Nebracin Bm

Uses

Indicated in atopic, infantile & discoid eczema; prurigo nodularis; Psoriasis (excluding widespread plague psoriasis); lichen simplex or planus; contact sensitivity reactions; seborrhoeic dermatitis; discoid lupus erythematosus & adjunct to systemic steroid therapy in generalized erythroderma.

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.

Nebracin Bm is also used to associated treatment for these conditions: Acute Gouty Arthritis, Adrenal cortical hypofunctions, Alopecia Areata (AA), Ankylosing Spondylitis (AS), Berylliosis, Blepharitis allergic, Blepharoconjunctivitis, Bullous dermatitis herpetiformis, Bursitis, Congenital Adrenal Hyperplasia (CAH), Congenital Hypoplastic Anemia, Conjunctivitis, Corneal Inflammation, Dermatitis, Eczematous, Dermatomyositis, Dermatosis, Discoid Lupus Erythematosus (DLE), Edema of the cerebrum, Epicondylitis, Episcleritis, External ear inflammation, Eye allergy, Hypercalcemia of Malignancy, Inflammatory Reaction of the ear, Iridocyclitis, Iritis, Itching caused by Allergies, Keloid Scars, Keratitis interstitial, Keratoconjunctivitis, Leukemias, Lichen Planus (LP), Lichen simplex chronicus, Lupus Erythematosus, Malignant Lymphomas, Multiple sclerosis exacerbation, Mycosis Fungoides (MF), Necrobiosis lipoidica diabeticorum, Nephrotic Syndrome, Ocular Inflammation, Ocular injuries, Ophthalmia, Sympathetic, Pemphigus, Plaque psoriasis of the body, Plaque psoriasis of the scalp, Polymyositis, Post-Surgical Ocular Inflammation, Pruritus, Psoriasis, Psoriasis Vulgaris (Plaque Psoriasis), Psoriatic Arthritis, Psoriatic plaque, Pulmonary Tuberculosis (TB), Pure Red Cell Aplasia, Regional Enteritis, Rheumatoid Arthritis, Rheumatoid Arthritis, Juvenile, Scleritis, Secondary thrombocytopenia, Severe Asthma, Severe Atopic Dermatitis, Skin Infections, Stevens-Johnson Syndrome, Systemic Lupus Erythematosus (SLE), Temporal Arteritis, Trichinosis, Tuberculous Meningitis, Ulcerative Colitis, Uveitis, Verrucous Lichen Planus (LP), Acquired immune hemolytic anemia, Acute nonspecific tenosynovitis, Acute rheumatic carditis, Bacterial blepharitis, Corticosteroid-responsive dermatoses, Eczematous rash, Exfoliative erythroderma, Granuloma annulare lesions, Idiopathic eosinophilic pneumonias, Non-suppurative Thyroiditis, Ocular bacterial infections, Severe Allergic rhinitis, Severe Contact dermatitis, Severe Serum sickness, Severe Transfusion Reactions, Severe drug hypersensitivity reactions, Superficial ocular infections, Symptomatic Sarcoidosis, Synovitis of osteoarthritisBacterial 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 Nebracin Bm works

Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10.

Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers.

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

Nebracin Bm dosage

Apply sparingly to the affected area 2 to 3 times daily until an improvement occurs.

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

Burning, itching, irritation, dryness, folliculitis, hypertrychosis acneiform eruptions, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliariamay be reported.

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

Chronic high doses of glucocorticoids can lead to the development of cataracts, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment.

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

Avoid long-term therapy particularly in infant & children; the treated area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. Avoid contact with eyes.

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

Increased hyperglycaemia and hypokalaemia with thiazide diuretics. Increased incidence of peptic ulcer or GI bleeding with concurrent NSAIDs admin. Response to anticoagulants altered. Dose of antidiabetics and antihypertensives needs to be increased. Decreases serum concentration of salicylates and antimuscarinic agents.

Potentially Fatal: Reduced efficacy with concurrent use of carbamazepine, phenytoin, primidone, barbiturates and rifampicin. Enhanced effect in women taking oestrogens or oral contraceptives.

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

In a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s).

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

Elimination Route

The absorption and potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent.

There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent.

It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects.

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

In a study that included Indian women of reproductive age, the half-life following a single intramuscular dose of betamethasone phosphate was 10.2 ± 2.5 hours.

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

Clearance

In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour.

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

Elimination Route

Corticosteroids are eliminated predominantly in the urine.

Tobramycin is primarily excreted unchanged in the urine.

Pregnancy & Breastfeeding use

There are no adequate and well controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids and should not be used extensively for a prolonged period. Caution should be excercised when topical corticosteroids are administered in nursing women.

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

Betamethasone is contraindicated in patients with a history of hypersensitivity to any of the components of the preparation. Betamethasone Eye/Ear/Nasal Drops is contraindicated in Herpes simplex virus infection of the eye; known sensitivity or allergy to any ingredient; red eye due to unknown causes; viral or fungal infections in the treatment area; tuberculosis, glaucoma etc.

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

Long-term intensive topical use may lead to systemic effects

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

Protect from light. Do not freeze. Store between 15 °C and 30 °C.

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.

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