Kedex

Uses

Endocrine disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance). Acute adrenocortical insufficiency, pre operatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful. Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer

Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: post-traumatic osteoarthritis, synovitis of osteoarthritis, rheumatoid arthritis including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), acute and sub-acute bursitis, epicondylitis, acute nonspecific tenosynovitis, acute gouty arthritis, psoriatic arthritis, ankylosing spondylitis.

Collagen diseases: During an exacerbation or as maintenance therapy in selected cases of Systemic lupus erythematosus and acute rheumatic carditis

Dermatologic diseases: Pemphigus,Severe erythema multiforme (Stevens-Johnson syndrome), Exfoliative dermatitis, Bullous dermatitis herpetiformis, Severe seborrheic dermatitis,Severe psoriasis, Mycosis fungoides

Allergic states: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness, seasonal or perennial allergic rhinitis, drug hypersensitivity reactions, urticarial transfusion reactions, acute non-infectious laryngeal edema (epinephrine is the drug of first choice)

Ophthalmic diseases: Severe acute and chronic allergic and inflammatory processes involving the eye, such as: herpes zoster ophthalmicus, iritis, iridocyclitis, chorioretinitis, diffuse posterior uveitis and choroiditis, optic neuritis, sympathetic ophthalmia, anterior segment inflammation, allergic conjunctivitis, keratitis, allergic corneal marginal ulcers.

Gastrointestinal diseases: To tide the patient over a critical period of the disease in ulcerative colitis (systemic therapy), regional enteritis (systemic therapy) Respiratory diseases Symptomatic sarcoidosis, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate anti-tuberculous chemotherapy, Loeffler's syndrome not manageable by other means, aspiration pneumonitis.

Hematologic disorders: Acquired (autoimmune) hemolytic anemia, idiopathic thrombocytopenic purpura in adults (I.V. only: I.M administration is contraused), secondary thrombocytopenia in adults, erythroblastopenia (RBC anemia), congenital (erythroid) hypoplasticanemia

Neoplastic diseases: For palliative management of leukemias and lymphomas in adults, acute leukemia of childhood.

Edematous states: To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy,Trichinosis with neurologic or myocardial involvement

Cerebral Edema: Cerebral Edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Use in cerebral edema is not a substitute for careful neurosurgical evaluation and definitive management such as neurosurgery or other specific therapy.May also be useful in cystic tumors of an aponeurosis or tendon (ganglia).

Ketorolac injections and tablets are used for the short-term management of moderate to severe acute post-operative pain.

Kedex is also used to associated treatment for these conditions: Acne Rosacea, Acute Gouty Arthritis, Acute Otitis Externa, Acute Otitis Media, Adrenal cortical hypofunctions, Adrenocortical Hyperfunction, Alopecia Areata (AA), Ankylosing Spondylitis (AS), Anterior Segment Inflammation, Aspiration Pneumonitis, Asthma, Atopic Dermatitis (AD), Berylliosis, Bullous dermatitis herpetiformis, Bursitis, Chorioretinitis, Choroiditis, Congenital Adrenal Hyperplasia (CAH), Congenital Hypoplastic Anemia, Conjunctivitis, Conjunctivitis allergic, Corneal Inflammation, Cushing's Syndrome, Dermatitis, Dermatitis exfoliative generalised, Dermatitis, Contact, Diabetic Macular Edema (DME), Discoid Lupus Erythematosus (DLE), Drug hypersensitivity reaction, Edema of the cerebrum, Epicondylitis, Episcleritis, Erythroblastopenia, Eye Infections, Eye allergy, Eye swelling, Glaucoma, Hypercalcemia, Idiopathic Thrombocytopenic Purpura, Infection, Inflammation, Inflammation of the External Auditory Canal, Intraocular Inflammation, Iridocyclitis, Iritis, Keloid Scars, Leukemia, Acute, Lichen Planus (LP), Lichen simplex chronicus, Loeffler's syndrome, Macular Edema, Malignant Lymphomas, Middle ear inflammation, Mucosal Inflammation of the eye, Multiple Myeloma (MM), Muscle Inflammation caused by Cataract Surgery of the eye, Mycosis Fungoides (MF), Necrobiosis lipoidica diabeticorum, Noninfectious Posterior Uveitis, Ocular Infections, Irritations and Inflammations, Ocular Inflammation, Ocular Inflammation and Pain, Ocular Irritation, Ophthalmia, Sympathetic, Optic Neuritis, Otitis Externa, Pemphigus, Perennial Allergic Rhinitis (PAR), Phlyctenular keratoconjunctivitis, Post-traumatic Osteoarthritis, Postoperative Infections of the eyes caused by susceptible bacteria, Regional Enteritis, Rheumatoid Arthritis, Rheumatoid Arthritis, Juvenile, Sarcoidosis, Scleritis, Seasonal Allergic Conjunctivitis, Seasonal Allergic Rhinitis, Secondary thrombocytopenia, Serum Sickness, Severe Seborrheic Dermatitis, Stevens-Johnson Syndrome, Synovitis, Systemic Lupus Erythematosus (SLE), Trichinosis, Tuberculosis (TB), Tuberculosis Meningitis, Ulcerative Colitis, Uveitis, Vernal Keratoconjunctivitis, Acquired immune hemolytic anemia, Acute nonspecific tenosynovitis, Acute rheumatic carditis, Corticosteroid-responsive dermatoses, Ear infection-not otherwise specified caused by susceptible bacteria, Granuloma annulare lesions, Non-suppurative Thyroiditis, Ocular bacterial infections, Severe Psoriasis, Steroid-responsive inflammation of the eye, Varicella-zoster virus acute retinal necrosis, Watery itchy eyesAcute Migraine, Cystoid Macular Edema, Eye Pain, Inflammation, Ocular Itching, Pseudophakic Cystoid Macular Edema, Acute Pericarditis, Acute, moderate Pain, Acute, severe Pain, Chronic aphakic cystoid macular edema, Intraoperative miosis, Postoperative ocular pain

How Kedex works

The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days.

Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.

Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels.

Ketorolac inhibits key pathways in prostaglandin synthesis which is crucial to it's mechanism of action. Although ketorolac is non-selective and inhibits both COX-1 and COX-2 enzymes, it's clinical efficacy is derived from it's COX-2 inhibition. The COX-2 enzyme is inducible and is responsible for converting arachidonic acid to prostaglandins that mediate inflammation and pain. By blocking this pathway, ketorolac achieves analgesia and reduces inflammation. Ketorolac is administered as a racemic mixture; however, the "S" enantiomer is largely responsible for it's pharmacological activity.

Dosage

Kedex dosage

Intraarticular-

Inflammatory joint diseases:

• Adult: 0.8-4 mg depending on the size of the affected joint. For soft-tissue inj, 2-6 mg may be used. May repeat inj every 3-5 days to every 2-3 wk.

Intravenous-

Prophylaxis of nausea and vomiting associated with cytotoxic therapy:

• Adult: Prevention: 10-20 mg 15-30 minutes before admin of chemotherapy on each treatment day. For continuous infusion regimen: 10 mg every 12 hr on each treatment day. For midly emetogenic regimen: 4 mg every 4-6 hr.

Unresponsive shock:

• Adult: As phosphate: Initially, 40 mg or 1-6 mg/kg as a single IV inj, may repeat every 2-6 hr. Continue high-dose treatment only until patient's condition has stabilised and not to be continued beyond 48-72 hr.

Bacterial meningitis:

• Adult: 0.15 mg/kg 4 times daily, to be given 10-20 min before or with the 1st dose of anti-infective treatment. Treatment should be given for the first 2-4 days of the anti-infective treatment.
• Child: As phosphate: 2 mth-18 yr: 150 mcg/kg every 6 hr for 4 days, starting before or with 1st dose of antibacterial treatment.

Cerebral oedema caused by malignancy:

• Adult: As phosphate: 10 mg IV followed by 4 mg IM every 6 hr until response is achieved, usually after 12-24 hr. May reduce dosage after 2-4 days then gradually discontinued over 5-7 days. In severe cases, an initial dose of 50 mg IV may be given on day 1, with 8 mg every 2 hr, reduced gradually over 7-13 days. Maintenance dose: 2 mg 2-3 times daily.
• Child: As phosphate: 35 kg: Initially 25 mg, then 4 mg every 2 hr for 3 days, then 4 mg every 4 hr for 1 day, then 4 mg every 6 hr for 4 days, then decrease by 2 mg daily. Doses are given via IV inj.

Oral-

Anti-inflammatory:

• Adult: 0.75-9 mg daily in 2-4 divided doses; may also be given via IM/IV admin.
• Child: 1 mth-18 yr: 10-100 mcg/kg daily in 1-2 divided doses via oral admin, adjusted according to response; up to 300 micrograms/kg daily may be used in emergency situations.

Screening test for Cushing's syndrome:

• Adult: 0.5 mg every 6 hr for 48 hr after determining baseline 24-hr urinary 17-hydroxycorticosteroid (17-OHCS) concentrations. During the second 24 hr of dexamethasone admin, urine is collected and analysed for 17-OHCS. Alternatively, after a baseline plasma cortisol determination, 1 mg may be given at 11 pm and plasma cortisol determined at 8 am the next morning. Plasma cortisol and urinary output of 17-OHCS are depressed after dexamethasone admin in normal individuals but remain at basal levels in patients with Cushing's syndrome.

Acute exacerbations in multiple sclerosis:

• Adult: 30 mg daily for 1 wk followed by 4-12 mg daily for 1 mth.
• Child: 1 mth-12 yr: 100-400 mcg/kg daily in 1-2 divided doses; 12-18 yr: Initially 0.5-24 mg daily. Max. 24 mg daily.

Ketorolac Tablet-

Ketorolac Tablet isrecommended for short-term use only (up to 7 days) and are not recommended for chronic use. 10 mg every 4 to 6 hours as required. Doses exceeding 40 mg/day are not recommended. For patients receiving parenteral Ketorolac tromethamine, and who are converted to Ketorolac tromethamine oral tablets, the total combined daily dose should not exceed 90 mg (60 mg for the elderly, renally impaired patients and patients less than 50 kg) and the oral component should not exceed 40 mg on the day the change of formulation is made. Patients should be converted to oral treatment as soon as possible.

Ketorolac injection-

Ketorolac injection may be used as a single or multiple doses, on a regular or when necessary schedule for the management of moderately severe, acute pain that requires analgesia at the opioid level, usually in a postoperative setting. When administering Ketorolac injection, the IV bolus must be given over no less than 15 seconds. The IM administration should be given slowly and deeply into the muscle. The analgesic effect begins within 30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM. Duration of analgesic effect is usually 4 to 6 hours. Single-Dose Treatment: The following regimen should be limited to single administration use only.

IM Dosing (Adult):

• Patients <65 years of age: One dose of 60 mg.
• Patients >65 years of age, renally impaired and/or less than 50 kg of body weight: One dose of 30 mg.

IV Dosing (Adult):

• Patients <65 years of age: One dose of 30 mg.
• Patients >65 years of age, renally impaired and/or less than 50 kg of body weight: One dose of 15 mg.

IV or IM Dosing (2 to 16 years of age):

• IM Dosing: One dose of 1 mg/kg up to a maximum of 30 mg.
• IV Dosing: One dose of 0.5 mg/kg up to a maximum of 15 mg.

Multiple-Dose Treatment (IV or IM):

• Patients <65 years of age: The recommended dose is 30 mg Ketorolac injection every 6 hours. The maximum daily dose should not exceed 120 mg. Patients >65 years of age, renally impaired patients and patients less than 50 kg: The recommended dose is 15 mg Ketorolac injection every 6 hours. The maximum daily dose for these populations should not exceed 60 mg. For breakthrough pain, do not increase the dose or the frequency of Ketorolac Tromethamine.
• Conversion from Parenteral to Oral Therapy: Ketorolac tablets may be used either as monotherapy or as follow-on therapy to parenteral Ketorolac. When Ketorolac tablets are used as a follow-on therapy to parenteral Ketorolac, the total combined daily dose of ketorolac (oral + parenteral) should not exceed 120 mg in younger adult patients or 60 mg in elderly patients on the day the change of formulation is made. On subsequent days, oral dosing should not exceed the recommended daily maximum of 40 mg. Ketorolac IM should be replaced by Ketorolac tablet as soon as feasible. The total duration of combined parenteral andoral treatment should not exceed 5 days.

Ketorolac Nasal spray-

• Adults weighing 50 kg or more: 31.5 mg or 2 spray in each nostril every 6 to 8 hours. Your doctor may adjust your dose if needed. However, the dose is not more than 126 mg (a total of 8 sprays) per day.
• Older adults and adults weighing less than 50 kg:15.75 mg or 1 spray in only one nostril every 6 to 8 hours. However, the dose is usually not more than 63 mg (a total of 4 sprays) per day.
• Children: Use and dose must be determined by your doctor.

Side Effects

Dexamethasone is generally well tolerated in standard low doses, Nausea, vomiting, increased appetite, and obesity may occur. Higher doses may result behavioral personality changes. Following adverse reactions have been associate with prolonged systemic glucocorticoid therapy, endocrine & metabolic disturbances, fluid & electrolyte disturbances, musculo-skeletal effects like osteoporosis etc; GI effects like ulcer, bleeding, perforation; Opthelmic effects like Glaucoma, increased intraocular pressure etc; immunosuppressive effects like increased susceptibility to infection etc.

Commonly occurring side-effects are nausea, vomiting, gastro intestinal bleeding,melaena, peptic ulcer, pancreatitis, anxiety, drowsiness, dizziness, headache, hallucinations,excessive thirst, inability to concentrate, insomnia, malaise, fatigue, pruritus, urticaria, skin photosensitivity, Lyell's syndrome, Stevens-Johnson syndrome, flushing, bradycardia, hypertension, palpitations, chest pain, infertility in female, dyspnoea, asthma, pulmonary oedema, fever, injection site pain.

Toxicity

The oral LD₅₀ in female mice was 6.5g/kg and 794mg/kg via the intravenous route.

Overdoses are not expected with otic formulations. Chronic high doses of glucocorticoids can lead to the development of cataract, 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.

The rate of adverse effects increases with higher doses of ketorolac. The most frequently observed adverse effects in patients occurring with an incidence of greater than 10% include: abdominal pain, dyspepsia, nausea, and headaches. Most adverse effects associated with short term use are mild in nature, related to the gastrointestinal tract and nervous system, and occur in roughly 39% of patients. Common symptoms of ketorolac overdose include nausea, vomiting, epigastric pain, gastrointestinal bleeding, lethargy and drowsiness. More rare symptoms of overdose include acute renal failure, hypertension, respiratory depression, and coma.

Ketorolac is classified as Pregnancy Category C since there is a lack of evidence demonstrating safety in pregnant women. NSAIDs including ketorolac increase the risk of premature closure of the fetal ductus arteriosus in the 3rd trimester; therefore, beginning at 30 weeks gestation, pregnant women should avoid ketorolac.

Ketorolac has been shown to be excreted in breast milk, and although available data has not demonstrated any adverse effects in nursing infants, practitioners should proceed with caution when suggesting ketorolac for nursing mothers. The benefits should outweigh the risks and the mother should be counselled to monitor the infant closely and to contact the infant's healthcare provider should any adverse effects arise.

Women who are trying to conceive are not advised to take ketorolac since it's effect on prostaglandin synthesis may impair fertility.

Precaution

The lowest possible dose of corticosteroids should be used to control the conditions under treatment. Dexamethasone should be used with caution in patient with cardiomyopathy, heart failure, hypertension, or renal insufficiency, drug induced secondary adrenocortical insufficiency, peptic ulcer, diverticulitis, intestinal anastomosis, ulcerative colitis, osteoporosis, & latent tuberculosis etc.

Patients over the age of 65 years may be at a greater risk of experiencing adverse events than younger patients. Ketorolac tromethamine can cause gastro-intestinal irritation, ulcers or bleeding in patients with or without a history of previous symptoms. Bronchospasm may be precipitated in patients with a history of asthma. Since ketorolac tromethamine and its metabolites are excreted primarily by the kidney, patients with moderate to severe impairment of renal function (serum creatinine greater than 160 micromol/l) should not receive. Fluid retention and oedema have been reported with the use of Ketorolac tromethamine.

Interaction

Drug interaction can be occurred with following drugs:Diuretics, cardiac glycosides, antidiabetics, NSAIDs, anticoagulants, antacids etc. Besides, if patients undergo long-term therapy of glucororticoids with concomitant salicylates, any reduction in glucocorticoid dosage should be made with caution, since salicylate intoxication has been reported in such cases.

Ketorolac tromethamine should not be used with other NSAIDs or in patients receiving aspirin because of the potential for additive side effects. Care should be taken when administering Ketorolac tromethamine with anti-coag ulants since co-administration may cause an enhanced anti-coagulant effect. Ketorolac tromethamine and other non-steroidal anti-inflammatory drugs can reduce the anti hypertensive effect of beta-blockers and may increase the risk of renal impairment when administered concurrently with ACE inhibitors, particularly in volume depleted patients. Caution is advised when methotrexate is administered concurrently, since some prostaglandin synthesis inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity. Probenecid should not be administered concurrently with ketorolac tromethamine because of increases in ketorolac plasma level and half-life.

Volume of Distribution

A 1.5mg oral dose of dexamethasone has a volume of distribution of 51.0L, while a 3mg intramuscular dose has a volume of distribution of 96.0L.

The apparent volume of distribution of ketorolac in healthy human subjects is 0.25 L/kg or less.

Elimination Route

Absorption via the intramuscular route is slower than via the intravenous route. A 3mg intramuscular dose reaches a C_max of 34.6±6.0ng/mL with a T_max of 2.0±1.2h and an AUC of 113±38ng*h/mL. A 1.5mg oral dose reaches a C_max of 13.9±6.8ng/mL with a T_max of 2.0±0.5h and an AUC of 331±50ng*h/mL. Oral dexamethasone is approximately 70-78% bioavailable in healthy subjects.

Ketorolac is rapidly, and completely absorbed after oral administration with a bioavailability of 80% after oral administration. Cmax is attained 20-60 minutes after administration, and after intramuscular administration, the area under the plasma concentration-time curve (AUC) is proportional to the dose administered.

After intramuscular administration, ketorolac demonstrates a time to maximal plasma concentration (tmax) of approximately 45-50 minutes, and a tmax of 30-40 minutes after oral administration. The rate of absorption may be reduced by food; however, the extent of absorption remains unaffected.

Half Life

The mean terminal half life of a 20mg oral tablet is 4 hours. A 1.5mg oral dose of dexamethasone has a half life of 6.6±4.3h, while a 3mg intramuscular dose has a half life of 4.2±1.2h.

Ketorolac tromethamine is administered as a racemic mixture, therefore the half-life of each enantiomer must be considered. The half life of the S-enantiomer is ~2.5 hours, while the half life of the R-enantiomer is ~5 hours. Based on this data, the S enantiomer is cleared about twice as fast as the R enantiomer.

Clearance

A 20mg oral tablet has a clearance of 15.7L/h. A 1.5mg oral dose of dexamethasone has a clearance of 15.6±4.9L/h while a 3.0mg intramuscular dose has a clearance of 9.9±1.4L/h.

The plasma clearance of ketorolac is 0.021 to 0.037 L/h/kg. Further, studies have illustrated that clearance of oral, IM and IV doses of ketorolac are comparable which suggests linear kinetics. It should also be noted that clearance in children is about double the clearance found in adults.

Elimination Route

Corticosteroids are generally eliminated predominantly in the urine. However, dexamethasone is 15

Ketorolac is primarily renally eliminated and approximately 92% of the dose can be recovered in the urine with 60% of this proportion recovered unchanged, and 40% recovered as metabolites. In addition 6% of a single dose is eliminated in the feces.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies. Glucocorticoids appear in breast milk, Mothers taking high dosages of corticosteroids should be advised not to breast-feed.

Safety in human pregnancy has not been established. Ketorolac has been detected in human milk at low levels. Ketorolac is therefore contraindicated during pregnancy, labour or delivery, or in mothers who are breast feeding.

Contraindication

In case of adrenal insufficiency, no absolute contraindications are applicable. In the treatment of non endocrine diseases where pharmacological doses are more likely to be used, the contraindications have to be considered carefully.

Relative contraindications include the followings: patient with Cushing’s syndrome, Osteoporosis, Diabetes mellitus, renal insufficiency, gastrointestinal ulcers, systemic fungal infection & acute infection.

Ketorolac Tromethamine is contraindicated in patients with known hypersensitivity to NSAIDs and any of the components of Ketorolac Tromethamine. Moreover, the patient with the history of asthma, nasal polyp, angioedema, peptic ulcer and bleeding, bleeding disorders are contraindicated for this drug.

Acute Overdose

Overdose is unlikely; however, treatment of overdose is by supportive and symptomatic therapy.

Symptoms: Abdominal pain, nausea, vomiting, hyperventilation, peptic ulceration, erosive gastritis and renal dysfunction.

Management: Symptomatic and supportive treatment. Consider gastric lavage or admin of activated charcoal within 1 hr of ingestion.

Storage Condition

Store at 15-30° C.

Tablet & injection should be store in a cool & dry place, protect from light & moisture.

Innovators Monograph

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