Quadriline

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.

Blepharitis, blepharoconjunctivitis, conjunctivitis, dacryocystitis, keratitis, keratoconjunctivitis, acute meibomianitis, and corneal ulcers caused by susceptible organisms. Otorrhea associated with external otitis, chronic suppurative otitis media or subacute purulent otitis media; or postoperative otorrhea, such as that following fenestration, mastoidectomy or tympanoplasty.

Gentamicin cream is used for the topical treatment of the primary and secondary bacterial infections of the skin caused by the organisms sensitive to Gentamicin. Gentamicin may clear infections that have not responded to other topical antibiotics.

Tolfenamic acid is used specifically for relieving the pain of migraine headaches and also recommended for use as an analgesic in post-operative pain, and fever.

Quadriline 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 Conjunctivitis, Bacterial Infections, Bacterial Peritonitis, Bacterial dacryocystitis, Blepharoconjunctivitis, Central Nervous System Infections, Conjunctivitis allergic, Corneal infection, Dermatitis infected, Ecthyma, Eczematous dermatitis infected, Folliculitis, Furunculosis, Gram-negative enteric bacilli neonatal sepsis, Impetigo contagious, Inflammation, Keratitis bacterial, Keratoconjunctivitis, Meibomianitis, Meningitis, Bacterial, Ocular Inflammation, Pustular Psoriasis (PP), Pustular acne, Pyoderma Gangrenosum, Seborrheic Dermatitis, Septicemia gram-negative, Skin Infections, Skin Infections, Bacterial, Skin and Subcutaneous Tissue Bacterial Infections, Sycosis barbae, Bacterial blepharitis, Bacterial corneal ulcers, Bacterial dermatoses, Complicated Bacterial Urinary Tract Infections, Complicated Respiratory tract infection bacterial, Corticosteroid-responsive dermatoses, Ocular bacterial infections, Severe Endocarditis enterococcal, Severe Infection Pseudomonas aeruginosa, Severe Staphylococcal infection

How Quadriline 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.

There are 3 key phases of aminoglycoside entry into cells. The first “ionic binding phase” occurs when polycationic aminoglycosides bind electrostatically to negatively charged components of bacterial cell membranes including with lipopolysaccharides and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids within the cell membrane of Gram-positive bacteria. This binding results in displacement of divalent cations and increased membrane permeability, allowing for aminoglycoside entry. The second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the proton-motive force and allows a limited amount of aminoglycoside access to its primary intracellular target - the bacterial 30S ribosome. This ultimately results in the mistranslation of proteins and disruption of the cytoplasmic membrane.[A233320] Finally, in the “energy-dependent phase II” stage, concentration-dependent bacterial killing is observed. Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and protein mistranslation and synthesis inhibition is amplified. The necessity of oxygen-dependent active transport explains why aminoglycosides are ineffective against anaerobic bacteria. Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modeling support this two-mechanism model. Inhibition of protein synthesis is a key component of aminoglycoside efficacy. 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.[A232324, A232329] Overall, aminoglycoside binding has several negative effects including inhibition of translation, initiation, 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.[A232329, A232339] Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation.[A232344] Mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.

Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors. As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid.

Dosage

Quadriline dosage

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

Eye: 1-2 drops instilled in affected eye up to 6 times a day or more frequently if required (severe infections may require 1-2 drops every 15-20 minutes initially, reducing the frequency of instillation gradually as the infection is controlled).

Ear: The area should be cleaned and 2-3 drops should be instilled every 3-4 times a day and at night, or more frequently if required.

A small amount of Gentamicin should be applied gently to the affected areas three to four times daily. The area treated may be covered with a gauze dressing if desired. Before applying the medication the affected area should be properly cleaned.

Acute migraine attacks:

• Adult: 200 mg when 1st symptoms appear may be repeated once after 1-2 hr.
• Renal impairment: Dose adjustments may be needed. Severe: Avoid.

Mild to moderate pain:

• Children: A pediatric dosage regimen has not yet been established.
• Adult: 100-200 mg tid.
• Renal impairment: Dose adjustments may be needed. Severe: Avoid. It should be taken with food. Take water/ or immediately after meals.

Preclinical safety data: The therapeutic index for Tolfenamic acid is high, and gastrointestinal ulceration and kidney changes have only been seen with oral doses approximately 6-10 times the maximum therapeutic dose recommended for tolfenamic acid.

Special Precautions: Asthma, bronchospasm, bleeding disorders, cardiovascular diseases, history of peptic ulceration, hypertension, patients with infections, liver, cardiac, or renal function impairment. Increase water intake or dose reduction to reduce dysuria. CHF; elderly; lactation.

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.

In patients with dermatoses treated with gentamicin, irritation (erythema and pruritus) had been reported in small number of cases. Itching, redness, swelling or other signs of irritation may develop. With the eye/ear drop bacterial and corneal ulcer have developed during treatment with gentamicin. Most frequently reported adverse reactions are ocular burning and irritation upon drug instillation, non specific conjunctivitis, conjunctival epithelial defects, and conjunctival hyperemia.

Gentamicin cream is well tolerated. There has been no evidence of irritation and sensitization after using Gentamicin cream.

Dysuria especially in males; diarrhoea, nausea, epigastric pain, vomiting, dyspepsia, erythema, headache. Tremor, euphoria, fatigue, pulmonary infiltration, & haematuria. Potentially Fatal: Blood dyscrasias, toxic hepatitis.

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.

As with other aminoglycosides, nephrotoxicity and ototoxicity are associated with gentamicin. Signs of nephrotoxicity include an increase in plasma creatinine and urea, while signs of ototoxicity include issues with balance, nausea, tinnitus, and hearing loss. It is important to note that aminoglycoside-induced nephrotoxicity is typically reversible, while ototoxicity is more likely to be permanent. The risk of both toxicities increases with long-term gentamicin therapy. Gentamicin is considered to be more vestibulotoxic than cochleotoxic compared to other aminoglycosides. Unfortunately, gentamicin-related ototoxicity does not correlate with cumulative dosing, peak and trough levels, or dosing schedule. The unpredictability of ototoxicity supports close monitoring of the patient throughout treatment. In cases of toxicity or overdose, the medication should be discontinued immediately; hemodialysis may be initiated to lower gentamicin serum concentrations.

Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis.

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.

If these occurs or if irritation, sensitization develops, treatment with gentamicin should be discontinued and appropriate therapy instituted. Gentamicin ear/eye drops is not for injection. It should never be injected subconjunctivally, nor it should be directly introduced into the anterior chamber of the eye.

Use of topical antibiotics occasionally cause overgrowth of nonsusceptible organisms including fungi. If this occurs or if irritation, sensitisation or super infection develops, treatment with Gentamicin should be discontinued and appropriate therapy should be instituted.

As is the case with other NSAIDs, tolfenamic acid should be used with caution in patients with a history of gastrointestinal ulceration, or impaired liver or kidney function.

The therapeutic index for tolfenamic acid is high, and gastrointestinal ulceration and kidney changes have only been seen with oral doses approximately 6-10 times the maximum therapeutic dose recommended for tolfenamic acid. In human volunteers, tolfenamic acid did not affect renal function.

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.

None has been reported so far with topical and Eye/Ear drops.

The rate of absorption of Tolfenamic acid increases with metoclopramide and magnesium hydroxide and decreases with aluminium hydroxide. Risk of bleeding with anticoagulants and other NSAIDs increases when use with Tolfenamic acid. It decreases antihypertensive response to loop diuretics, β-blockers and ACE inhibitors. Co-administration increases plasma concentrations of lithium, methotrexate and cardiac glycosides. It also increases the risk of nephrotoxicity with ACE inhibitors, ciclosporin, tacrolimus or diuretics.

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).

The volume of distribution is of 1.79-3.2 L/kg. When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg.

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.

Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h. It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively. The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml. The bioavailability of tolfenamic acid is around 75%.

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.

One study assessing the pharmacokinetics of gentamicin in children and adults reported a mean half-life of 75 minutes after intravenous administration. The mean half-life associated with intramuscular administration was about 29 minutes longer. Fever and anemia may result in a shorter half-life although dose adjustments are not usually necessary. Severe burns are also associated with a shorter half-life and may result in lower gentamicin serum concentrations.

The estimated half-life of tolfenamic acid is 8.01-13.50 hours. When tested intravenously, the reported half-life was 6.1h.

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.

The renal clearance of gentamicin is comparable to individual creatinine clearance.

The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg. When tested intravenously, the reported clearance rate was 72.4 ml.h/kg.

Elimination Route

Corticosteroids are eliminated predominantly in the urine.

Gentamicin is excreted primarily by the kidneys. In patients with normal renal function, 70% or more of an initial gentamicin dose can be recovered in the urine within 24 hours. Excretion of gentamicin is significantly reduced in patients with renal impairment.

Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates. Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose.

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.

Consideration should be given the possibility of foetal ototoxicity when gentamicin is applied topically to large denuded areas of skin. For Gentamicin Eye/Ear Drops safety profile in pregnancy is not yet established and should be administered when considered essential.

Pregnancy: This medicine is not recommended for use during pregnancy unless considered essential by your doctor. This is particularly important in the first and third trimesters. Not to be given during the third trimester of pregnancy.

Lactation: In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

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.

Gentamicin is contraindicated in individuals with a history of sensitivity reaction to any of its components. Use of topical Gentamicin may occasionally allow overgrowth of nonsusceptible organisms, including fungi.

Not to be used in-

• Children and adolescents under 18 years of age
• People with an active peptic ulcer or bleeding in the gut
• Severe heart failure, severe kidney failure, Severe liver failure
• People taking other NSAIDs, including COX-2 inhibitors

This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor if you have previously experienced such an allergy. If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately

Acute Overdose

Long-term intensive topical use may lead to systemic effects

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, excitation, coma, drowsiness, dizziness, tinnitus, fainting, and convulsions. In cases of significant poisoning acute renal failure and liver damage are possible. Patients should be treated symptomatically as required.

Storage Condition

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

To avoid contamination, do not touch the tip of the container to the eye, eyelid or any surface.

Store in a cool and dry place. Keep out of reach of children

Innovators Monograph

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