SOLU CORTEF 100 MG

,ה/דבכנ ת/חקור ,ה/אפור

ינוי

2019

ןוכדע לע ךעידוהל וננוצרב אפורל םינולעב

לש

Solu cortef 100 mg

ו

-

Solu cortef 500

.הרמחה העמשמ השגדה ,טסקט תקיחמ ועמשמ הצוח וק ,טסקט תפסות ועמשמ יתחת וק

:קזוחו בכרה

Hydrocortisone (as sodium succinate) 100mg or 500mg

:היוותה

Solu-Cortef is indicated to treat any condition in which IM or IV corticosteroid treatment

is required such as: allergic states, dermatologic diseases, endocrine disorders,

gastrointestinal diseases, hematologic disorders, neoplastic diseases, nervous system

disorders, ophthalmic diseases, renal diseases, respiratory diseases, rheumatic

disorders, certain medical emergencies.

:אפורל ןולעב םיירקיעה םינוכדעה ןלהל

PRECAUTIONS

Other:

Pheochromocytoma crisis, which can be fatal, has been reported after administration of

systemic corticosteroids. In patients with suspected pheochromocytoma, consider the

risk of pheochromocytoma crisis prior to administering corticosteroids.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

adequate

studies

have

been

conducted

animals

determine

whether

corticosteroids have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some

patients.

Corticosteroids have been shown to impair fertility in male rats.

ADVERSE REACTIONS

The following adverse reactions have been reported with SOLU-CORTEF or other

corticosteroids:

Blood and lymphatic system disorders: Leukocytosis.

Neurologic/Psychiatric: …epidural lipomatosis.

Ophthalmic: Central serous chorioretinopathy…

םייונישה

מה םישגדו

עקרב

בוהצ

םיווהמ

רמחה

ומכ

ןכ

ועצוב

םייוניש

םיפסונ

םיללוכה

תפסות

עדימ

תטמשה

עדימ

ינוכדעו

חסונ

םניאש

םיווהמ

הרמחה

םינולעה אפורל

םינונימהמ דחא לכ רובע דרשמל וחלשנ םינכדועמה

:תואירבה דרשמ רתאבש תופורתה רגאמב םמוסרפ ךרוצל תואירבה

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

רזייפ תרבחל תונפל ןתינ ספדומ אלמ ןולע תלבקל ,ןיפוליחל יא ףא יפ ,מ"עב לארשי הקיטבצמרפ רקנש

.ד.ת ,

12133

,חותיפ הילצרה

46725

,הכרבב

השבק יליג

הנוממ תחקור

רזייפ יא ףא יפ מ"עב לארשי הקיטבצמרפ

רקנש 'חר

.ד.ת ,

12133

לארשי ,חותיפ הילצרה

46725

:לט

972-9-9700500

:סקפ

972-9-9700501

רזייפ יא ףא יפ מ"עב לארשי הקיטבצמרפ

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

SOLU-CORTEF

®

500

NAME OF THE MEDICINAL PRODUCT

SOLU-CORTEF

QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient in SOLU-CORTEF

is Hydrocortisone sodium succinate

equivalent to 500 mg Hydrocortisone.

For the full list of excipients, see section "

DESCRIPTION

" below.

PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

NOT FOR USE IN NEONATES

CONTAINS BENZYL ALCOHOL

For Intravenous or Intramuscular Administration

DESCRIPTION

SOLU-CORTEF

Sterile Powder is an anti-inflammatory glucocorticoid that contains

hydrocortisone sodium succinate as the active ingredient. SOLU-CORTEF

Sterile

Powder is available in several packages for intravenous or intramuscular administration.

ACT-O-VIAL™ System (Single-Dose Vial)

500 mg ACT-O-VIAL

Each 4 mL contains (when mixed):

Hydrocortisone sodium succinate equiv. to 500 mg Hydrocortisone

Monobasic sodium phosphate monohydrate 4.6 mg

Dibasic sodium phosphate dried 44 mgBenzyl alcohol added as preservative 36 mg

Sodium hydroxide q.s.

Water for injections q.s.

When necessary, the pH was adjusted with sodium hydroxide so that the pH of the

reconstituted solution is within the USP specified range of 7 to 8.

The chemical name for hydrocortisone sodium succinate is pregn-4-ene-3,20-dione,21-

(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)- and its molecular

weight is 484.52.

The structural formula is represented below:

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic

amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in

acetone, and insoluble in chloroform.

CLINICAL PHARMACOLOGY

Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are

readily absorbed from the gastrointestinal tract.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-

retaining properties, are used as replacement therapy in adrenocortical deficiency states.

Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders

of many organ systems.

Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions

as hydrocortisone. When given parenterally and in equimolar quantities, the two

compounds are equivalent in biologic activity. The highly water-soluble sodium

succinate ester of hydrocortisone permits the immediate intravenous administration of

high doses of hydrocortisone in a small volume of diluent and is particularly useful where

high blood levels of hydrocortisone are required rapidly. Following the intravenous

injection of hydrocortisone sodium succinate, demonstrable effects are evident within one

hour and persist for a variable period.

Excretion of the administered dose is nearly complete within 12 hours. Thus, if

constantly high blood levels are required, injections should be made every 4 to 6 hours.

This preparation is also rapidly absorbed when administered intramuscularly and is

excreted in a pattern similar to that observed after intravenous injection.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify

the body's immune response to diverse stimuli.

INDICATIONS AND USAGE

When oral therapy is not feasible, and the strength, dosage form, and route of

administration of the drug reasonably lend the preparation to the treatment of the

condition, the

intravenous or intramuscular use

of SOLU-CORTEF

Sterile Powder is

indicated as follows:

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Allergic states:

Control of severe or incapacitating allergic conditions intractable to

adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis,

drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness,

transfusion reactions, acute noninfectious laryngeal edema (epinephrine is the drug of

first choice).

Dermatologic diseases

: Bullous dermatitis herpetiformis, exfoliative erythroderma,

mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson

syndrome), severe psoriasis, severe seborrheic dermatitis.

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 (hydrocortisone or cortisone is

the drug of choice; mineralocorticoid supplementation may be necessary, particularly

when synthetic analogues are used), preoperatively, 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, hypercalcemia associated with

cancer, nonsuppurative thyroiditis.

Gastrointestinal diseases:

To tide the patient over a critical period of the disease in

regional enteritis (systemic therapy)

and ulcerative colitis (systemic therapy).

Hematologic disorders:

Acquired (autoimmune) hemolytic anemia, congenital

(erythroid) hypoplastic anemia (Diamond Blackfan anemia), idiopathic thrombocytopenic

purpura in adults (intravenous administration only; intramuscular administration is

contraindicated), pure red cell aplasia, select cases of secondary thrombocytopenia.

Miscellaneous:

Trichinosis with neurologic or myocardial involvement, tuberculous

meningitis with subarachnoid block or impending block when used concurrently with

appropriate antituberculous chemotherapy.

Neoplastic diseases:

For the palliative management of leukemias and lymphomas in

adults and acute leukemia of childhood.

Nervous System:

Acute exacerbations of multiple sclerosis; cerebral edema associated

with primary or metastatic brain tumor, or craniotomy.

Ophthalmic diseases:

Severe acute and chronic allergic and inflammatory processes

involving the eye unresponsive to topical corticosteroids, such as: herpes zoster

ophthalmicus, iritis, iridocyclitis, chorioretinitis, diffuse posterior uveitis and choroiditis,

optic neuritis sympathetic ophthalmia, anterior segment inflammation, allergic

conjunctivitis, allergic corneal marginal ulcers, keratitis.

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Renal diseases:

To induce diuresis or remission of proteinuria in idiopathic nephrotic

syndrome, or that due to lupus erythematosus.

Respiratory diseases:

Berylliosis, fulminating or disseminated pulmonary tuberculosis

when used concurrently with appropriate antituberculous chemotherapy, idiopathic

eosinophilic pneumonias, aspiration pneumonitis, Loeffler's syndrome not manageable by

other means, symptomatic sarcoidosis.

Rheumatic disorders:

As adjunctive therapy for short-term administration (to tide the

patient over an acute episode or exacerbation) in acute and subacute bursitis; acute gouty

arthritis; acute nonspecific tenosynovitis; ankylosing spondylitis; epicondylitis; post-

traumatic osteoarthritis; synovitis of osteoarthritis; psoriatic arthritis; rheumatoid arthritis,

including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance

therapy).

For the treatment of temporal arteritis.

Collagen Diseases

: During an exacerbation or as maintenance therapy in selected cases

of acute rheumatic carditis; systemic dermatomyositis (polymyositis); systemic lupus

erythematosus.

Medical emergencies:

SOLU-CORTEF

Sterile Powder is indicated in the treatment of

1) shock secondary to adrenocortical insufficiency or shock unresponsive to conventional

therapy when adrenocortical insufficiency may be present, and 2) acute allergic disorders

(status asthmaticus, anaphylactic reactions, insect stings, etc.) following epinephrine.

Although there are no well controlled (double-blind, placebo) clinical trials, data from

experimental animal models indicate that corticosteroids may be useful in hemorrhagic,

traumatic and surgical shock in which standard therapy (e.g. fluid replacement, etc.) has

not been effective.

CONTRAINDICATIONS

SOLU-CORTEF

Sterile Powder is contraindicated in systemic fungal infections and

patients with known hypersensitivity to the product and its constituents (see

DESCRIPTION).

Intramuscular corticosteroid preparations are contraindicated for idiopathic

thrombocytopenic purpura.

SOLU-CORTEF

500 Sterile Powder is contraindicated for use in premature infants

because the formulation contains benzyl alcohol (see

WARNINGS

PRECAUTIONS

: Pediatric Use).

SOLU-CORTEF

Sterile Powder is contraindicated for intrathecal administration.

Reports of severe medical events have been associated with this route of administration.

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

WARNINGS

Serious Neurologic Adverse Reactions with Epidural Administration

Serious neurologic events, some resulting in death, have been reported with epidural

injection of corticosteroids. Specific events reported include, but are not limited to, spinal

cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious

neurologic events have been reported with and without use of fluoroscopy. The safety

and effectiveness of epidural administration of corticosteroids have not been established,

and corticosteroids are not approved for this use.

General:

This product contains benzyl alcohol which is potentially toxic when administered locally

to neural tissue. Exposure to excessive amounts of benzyl alcohol has been associated

with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased

incidence of kernicterus, particularly in small preterm infants. There have been rare

reports of deaths, primarily in preterm infants, associated with exposure to excessive

amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually

considered negligible compared to that received in flush solutions containing benzyl

alcohol. Administration of high dosages of medications containing this preservative must

take into account the total amount of benzyl alcohol administered. The amount of benzyl

alcohol at which toxicity may occur is not known. If the patient requires more than the

recommended dosages or other medications containing this preservative, the practitioner

must consider the daily metabolic load of benzyl alcohol from these combined sources

(see

WARNINGS

PRECAUTIONS: Pediatric Use

Injection of SOLU-CORTEF

may result in dermal and/or subdermal changes forming

depressions in the skin at the injection site. In order to minimize the incidence of dermal

and subdermal atrophy, care must be exercised not to exceed recommended doses in

injections. Injection into the deltoid muscle should be avoided because of a high

incidence of subcutaneous atrophy.

Rare instances of anaphylactoid reactions have occurred in patients receiving

corticosteroid therapy (see

ADVERSE REACTIONS

Increased dosage of rapidly acting corticosteroids is indicated in patients on

corticosteroid therapy subjected to any unusual stress before, during, and after the

stressful situation.

Results from one multicenter, randomized, placebo-controlled study with

methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at

2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were

determined not to have other clear indications for corticosteroid treatment. High doses of

systemic corticosteroids, including SOLU-CORTEF

, should not be used for the

treatment of traumatic brain injury.

Cardio-renal:

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and

water retention, and increased excretion of potassium. These effects are less likely to

occur with the synthetic derivatives except when used in large doses. Dietary salt

restriction and potassium supplementation may be necessary. All corticosteroids increase

calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left

ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with

corticosteroids should be used with great caution in these patients.

Endocrine:

Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and

hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids

can produce reversible HPA axis suppression with the potential for glucocorticosteroid

insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical

insufficiency may be minimized by gradual reduction of dosage. This type of relative

insufficiency may persist for months after discontinuation of therapy; therefore, in any

situation of stress occurring during that period, hormone therapy should be reinstituted.

Infections

General:

Patients who are on corticosteroids are more susceptible to infections than are healthy

individuals. There may be decreased resistance and inability to localize infection when

corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan

or helminthic) in any location of the body may be associated with the use of

corticosteroids alone or in combination with other immunosuppressive agents.

These infections may be mild, but can be severe and at times fatal. With increasing doses

of corticosteroids, the rate of occurrence of infectious complications increases.

Corticosteroids may also mask some signs of current infection. Do not use intra-

articularly, intrabursally or for intratendinous administration for

local

effect in the

presence of acute local infection.

Fungal infections:

Corticosteroids may exacerbate systemic fungal infections and therefore should not be

used in the presence of such infections unless they are needed to control drug reactions.

There have been cases reported in which concomitant use of amphotericin B and

hydrocortisone was followed by cardiac enlargement and congestive heart failure (see

CONTRAINDICATIONS

PRECAUTIONS

Drug Interactions

, Amphotericin B

injection and potassium-depleting agents).

Special pathogens:

Latent disease may be activated or there may be an exacerbation of intercurrent infections

due to pathogens, including those caused by

Amoeba, Candida, Cryptococcus,

Mycobacterium, Nocardia, Pneumocystis,

Toxoplasma

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating

corticosteroid therapy in any patient who has spent time in the tropics or in any patient

with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or

suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-

induced immunosuppression may lead to Strongyloides hyperinfection and dissemination

with widespread larval migration, often accompanied by severe enterocolitis and

potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria. There is currently no evidence of

benefit from steroids in this condition.

Tuberculosis:

The use of corticosteroids in active tuberculosis should be restricted to those cases of

fulminating or disseminated tuberculosis in which the corticosteroid is used for the

management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity,

close observation is necessary as reactivation of the disease may occur. During prolonged

corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination:

Administration of live or live-attenuated vaccines is contraindicated in patients

receiving immunosuppressive doses of corticosteroids.

Killed or inactivated vaccines

may be administered. However, the response to such vaccines cannot be predicted.

Immunization procedures may be undertaken in patients who are receiving

corticosteroids as replacement therapy (e.g., for Addison’s disease).

Viral infections:

Chicken pox and measles can have a more serious or even fatal course in pediatric and

adult patients on corticosteroids. In pediatric and adult patients who have not had these

diseases, particular care should be taken to avoid exposure. The contribution of the

underlying disease and/or prior corticosteroid treatment to the risk is not known. If

exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may

be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be

indicated. (See the respective package inserts for complete VZIG and IG prescribing

information.) If chicken pox develops, treatment with antiviral agents should be

considered.

Neurologic:

Reports of severe medical events have been associated with the intrathecal route of

administration (see

ADVERSE REACTIONS

, Neurologic/Psychiatric).

Ophthalmic:

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with

possible damage to the optic nerves, and may enhance the establishment of secondary

ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not

recommended in the treatment of optic neuritis and may lead to an increase in the risk of

new episodes. Corticosteroids should be used cautiously in patients with ocular herpes

simplex because of corneal perforation. Corticosteroids should not be used in active

ocular herpes simplex.

PRECAUTIONS

General:

The lowest possible dose of corticosteroid should be used to control the condition under

treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the

dose and the duration of treatment, a risk/benefit decision must be made in each

individual case as to dose and duration of treatment and as to whether daily or

intermittent therapy should be used.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy,

most often for chronic conditions. Discontinuation of corticosteroids may result in

clinical improvement.

Cardio-renal:

As sodium retention with resultant edema and potassium loss may occur in patients

receiving corticosteroids, these agents should be used with caution in patients with

congestive heart failure, hypertension, or renal insufficiency.

Endocrine:

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual

reduction of dosage. This type of relative insufficiency may persist for months after

discontinuation of therapy; therefore, in any situation of stress occurring during that

period, hormone therapy should be reinstituted. Metabolic clearance of corticosteroids is

decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in

thyroid status of the patient may necessitate adjustment in dosage.

Gastrointestinal:

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh

intestinal anastomoses, and non-specific ulcerative colitis, since they may increase the

risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in

patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect due to decreased metabolism of corticosteroids in patients

with cirrhosis.

Musculoskeletal:

Corticosteroids decrease bone formation and increase bone resorption both through their

effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

inhibition of osteoblast function. This, together with a decrease in the protein matrix of

the bone secondary to an increase in protein catabolism, and reduced sex hormone

production, may lead to inhibition of bone growth in pediatric patients and the

development of osteoporosis at any age. Special consideration should be given to patients

at increased risk of osteoporosis (i.e., postmenopausal women) before initiating

corticosteroid therapy.

Local injection of a steroid into a previously infected site is not usually recommended.

Neurologic-psychiatric:

Although controlled clinical trials have shown corticosteroids to be effective in speeding

the resolution of acute exacerbations of multiple sclerosis, they do not show that

corticosteroids affect the ultimate outcome or natural history of the disease. The studies

do show that relatively high doses of corticosteroids are necessary to demonstrate a

significant effect. (See

DOSAGE AND ADMINISTRATION

An acute myopathy has been observed with the use of high doses of corticosteroids, most

often occurring in patients with disorders of neuromuscular transmission (e.g.,

myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular

blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve

ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine

kinase may occur. Clinical improvement or recovery after stopping corticosteroids may

require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria,

insomnia, mood swings, personality changes, and severe depression to frank psychotic

manifestations. Also, existing emotional instability or psychotic tendencies may be

aggravated by corticosteroids.

Ophthalmic:

Intraocular pressure may become elevated in some individuals. If steroid therapy is

continued for more than 6 weeks, intraocular pressure should be monitored.

Other:

Pheochromocytoma crisis, which can be fatal, has been reported after administration of

systemic corticosteroids. In patients with suspected pheochromocytoma, consider the risk

of pheochromocytoma crisis prior to administering corticosteroids.

Information for Patients:

Patients should be warned not to discontinue the use of corticosteroids abruptly or

without medical supervision, to advise any medical attendants that they are taking

corticosteroids, and to seek medical advice at once should they develop fever or other

signs of infection.

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or

measles. Patients should also be advised that if they are exposed, medical advice should

be sought without delay.

Drug Interactions:

Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced

adrenal suppression.

Amphotericin B injection and potassium-depleting agents: When corticosteroids are

administered concomitantly with potassium-depleting agents (e.g., amphotericin B,

diuretics), patients should be observed closely for development of hypokalemia. There

have been cases reported in which concomitant use of amphotericin B and hydrocortisone

was followed by cardiac enlargement and congestive heart failure.

Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in

corticosteroid clearance (see

PRECAUTIONS

Drug Interactions

, Hepatic Enzyme

Inhibitors).

Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids

may produce severe weakness in patients with myasthenia gravis. If possible,

anticholinesterase agents should be withdrawn at least 24 hours before initiating

corticosteroid therapy.

Anticoagulants, oral: Coadministration of corticosteroids and warfarin usually results in

inhibition of response to warfarin, although there have been some conflicting reports.

Therefore, coagulation indices should be monitored frequently to maintain the desired

anticoagulant effect.

Antidiabetics: Because corticosteroids may increase blood glucose concentrations,

dosage adjustments of antidiabetic agents may be required.

Antitubercular drugs: Serum concentrations of isoniazid may be decreased.

Cholestyramine: Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur

when the two are used concurrently. Convulsions have been reported with this concurrent

use.

Digitalis glycosides: Patients on digitalis glycosides may be at increased risk of

arrhythmias due to hypokalemia.

Estrogens, including oral contraceptives: Estrogens may decrease the hepatic metabolism

of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin): Drugs

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

that induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of

corticosteroids and require that the dosage of the corticosteroid be increased.

Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as

erythromycin and troleandomycin): Drugs that inhibit cytochrome P450 3A4 have the

potential to result in increased plasma concentrations of corticosteroids.

Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism

of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side

effects.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other

nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of

gastrointestinal side effects. Aspirin should be used cautiously in conjunction with

corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased

with concurrent use of corticosteroids.

Skin tests: Corticosteroids may suppress reactions to skin tests.

Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished

response to toxoids and live or inactivated vaccines due to inhibition of antibody

response. Corticosteroids may also potentiate the replication of some organisms

contained in live attenuated vaccines. Routine administration of vaccines or toxoids

should be deferred until corticosteroid therapy is discontinued if possible (see

WARNINGS

Infections

Vaccination

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No adequate studies have been conducted in animals to determine whether corticosteroids

have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Corticosteroids have been shown to impair fertility in male rats.

Pregnancy: Teratogenic Effects:

Corticosteroids have been shown to be teratogenic in many species when given in doses

equivalent to the human dose. Animal studies in which corticosteroids have been given to

pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the

offspring. There are no adequate and well-controlled studies in pregnant women.

Corticosteroids should be used during pregnancy only if the potential benefit justifies the

potential risk to the fetus. Infants born to mothers who have received corticosteroids

during pregnancy should be carefully observed for signs of hypoadrenalism.

This product contains benzyl alcohol as a preservative.

Benzyl alcohol can cross the placenta (see

PRECAUTIONS: Pediatric use

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Nursing Mothers:

Systemically administered corticosteroids appear in human milk and could suppress

growth, interfere with endogenous corticosteroid production, or cause other untoward

effects. Because of the potential for serious adverse reactions in nursing infants from

corticosteroids, a decision should be made whether to continue nursing or discontinue the

drug, taking into account the importance of the drug to the mother.

Pediatric Use:

This product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of

this product, has been associated with serious adverse events and death, particularly in

pediatric patients. The “gasping syndrome”, (characterized by central nervous system

depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol

and its metabolites found in the blood and urine) has been associated with benzyl alcohol

dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms

may include gradual neurological deterioration, seizures, intracranial hemorrhage,

hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension,

bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this

product ordinarily deliver amounts of benzyl alcohol that are substantially lower than

those reported in association with the “gasping syndrome”, the minimum amount of

benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol

toxicity depends on the quantity administered and the hepatic capacity to detoxify the

chemical. Premature and low-birth-weight infants, as well as patients receiving high

dosages, may be more likely to develop toxicity. Practitioners administering this and

other medications containing benzyl alcohol should consider the combined daily

metabolic load of benzyl alcohol from all sources.

The efficacy and safety of corticosteroids in the pediatric population are based on the

well-established course of effect of corticosteroids, which is similar in pediatric and adult

populations. Published studies provide evidence of efficacy and safety in pediatric

patients for the treatment of nephrotic syndrome (>2 years of age) and aggressive

lymphomas and leukemias (>1 month of age). Other indications for pediatric use of

corticosteroids (e.g., severe asthma and wheezing) are based on adequate and well-

controlled trials conducted in adults, on the premises that the course of the diseases and

their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults

(see

ADVERSE REACTIONS

). Like adults, pediatric patients should be carefully

observed with frequent measurements of blood pressure, weight, height, intraocular

pressure, and clinical evaluation for the presence of infection, psychosocial disturbances,

thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are

treated with corticosteroids by any route, including systemically administered

corticosteroids, may experience a decrease in their growth velocity. This negative impact

of corticosteroids on growth has been observed at low systemic doses and in the absence

of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal

cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of

systemic corticosteroid exposure in pediatric patients than some commonly used tests of

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

HPA axis function. The linear growth of pediatric patients treated with corticosteroids

should be monitored, and the potential growth effects of prolonged treatment should be

weighed against clinical benefits obtained and the availability of treatment alternatives.

In order to minimize the potential growth effects of corticosteroids, pediatric patients

should be titrated to the lowest effective dose.

Geriatric Use:

Clinical studies did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported

clinical experience has not identified differences in responses between the elderly and

younger patients. In general, dose selection for an elderly patient should be cautious,

usually starting at the low end of the dosing range, reflecting the greater frequency of

decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug

therapy.

ADVERSE REACTIONS

The following adverse reactions have been reported with SOLU-CORTEF

or other

corticosteroids:

Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction,

anaphylaxis, angioedema.

Blood and lymphatic system disorders: Leukocytosis.

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement,

circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic

cardiomyopathy in premature infants, myocardial rupture following recent myocardial

infarction (see

WARNINGS

), pulmonary edema, syncope, tachycardia,

thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal

area, after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin,

ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation,

impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed

reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid

state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral

hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual

irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in

times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric

patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid

retention, hypokalemic alkalosis, potassium loss, sodium retention.

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal

administration), elevation in serum liver enzyme levels (usually reversible upon

discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with

possible perforation and hemorrhage, perforation of the small and large intestine

(particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like

arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of

long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon

rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria,

headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually

following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy,

paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis,

paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal

administration (see

WARNINGS

Neurologic

), epidural lipomatosis.

Ophthalmic: Central serous chorioretinopathy, exophthalmoses, glaucoma, increased

intraocular pressure, posterior subcapsular cataracts, rare instances of blindness

associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or

decreased motility and number of spermatozoa, injection site infections following non-

sterile administration (see

WARNINGS

), malaise, moon face, weight gain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMe

dic@moh.gov.il

OVERDOSAGE

Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic

overdosage in the face of severe disease requiring continuous steroid therapy, the dosage

of the corticosteroid may be reduced only temporarily, or alternate day treatment may be

introduced.

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

DOSAGE AND ADMINISTRATION

NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS:

Pediatric Use)

Because of possible physical incompatibilities, SOLU-CORTEF

should not be

diluted or mixed with other solutions.

Parenteral drug products should be inspected visually for particulate matter and

discoloration prior to administration, whenever solution and container permit.

This preparation may be administered by intravenous injection, by intravenous infusion,

or by intramuscular injection, the preferred method for initial emergency use being

intravenous injection. Following the initial emergency period, consideration should be

given to employing a longer acting injectable preparation or an oral preparation.

Therapy is initiated by administering SOLU-CORTEF

Sterile Powder intravenously

over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In

general, high dose corticosteroid therapy should be continued only until the patient’s

condition has stabilized, usually not beyond 48 to 72 hours. When high dose

hydrocortisone therapy must be continued beyond 48–72 hours, hypernatremia may

occur. Under such circumstances, it may be desirable to replace SOLU-CORTEF

with a

corticoid such as methylprednisolone sodium succinate which causes little or no sodium

retention.

The initial dose of SOLU-CORTEF

Sterile Powder is 100 mg to 500 mg, depending on

the specific disease entity being treated. However, in certain overwhelming, acute, life-

threatening situations, administration in dosages exceeding the usual dosages may be

justified and may be in multiples of the oral dosages.

This dose may be repeated at intervals of 2, 4, or 6 hours as indicated by the patient’s

response and clinical condition.

It Should Be Emphasized that Dosage Requirements Are Variable and Must Be

Individualized on the Basis of the Disease Under Treatment and the Response of the

Patient

. After a favorable response is noted, the proper maintenance dosage should be

determined by decreasing the initial drug dosage in small decrements at appropriate time

intervals until the lowest dosage that maintains an adequate clinical response is reached.

Situations that may make dosage adjustments necessary are changes in clinical status

secondary to remissions or exacerbations in the disease process, the patient’s individual

drug responsiveness, and the effect of patient exposure to stressful situations not directly

related to the disease entity under treatment. In this latter situation, it may be necessary to

increase the dosage of the corticosteroid for a period of time consistent with the patient’s

condition. If after long-term therapy the drug is to be stopped, it is recommended that it

be withdrawn gradually rather than abruptly.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 800 mg of

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

hydrocortisone for a week followed by 320 mg every other day for one month are

recommended (see

PRECAUTIONS

Neurologic-psychiatric

In pediatric patients, the initial dose of hydrocortisone may vary depending on the

specific disease entity being treated. The range of initial doses is 0.56 to 8 mg/kg/day in

three or four divided doses (20 to 240 mg/m

bsa/day). For the purpose of comparison, the

following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25

Triamcinolone, 4

Hydrocortisone, 20

Paramethasone, 2

Prednisolone, 5

Betamethasone, 0.75

Prednisone, 5

Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these

compounds. When these substances or their derivatives are injected intramuscularly or

into joint spaces, their relative properties may be greatly altered.

This product, like many other steroid formulations, is sensitive to heat. Therefore, it

should not be autoclaved when it is desirable to sterilize the exterior of the vial.

DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM

Press down on plastic activator to force diluent into the lower compartment.

Gently agitate to effect solution.

Remove plastic tab covering center of stopper.

Sterilize top of stopper with a suitable germicide.

Insert needle

squarely through center

of stopper until tip is just visible. Invert

vial and withdraw dose.

Further dilution is not necessary for intravenous or intramuscular injection. For

intravenous infusion,

first prepare solution as just described. The

500 mg

solution may

be added to 500 to 1000 mL of 5% dextrose in water (or isotonic saline solution or 5%

dextrose in isotonic saline solution if patient is not on sodium restriction). In cases where

administration of a small volume of fluid is desirable, 100 mg to 3000 mg of SOLU-

CORTEF

may be added to 50 mL of the above diluents. The resulting solutions are

stable for at least 4 hours and may be administered either directly or by IV piggyback.

When reconstituted as directed, pH of the solution ranges from 7 to 8 and the tonicity is

0.57 osmolar (Isotonic saline=0.28 osmolar).

Solu Cortef 500 mg LPD CC technical change 30 April 2020

2020-0059448

HOW SUPPLIED

500 mg ACT-O-VIAL (Single-Dose Vial)

SHELF LIFE

The expiry date of the product is indicated on the packaging materials.

STORAGE CONDITIONS

Store below 25°C.

After reconstitution, store solution at 25°C and protect from light.

Use solution only if it is clear.

Unused solution should be discarded after 12 hours.

MANUFACTURER

Pfizer Manufacturing Belgium NV/SA, Puurs, Belgium.

LICENSE HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.

LICENSE NUMBER

034-93-22552

Revised in April 2020