The format of this insert was determined by the Ministry of Health and his content was checked and

approved by the Ministry of Health. November 2007

DIPROSPAN* Sterile Aqueous Suspension

Brand of betamethasone dipropionate and betamethasone sodium phosphate. FOR INTRAMUSCULAR, INTRA-ARTICULAR, PERI-ARTICULAR, INTRABURSAL, INTRADERMAL, INTRALESIONAL, AND SOFT TISSUE INJECTION DESCRIPTION DIPROSPAN Suspension is a sterile aqueous injectable suspension of betamethasone dipropionate and betamethasone sodium phosphate. Each ml of DIPROSPAN Suspension contains 5 mg of betamethasone as dipropionate and 2 mg of betamethasone as sodium phosphate in a sterile buffered vehicle. ACTION DIPROSPAN Sterile Aqueous Suspension provides a combination of highly soluble and very slightly soluble esters of betamethasone that produce anti-inflammatory, antirheumatic and anti-allergic effects. Prompt therapeutic activity is achieved by the soluble ester, betamethasone sodium phosphate, which is quickly absorbed after injection. Sustained activity is provided by betamethasone dipropionate, which is only slightly soluble and becomes a repository for slow absorption, thereby controlling symptoms over a prolonged period. The small crystal size of betamethasone dipropionate permits the use of a fine- gauge needle (up to 26 g) for intradermal and intralesional administration. INDICATIONS AND USAGE DIPROSPAN Sterile Aqueous Suspension is indicated for the treatment of acute and chronic corticosteroid-responsive disorders such as the following conditions: Musculoskeletal and Soft Tissue Conditions: Rheumatoid arthritis, osteoarthritis, bursitis, ankylosing spondylitis, epicondylitis, radiculitis, coccydynia, torticollis, sciatica, lumbago, ganglion cyst, exostosis, fasciitis. Allergic Conditions: Chronic bronchial asthma (including adjunctive therapy for status asthmaticus), hay fever, angioneurotic edema, allergic bronchitis, seasonal or perennial allergic rhinitis, drug reactions, serum sickness, insect bites. Dermatologic Conditions: Atopic dermatitis (nummular eczema), neurodermatitis (circumscribed lichen simplex), necrobiosis lipoidica diabeticorum, alopecia areata, discoid lupus erythematosus, psoriasis, keloids, pemphigus, dermatitis herpetiformis, urticaria, hypertrophic lichen planus, contact dermatitis, severe solar dermatitis, cystic acne. Collagen Diseases: Disseminated lupus erythematosus, scleroderma, dermatomyositis, polyarteritis nodosa. Neoplastic Diseases: 1 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.docThe format of this insert was
determined by the Ministry of Health and his content was checked and approved by the Ministry of Health. November 2007

For palliative management of leukemias and lymphomas in adults; acute leukemia of childhood. Other Conditions: Adrenogenital syndrome, ulcerative colitis, regional ileitis, sprue, podiatric conditions (bursitis under heloma durum, hallux rigidus, digiti quinti varus), disorders requiring subconjunctival injection, corticosteroid-responsive blood dyscrasias, nephritis and nephrotic syndrome. Primary or secondary adrenocortical insufficiency may be treated with DIPROSPAN Sterile

Aqueous Suspension but should be supplemented with mineralocorticoids. DIPROSPAN Sterile Aqueous Suspension is recommended for (1) intramuscular injection in conditions responsive to systemic corticosteroids; (2) injection directly into the affected soft tissues where indicated; (3) intra-articular and peri-articular injection in arthritis; (4) intralesional injection in various dermatologic conditions; (5) local injection in certain inflammatory and cystic disorders of the foot and soft tissue. DOSAGE AND ADMINISTRATION: DOSING REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE SPECIFIC DISEASE, THE SEVERITY OF THE CONDITION AND THE RESPONSE OF THE PATIENT. The initial dose should be maintained or adjusted until a satisfactory response is observed. If a satisfactory clinical response does not occur after a reasonable period of time, treatment with DIPROSPAN Suspension should be discontinued and other appropriate therapy initiated. Systemic Administration: For systemic therapy, treatment is initiated with 1 to 2 ml in most conditions and repeated as necessary. Administration is by deep intramuscular (IM) injection in the gluteal region. Dosage and frequency of administration will depend on the severity of the patients condition and the therapeutic response. In a severe illness, such as lupus erythematosus or status asthmaticus which has been resolved by appropriate life-saving procedures, 2 ml might be required initially. A wide variety of dermatologic conditions respond to IM injections of corticosteroids. An IM injection of 1 ml, repeated according to the response of the condition, has been found to be effective. In respiratory tract disorders, onset of relief of symptoms has occurred within a few hours after IM injection of DIPROSPAN Suspension. Effective control of symptoms with 1 to 2 ml is obtained in bronchial asthma, hay fever, allergic bronchitis and allergic rhinitis. In the treatment of acute or chronic bursitis, excellent results are obtained with 1 to 2 ml IM injection of DIPROSPAN Suspension, repeated as necessary. Local Administration: Concomitant use of local anesthetic is rarely necessary. If coadministration of a local anesthetic is desired, DIPROSPAN Suspension may be mixed (in the syringe) with 1% or 2% procaine hydrochloride or lidocaine, using formulations which do not contain parabens. Similar local anesthetics may also be used. Anesthetics containing methylparaben, 2 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.doc
The format of this insert was determined by the Ministry of Health and his content was checked and approved by the Ministry of Health. November 2007

propylparaben, phenol, etc. should be avoided. The required dose of DIPROSPAN Suspension is first withdrawn into the syringe. The local anesthetic is then drawn in, and the syringe is shaken briefly. In acute subdeltoid, subacromial, olecranon, and prepatellar bursitis, an intrabursal injection of 1 to 2 ml of DIPROSPAN Suspension may relieve pain and restore full range of movement within a few hours. Chronic bursitis may be treated with reduced dosage once acute symptoms are controlled. In acute tenosynovitis, tendinitis, and peritendinitis, one injection of DIPROSPAN Suspension should alleviate the condition. In chronic forms of these conditions, it may be necessary to repeat the injections as the patients condition requires. Following 0.5 to 2 ml intra-articular administration of DIPROSPAN Suspension, relief of pain, soreness, and stiffness associated with rheumatoid arthritis and osteoarthritis may be experienced within two to four hours. Duration of relief, which varies widely in both diseases, is four or more weeks in the majority of cases. An intra-articular injection of DIPROSPAN

Suspension is well tolerated in the joint and peri-articular tissues. Recommended doses for intra-articular injection are: large joints (knee, hip, shoulder), 1 2 ml; medium joints (elbow, wrist, ankle), 0.5 1 ml; small joints (foot, hand, chest), 0.25 0.5 ml. Dermatologic conditions may respond to intralesional administration of DIPROSPAN Suspension. An intradermal dosage of 0.2 ml/cm2 of DIPROSPAN Suspension evenly injected with a tuberculin syringe and a 26-gauge needle is recommended. The total amount of DIPROSPAN Suspension injected at all sites each week should not exceed 1 ml. DIPROSPAN Suspension may be used effectively in disorders of the foot that are responsive to corticosteroids. Bursitis under heloma durum may be controlled with two successive injections of 0.25 ml each. In some conditions such as hallux rigidus, digiti quinti varus and acute gouty arthritis, onset of relief may be rapid. A tuberculin syringe with a 25-gauge needle is suitable for most injections. Recommended doses at intervals of approximately one week: bursitis under heloma durum or molle, 0.25 0.5 ml; bursitis under calcaneal spur, 0.5 ml; bursitis over hallux rigidus, 0.5 ml; bursitis over digiti quinti varus, 0.5 ml; synovial cyst, 0.25 0.5 ml; Mortons neuralgia (metatarsalgia), 0.25 0.5 ml; tenosynovitis, 0.5 ml; periostitis of cuboid, 0.5 ml; acute gouty arthritis, 0.5 1 ml. After a favorable response is obtained, the proper maintenance dosage should be determined by decreasing the initial dose in small decrements at appropriate time intervals until the lowest dose which will maintain an adequate clinical response is determined. Exposure of the patient to stressful situations unrelated to the existing disease may necessitate an increased dose of DIPROSPAN Suspension. If the drug is to be discontinued after long-term therapy, the dose should be decreased gradually. DRUG INTERACTIONS Concurrent use of phenobarbital, rifampin, phenytoin or ephedrine may enhance corticosteroid metabolism, thus reducing therapeutic effects. Excessive corticosteroid effects may occur in patients receiving both a corticosteroid and an estrogen. Concurrent use of corticosteroids with potassium-depleting diuretics may enhance hypokalemia. Concurrent use of corticosteroids with cardiac glycosides may enhance the possibility of 3 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.doc
The format of this insert was determined by the Ministry of Health and his content was checked and approved by the Ministry of Health. November 2007

arrhythmias or digitalis toxicity associated with hypokalemia. Corticosteroids may enhance the potassium depletion caused by amphotericin B. Concurrent use of corticosteroids with coumarin-type anticoagulants may increase or decrease the anticoagulant effects, possibly requiring adjustment in dosage. Combined effects of nonsteroidal anti-inflammatory drugs or alcohol with glucocorticoids may result in an increased occurrence or increased severity of gastrointestinal ulceration. Corticosteroids may decrease blood salicylate concentrations. When corticosteroids are given to diabetics, dosage adjustments of the antidiabetic drug may be necessary. Concomitant glucocorticoid therapy may inhibit the response to somatotropin. DRUG/LABORATORY TEST INTERACTIONS Corticosteroids may affect the nitroblue tetrazolium test for bacterial infection and produce false-negative results. ADVERSE REACTIONS Adverse reactions of DIPROSPAN Suspension can usually be reversed or minimized by a reduction in dosage; this is generally preferable to withdrawal of drug treatment. Although the incidence of adverse reactions to DIPROSPAN Suspension has been low, the possible occurrence of the known side effects with corticosteroid use should be considered: fluid and

electrolyte, musculoskeletal, gastrointestinal, dermatologic, neurologic, endocrine, ophthalmic, metabolic and psychiatric disturbances. Adverse reactions relate both to dose and to duration of therapy. Adverse reactions related to parenteral corticosteroid therapy include: rare instances of blindness associated with intralesional therapy around the face and head; hyperpigmentation or hypopigmentation; subcutaneous and cutaneous atrophy; sterile abscess; post-injection flare (following intra-articular use); Charcot-like arthropathy. CONTRA-INDICATIONS As with other corticosteroids, DIPROSPAN Suspension is contra-indicated in patients with systemic fungal infections, in patients hypersensitive to betamethasone dipropionate, betamethasone sodium phosphate, other corticosteroids, or to any component of this product. DIPROSPAN Suspension is not to be administered intramuscularly to patients with idiopathic thrombocytopenic purpura. PRECAUTIONS DIPROSPAN Suspension is not for intravenous or subcutaneous use. Strict aseptic technique is mandatory in use of DIPROSPAN Suspension. Dosage adjustments may be required for remissions or exacerbations of the disease process, the patients individual response to therapy and exposure of the patient to stress, e.g. serious infection, surgery or injury. Following cessation of long-term or high-dose corticosteroid therapy, monitoring may be necessary for up to one year. Drug-induced secondary adrenocortical insufficiency may result from too rapid corticosteroid withdrawal and may be minimized by gradual dose reduction. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When dose reduction is possible, the reduction should be gradual. 4 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.doc
The format of this insert was determined by the Ministry of Health and his content was checked and approved by the Ministry of Health. November 2007

DIPROSPAN Suspension contains two betamethasone esters, one of which, betamethasone sodium phosphate, disappears rapidly from the injection site. The potential for systemic effect produced by this soluble portion of DIPROSPAN Suspension should therefore be taken into account by the physician when using this preparation. Corticosteroid effect is enhanced in patients with hypothyroidism and in those with cirrhosis. Cautious use of corticosteroids is advised in patients with ocular herpes simplex. Corticosteroids may aggravate existing emotional instability or psychotic tendencies. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Corticosteroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Since complications of glucocorticoid treatment are dependent on dose size and duration of treatment, a risk/benefit decision must be made in each individual case. Corticosteroids may mask signs of infection. Prolonged corticosteroid use may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Elevation of blood pressure, and salt and fluid retention and increased potassium excretion are less likely to occur with the synthetic derivatives, except when used in large doses. While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients receiving corticosteroids, especially high doses. Corticosteroid therapy in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis, close observation is necessary. During prolonged corticosteroid therapy, these

patients should receive chemoprophylaxis. Growth and development of infants and children on prolonged corticosteroid therapy should be followed carefully. Corticosteroid therapy may alter the motility and number of spermatozoa. Because rare instances of anaphylactoid reactions have occurred with parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy. With long-term corticosteroid therapy, transfer from parenteral to oral administration should be considered after weighing the potential benefits and risks. Intra-articular administration may produce systemic as well as local effects. This should be considered in patients being treated concomitantly with oral or parenteral corticosteroids. Examination of joint fluid is necessary to exclude a septic process. Local injection into a previously infected joint is to be avoided. Increase in pain and local swelling, further restriction of joint motion, fever and malaise are suggestive of septic arthritis. If sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Corticosteroids should not be injected into unstable joints, infected areas or intervertebral spaces. Repeated injections into osteoarthritic joints may increase joint destruction. Avoid injecting corticosteroids directly into tendons. Following intra-articular corticosteroid therapy, care should be taken by the patient to avoid overuse of the joint in which symptomatic benefit has been obtained. 5 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.doc
The format of this insert was determined by the Ministry of Health and his content was checked and approved by the Ministry of Health. November 2007

Intramuscular corticosteroid administration should be given deep into large muscle masses to avoid local tissue atrophy. Soft-tissue and intralesional corticosteroid injections may produce systemic and local effects. The use of corticosteroids during pregnancy, in nursing mothers, or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and fetus or infant. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Results from a single, multicenter, randomized, controlled study with another corticosteroid, methylprednisolone hemisuccinate, showed an increase of early mortality (at 2 weeks) and late mortality (at 6 months) in patients with cranial trauma who had received methylprednisolone, compared to placebo. The causes of mortality in the methylprednisolone group have not been established. Of note, this study excluded patients who were felt to have a clear indication for corticosteroids. HOW SUPPLIED DIPROSPAN Injection, 1 ml ampule and 2 ml ampule. Shake well before using. Store between 2 and 25 C. Protect from freezing. Manufacturer: License holder: Schering-Plough Labo N.V .,Belgium A wholly owned subsidiary of Schering-Plough Corp./ U.S.A. Schering Plough Israel A.G. P.O.Box 7102, Petah-Tiqva 49170, Israel 6 C:\Documents and Settings\efrat.nisan\Local Settings\Temporary Internet Files\OLK242\2007-11-25 (2007-09-16-PHY-mortality)-clean.doc

DIPROSPAN

Generic Name: PPD Drug Classification: Prescription Drug: Indications:

Betamethasone dipropionate, Betamethasone Na phosphate Hormones and Related Drugs/ Adrenocorticosteroid Hormones Yes Allergic, dermatologic, musculoskeletal & soft tissue conditions, collagen & neoplastic diseases, adrenogenital, nephritis & nephrotic syndrome. For dosage information of prescription medicine, please consult with your doctor. Systemic fungal infections, hypersensitivity, IM administration in idiopathic thrombocytopenic purpura, immunization procedures. Hypothyroidism, herpes simplex, psychotic tendencies, ASA, ulcerative colitis, TB, pregnancy & lactation. Cardiac glycosides, K+-depleting diuretics, ASA, phenobarbital, phenytoin, rifampicin, ephedrine, somatotropin. Fluid & electrolyte disturbances, muscle weakness, loss muscle mass, tendon rupture, peptic ulcer, impaired wound healing, skin atrophy, convulsions, menstrual irregularities, anaphylactoid reactions, negative nitrogen balance. Amp 1 mL (P453.31). Vial 2 mL (P911.56). Essex Pharmaceuticals, Inc. Zuellig Pharma Corp.

Recommended Dosage: Contraindication: Precaution: Drug Interaction: Side Effect:

Preparations: Manufacturer: Distributor: