METHYLPREDNISOLONE tablet

METHYLPREDNISOLONE by

Drug Labeling and Warnings

METHYLPREDNISOLONE by is a Prescription medication manufactured, distributed, or labeled by Ingenus Pharmaceuticals, LLC, RiconPharma LLC, Nutra-Med Packaging Inc., Ingenus Pharmaceuticals NJ, LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DESCRIPTION

Methylprednisolone Tablets, USP contain methylprednisolone which is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. Methylprednisolone occurs as a white to practically white, odorless, crystalline powder. It is sparingly soluble in alcohol, in dioxane, and in methanol, slightly soluble in acetone, and in chloroform, and very slightly soluble in ether. It is practically insoluble in water.

The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6- methyl-, (6α,11β)- and the molecular weight is 374.48. The structural formula is represented below:

Each methylprednisolone tablet, USP for oral administration contains 4 mg of methylprednisolone, USP. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, lactose monohydrate, pregelatinized starch, microcrystalline cellulose and magnesium stearate.

ACTIONS

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 potent anti-inflammatory effects in disorders of many organ systems.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.

INDICATIONS AND USAGE

Methylprednisolone Tablets are indicated in the following conditions:

1.Endocrine Disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance).

Congenital adrenal hyperplasia

Nonsuppurative thyroiditis

Hypercalcemia associated with cancer

2.Rheumatic Disorders

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)

Ankylosing spondylitis

Acute and subacute bursitis

Synovitis of osteoarthritis

Acute nonspecific tenosynovitis

Post-traumatic osteoarthritis

Psoriatic arthritis

Epicondylitis

Acute gouty arthritis

3.Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of:

Systemic lupus erythematosus

Systemic dermatomyositis (polymyositis)

Acute rheumatic carditis

4.Dermatologic Diseases

Bullous dermatitis herpetiformis

Severe erythema multiforme

(Stevens-Johnson syndrome)

Severe seborrheic dermatitis

Exfoliative dermatitis

Mycosis fungoides

Pemphigus

Severe psoriasis

5.Allergic States

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment:

Seasonal or perennial allergic rhinitis

Drug hypersensitivity reactions

Serum sickness

Contact dermatitis

Bronchial asthma

Atopic dermatitis

6.Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as:

Allergic corneal marginal ulcers

Herpes zoster ophthalmicus

Anterior segment inflammation

Diffuse posterior uveitis and choroiditis

Sympathetic ophthalmia

Keratitis

Optic neuritis

Allergic conjunctivitis

Chorioretinitis

Iritis and iridocyclitis

7.Respiratory Diseases

Symptomatic sarcoidosis

Berylliosis

Loeffler's syndrome not manageable by other means

Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy

Aspiration pneumonitis

8.Hematologic Disorders

Idiopathic thrombocytopenic purpura in adults

Secondary thrombocytopenia in adults

Acquired (autoimmune) hemolytic anemia

Erythroblastopenia (RBC anemia)

Congenital (erythroid) hypoplastic anemia

9.Neoplastic Diseases

For palliative management of:

Leukemias and lymphomas in adults

Acute leukemia of childhood

10.Edematous States

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

11.Gastrointestinal Diseases

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

Ulcerative colitis

Regional enteritis

12.Nervous System

Acute exacerbations of multiple sclerosis

13.Miscellaneous

Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.

Trichinosis with neurologic or myocardial involvement.

CONTRAINDICATIONS

Systemic fungal infections and known hypersensitivity to components.

WARNINGS

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.

Corticosteroids may mask some signs of infection, and new infections may appear during their use. Infections with any pathogen including viral, bacterial, fungal, protozoan or helminthic infections, in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function.1

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.2 There may be decreased resistance and inability to localize infection when corticosteroids are used.

Prolonged 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 fungi or viruses.

Usage in pregnancy: Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism.

Average and large doses of hydrocortisone or cortisone 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.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered to patients receiving immunosuppressive doses of corticosteroids; however, the response to such vaccines may be diminished. Indicated immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids.

The use of Methylprednisolone Tablets 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.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal   course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.  If exposed, to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular 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 may be considered. 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.

PRECAUTIONS

General Precautions

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. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.

The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual.

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.

Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.

Steroids 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.

Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission.

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.)

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.

Drug Interactions

The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur.

Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of methylprednisolone and may require increases in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity.

Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia.

The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect.

Information for the Patient

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

ADVERSE REACTIONS

Fluid and Electrolyte Disturbances

• Sodium retention
• Congestive heart failure in susceptible patients
• Hypertension
• Fluid Retention
• Potassium Loss
• Hypokalemic alkalosis

Musculoskeletal

• Muscle weakness
• Loss of muscle mass
• Steroid myopathy
• Osteoporosis
• Tendon rupture, particularly of the Achilles tendon
• Vertebral compression fractures
• Aseptic necrosis of femoral and humeral heads
• Pathologic fracture of long bones

Gastrointestinal

• Peptic ulcer with possible perforation and hemorrhage
• Pancreatitis
• Abdominal distention
• Ulcerative esophagitis

Increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST, SGOT), and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome  and are  reversible upon  discontinuation.

Dermatologic

• Impaired wound healing
• Petechiae and ecchymoses
• May suppress reactions to skin tests
• Thin fragile skin
• Facial erythema
• Increased sweating

Neurological

• Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment
• Convulsions
• Vertigo
• Headache

Endocrine

• Development of Cushingoid state
• suppression of growth in children
• Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness
• Menstrual irregularities
• Decreased carbohydrate tolerance
• Manifestations of latent diabetes mellitus
• Increased requirements of insulin or oral hypoglycemic agents in diabetics

Ophthalmic

• Posterior subcapsular cataracts
• Increased intraocular pressure
• Glaucoma
• Exophthalmos

Metabolic

• Negative nitrogen balance due to protein catabolism

The following additional reactions have been reported following oral as well as parenteral therapy: Urticaria and other allergic, anaphylactic or hypersensitivity reactions.

"To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch"

DOSAGE AND ADMINISTRATION

The initial dosage of Methylprednisolone Tablets may vary from 4 mg to 48 mg of methylprednisolone per day depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, Methylprednisolone Tablets should be discontinued and the patient transferred to other appropriate therapy.

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 which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which 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 methylprednisolone tablets 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.

Multiple Sclerosis: In treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).

ADT® (Alternate Day Therapy): Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for reestablishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.

A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low   point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenal cortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenal cortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenal cortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.

During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every six hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenal cortical suppression for two   or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenal cortical suppression for 1¼ to 1½ days following a single dose) and thus are recommended for alternate day therapy.

The following should be kept in mind when considering alternate day therapy:

1. Basic principles and indications for corticosteroid therapy should apply. The benefits of ADT should not encourage the indiscriminate use of steroids.
2. ADT is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.
3. In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with ADT. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to ADT and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable.
4. Because of the advantages of ADT, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (eg, patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on ADT may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.
5. As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (eg, dexamethasone and betamethasone).
6. The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time f maximal activity (am).
7. In using ADT it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of ADT will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed.
8. In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be reinstituted.
9. Although many of the undesirable features of corticosteroid therapy can be minimized by ADT, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.

HOW SUPPLIED

Methylprednisolone tablets, USP are supplied as follows:

4 mg tablets: White to off-white, elliptical shaped, flat faced bevel edged tablets debossed with "ING" above "615" on one side and double scoreline (quadrisect) on the other side, available in bottles of 100 and unit of use blister packages of 21.

Bottles of 100 - NDC: 50742-189-01

Unit of use blister packages of 21 tablets - NDC: 50742-189-21

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in USP with child resistant closure.

REFERENCES

1 Fekety R. Infections associated with corticosteroids and immunosuppressive therapy. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. Philadelphia: WBSaunders Company  1992:1050–1.

2 Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking    glucocorticoids. Rev Infect Dis 1989:11(6):954–63.

Manufactured for:

Ingenus Pharmaceuticals, LLC

Orlando, FL 32839-6408

Rx only

Revised: 1/2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Bottle Label 100s Count

Blister Label 21s Count

Blister Carton Label

INGREDIENTS AND APPEARANCE

METHYLPREDNISOLONE 
methylprednisolone tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 50742-189
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
METHYLPREDNISOLONE (UNII: X4W7ZR7023) (METHYLPREDNISOLONE - UNII:X4W7ZR7023)	METHYLPREDNISOLONE	4 mg

Inactive Ingredients
Ingredient Name	Strength
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
STARCH, CORN (UNII: O8232NY3SJ)
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics
Color	WHITE (white to off-white)	Score	4 pieces
Shape	OVAL (elliptical)	Size	8mm
Flavor		Imprint Code	ING615
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 50742-189-01	100 in 1 BOTTLE; Type 0: Not a Combination Product	01/17/2019
2	NDC: 50742-189-21	1 in 1 CARTON	01/17/2019
2		21 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA210985	01/17/2019

Labeler - Ingenus Pharmaceuticals, LLC (833250017)

Registrant - Novast Laboratories , Ltd. (527695995)

Establishment
Name	Address	ID/FEI	Business Operations
Nutra-Med Packaging Inc.		080274725	PACK(50742-189)

Establishment
Name	Address	ID/FEI	Business Operations
Ingenus Pharmaceuticals NJ, LLC		964680206	ANALYSIS(50742-189) , LABEL(50742-189) , MANUFACTURE(50742-189) , PACK(50742-189)