applied as a topical antibacterial, antiseptic, disinfectant, or sanitizer it is believed that molecules of benzalkonium chloride are poorly absorbed (perhaps due to their large, positively charged nature ), especially considering expectations for such topical applications to keep their biocidal agents available for action at the topical level and to not be absorbed significantly beyond it.

When benzalkonium chloride is implemented as an excipient preservative ingredient in various eye, nose, and ear aqueous products, such products will always have other active pharmacological agents whose volume of distribution will be of greater importance. In these cases the excipients will only ever be present at the minimal levels necessary to maintain the integrity of the product substance.

Moreover, Benzalkonium chloride is currently listed as a Category III ingredient by the United States Food and Drug Administration . Ingredients are listed in the FDA Category III when the data available about them are insufficient to classify as safe and effective, requiring further testing to determine more formal details about elements like human pharmacokinetic studies, and studies on the ingredients' absorption, distribution, metabolism, and excretion.

Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.

Elimination Route

Percutaneous absorption is considered to be insignificant .

In one study, benzalkonium chloride absorption was evaluated in women using tampons containing the agent. Venous blood samples were drawn 15 minutes before the tampon application and then again at 15 min, 1 h, 3 h, and 24 h after application. Benzalkonium chloride was not detected in any of the blood samples at any time tested.

Similarly, in another study, benzalkonium chloride absorption was tested in women using tampons containing the agent. Venous blood and breast milk samples were taken 15 minutes before application and 3 h and 24 h after tampon administration. Benzalkonium chloride was not found in any of the subjects' samples. .

Moreover, in a study where benzalkonium chloride solution was placed on the corneal surface of rabbit subjects, at various intervals after administration, the rabbits' eyes would be washed with 1 mL saline and the following tissues and fluids were removed: bulbar and palpebral conjunctiva, aqueous humour, corneal epithelium, endothelium and stroma, iris-ciliary body, lens, vitreous, retina, and choroid. Plasma samples were obtained with direct cardiac punctures. After administration of one drop, benzalkonium chloride was found in the corneal epithelium, endothelium, and stroma, and in the bulbar and palpebral conjunctivae. Benzalkonium chloride loss from ocular tissues was such that about one-third to two thirds of its concentration (depending on the tissue) at 30 min remained after 24 hr; measurable values existed for as long as 120 hr. The administration of multiple drops led to continued accumulation of benzalkonium chloride. .

Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum C_max was 1.02 ± 0.53 μg/mL, which was reached in one hour (T_max), while the sputum C_max was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum C_max was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum C_max was 737 ± 1028 μg/g. The systemic exposure (AUC_0-12) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the C_max measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.

Half Life

Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients.

Clearance

Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.

Elimination Route

Administered benzalkonium chloride is likely eliminated largely in faeces, similar to other quaternary ammonium compounds .

Tobramycin is primarily excreted unchanged in the urine.

Pregnancy & Breastfeeding use

Pregnancy: This drug should be used during pregnancy only if clearly needed.

Lactation: Because of the potential for adverse reactions in nursing infants from Tobramycin, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Incompatible with soaps and other anionic surfactants, citrates, iodides, nitrates, permanganates, salicylates, silver salts, tartrates, and zinc oxide and sulfate.

In patients with known hypersensitivity to any component of the product. Partial crossallergenicity to other aminoglycosides has been established.

Special Warning

Renal Impairment: Inhalation: Dosage adjustment needed.

Acute Overdose

Symptoms: Nephrotoxicity, auditory and vestibular toxicity (e.g. dizziness, tinnitus, vertigo, loss of high-tone hearing acuity), neuromuscular blockade or resp failure.

Management: Initiate resuscitative measures if resp paralysis occurs. Ca salts may be given to reverse neuromuscular blockade. Haemodialysis or peritoneal dialysis will help remove drug serum levels.

Storage Condition

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Store under refrigeration at 2-8° C, and protected from light. Slight color change when unrefrigerated do not indicate any change in the quality of the product. The preparation must not be used if it is cloudy, particles appear in the solution or has been stored at room temperature for over 28 dyas. For use only under the prescription of a registered physician. Do not use beyond the expiration date stamped on the ampoule.

Eye Drops Store in a cool and dry place, away from light. Keep out of reach of children.

Innovators Monograph

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