METHYLPREDNISOLONE 4mg Tablet

COMPOSITIONS :

Methylprednisolone Tablet 4 mg, each tablet contains : Methylprednisolone 4 mg.

 

DESCRIPTIONS : 

Methylprednisolone with active ingredient Methylprednisolone is available in tablet 4 mg and 8 mg. 

 

INDICATIONS :

• Endocrine disorders

1. 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 mineralcorticoids supplementation is of particular importance
2. Congenital adrenal hyperplasia 
3. Nonsuppurative thyroiditis
4. Hypercalcemia associated with cancer 

• Rheumatic disorders 

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

1. Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may required low-dose maintenance therapy)
2. Ankylosing spondylitis 
3. Psoriatic arthritis 
4. Acute and subacute bursitis 
5. Epicondylitis 
6. Synovitis of osteoarthritis 
7. Acute gouty arthritis 
8. Acute nonspesific tenosynovitis 
9. Post-traumatic osteoarthritis 

• Collagen disorders 

During an exacerbation or as maintenance therapy in selected cases of : Systemic lupus erythematosus, systemic dermatomyositis (polymyositis) and acute rheumatic carditis. 

• Dermatologic diseases 

1. Bullous dermatitis herpetiformis
2. Severe erythema multiforme (Steven-Johnson syndrome)
3. Severe seborrhoeic dermatitis
4. Exfoliative dermatitis
5. Pemphigus 
6. Mycosis fungoides 
7. Severe psoriasis

• Allergy states 

Control of severe or incapacitating allergic condition intractable to adequate trials of conventional treatments :

1. Seasonal or perennial allergic rhinitis 
2. Drug hypersensitivity reactions
3. Serum sickness 
4. Bronchial asthma
5. Contact dermatitis 
6. Atopic dermatitis 

• Ophthalmic diseases

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

1. Allergic corneal marginal ulcers 
2. Herpes zoster ophthalmicus
3. Anterior segment inflammation 
4. Diffuse posterior uveitis and choroiditis 
5. Sympathetic ophthalmia 
6. Keratitis 
7. Allergic conjunctivitis 
8. Optic neuritis 
9. Chorioeretinitis 
10. Iritis and iridocylitis 

• Respiratory diseases

1. Symptomatic sarcoidosis
2. Berylliosis 
3. Leoffler’s syndrome not manageable by other means 
4. Fulminating or disseminated pulmonary tuberculosis when use concurrently with appropriate antituberculous chemotherapy
5. Aspiration pneumonitis 

• Hematologic disorders : 

1. Idiopathic thrombocytopenic purpura in adults 
2. Secondary thrombocytopenia in adults
3. Acquired (autoimmune) hemolytic anemia 
4. Erythroblastopenia (RBC anemia)
5. Congenital (erythroid) hypoplastic anemia

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

• Edematous state : To induce a diuresis or remission of proteinuria in the nephrotic syndrome without uremia, or the idiopathic type or that due to lupus erythematosus.
• Gastrointestinal disease : To tide the patient over a critical period of the diseases in ulcerative colitis and regional enteritis.
• Nervous system : Acute exacerbations of multiple sclerosis.
• Micellaneous 

1. Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. 
2. Trichinosis with neurologic or myocardial involvement. 

 

DOSAGE AND ADMINISTRATIONS : 

• Initial dose : Varies between 4 – 48 mg Methylprednisolone daily, 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. Clinical situations in which high dose therapy may be indicated include multiple sclerosis (160 mg/day for a week, followed by 64 mg/day for 1 month have been shown to be effective). If after a reasonable period of time there is a lack of satisfactory clinical response, Methylprednisolone should be discontinued and the patient transferred to other appropriate therapy. If after long-term therapy the drug is to be stopped; it is recommended that it be withdrawn gradually rather than abruptly.
• After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decreasement 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 for a period of time consistent with the patient’s condition.

IT SHOULD BE EMPHASISED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.

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

• Elderly : Treatment of elderly patients, particularly if long term, should be planned bearing in mind the more serious consequences of the common side effects of corticosteroids in old age, particularly osteoporosis, diabetes, hypertension, susceptibility to infection and thinning of skin.

• Children : In general dosage for children should be based upon clinical response and is at the  discretion of the clinician. Treatment should be limited to the minimum dosage for the shortest period of time. If possible, treatment should be administered as a single dose on alternate days.

 

OVERDOSAGE :

There is no clinical syndrome of acute overdosage with corticosteroids. Reports of acute toxicity and/or death following overdosage of corticosteroids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic. Methylprednisolone is dialyzable.

 

CONTRAINDICATIONS :

Systemic fungal infection and known hypersensitivity to components. 

 

WARNINGS AND PRECAUTIONS :

Warnings :

• Immunosuppressant effects/increased susceptibility to infections

1. Corticosteroids may increase susceptibility to infection, may mask some sign of infection and new infections may appear during their use. There may be decreased resistance and inability to localized infection when corticosteroids are used.
2. 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. 
3. Similarly, corticosteroids should be used with great care in patients with known or suspected parasitic infections such as strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosupperssion may lead to strongyloides hyperinfection and dissemination with widespread larval migration, often accompained by severe enterocolitis and potentially fatal gram-negative septicemia. 
4. The role of corticosteroids in septic shock has been controversial, with early studies reporting both beneficial and detrimental effects. More recently, supplemental corticosteroids have been suggested to be beneficial in patients with established septic shock who exhibit adrenal insufficiency. However, their routine use in septic shock is not recommended and a systematic review concluded that short-course, high dose corticosteroids did not support their use. However, meta-analyses and a review suggest that longer courses (5 – 11 days) of lowdose corticosteroids might reduce mortality, especially in those with vasopressor-dependent septic shock. 
5. While on corticosteroids therapy, patients should not be vaccinated against smallpox. Other immunization procedure should not be undertaken in patients who are on corticosteroids, especially on high doses, because of possible hazards of neurological complication and lack of antibody response. 
6. The use 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 appropriate antituberculosis regimen. 
7. If corticosteroids are indicated in patient with latent tuberculosis or tuberculin reactivity, close observation if necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. 

• Blood and lymphatic system

Aspirin and nonsteroidal anti-inflammatory agents should be used cautiously in conjuction with corticosteroids in patients with hypoprothrombinemia.

• Immune system 

Allergic reactions (e.g., angioedema) may occur.

• Endocrine  

1. Pharmacologic doses of corticosteroids administered for prolonged periods may result in hypothalamic-pituitary-adrenal (HPA) suppression (secondary adrenocortical insufficiency). The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, time of administration and duration of glucocorticoid therapy. This effect may be minimized by the use of alternate-day therapy (see DOSAGE AND ADMINISTRATIONS).
2. In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly. 
3. Drug-induced 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 stress occuring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or mineralocorticoid should be administered concurrently. 
4. Because glucocorticoid can produce or aggravate Chusing’s syndrome, glucocorticoids should be avoided in patients with Cushing’s disease. There is an enhanced effect of corticosteroids on patients with hypothyroidism. 

• Metabolism and nutrition 

Corticosteroids, including Methylprednisolone, can increase blood glucose, worsen pre-existing diabetes and predispose those on long-term corticosteroid therapy to diabetes mellitus. 

• Psychiatric 

1. Psychic derangements may appear when corticosteroids are used ranging from euphoria, insomnia, mood swings, personality changes and severe depression to frank psychotic manifestation. Also existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Potentially severe psychiatric adverse reactions may occur with systemic steroids (see section ADVERSE REACTIONS). Symptoms typically emerge within a few days or weeks of starting treatment. Most reaction recover after either dose reduction or withdrawl, although specific treatment may be necessary. Psychological effects have been reported upon withdrawal of corticosteroids; the frequency is unknown. Patients/caregivers should be encouraged to seek medical attention if psychological symptoms develop in the patient, especially if depressed mood or suicidal ideation is suspected. Patients/caregivers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids. 
2. In patients on corticosteroids therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after stressful situation is indicated. 

• Nervous system

1. Corticosteroids should be used with caution in patients with seizure disorders.
2. Corticosteroids should be used with caution in patients with myasthenia gravis.  

• Ocular

Corticosteroids should be use cautiously in patient with ocular herpes simplex because of possible corneal perforation. Prolonged used of corticosteroids may produce posterior subcapsular cataracts and nuclear cataracts (particularly in children), exophthalmos or increased intraocular pressure, which may result in glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses. 

• Cardiac 

Systemic corticosteroids should be used with caution and only if strictly necessary, in cases of congestive heart failure. 

• Vascular 

Corticosteroids should be used with caution in patients with hypertension.

• Gastrointestinal 

There is no universal agreement on whether corticosteroids are responsible for peptic ulcer encountered during therapy; however, glucocorticoid therapy may mask the symptoms of peptic ulcer so that perforation or hemorrhage may occur without significant pain. Corticosteroid should be used with caution in non specific ulcerative colitis if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer.

• Hepatobiliary 

There is an enhanced effect of corticosteroids on patients with cirrhosis. 

• Musculoskeletal 

An acute myopathy has been reported with the use of high doses of corticosteroids, most often occuring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) or in patients receiving concomitant therapy with anticholinergics, such as neuromuscular blocking agent (e.g., Pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevations of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Osteoporosis is a common but infrequently recognize adverse effects associated with a long-term use of large doses of glucocorticoid.

• Renal and urinary 

Corticosteroids should be used with caution in patients with renal insufficiency. 

• Investigations 

Average and large doses of Hydrocortisone or Cortisone can cause elevation blood pressure, salt and water retention and increased excretion of potassium. These affects 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. 

• Injury, poisoning and procedural complications

High doses of systemic corticosteroids should not be used for the treatment of traumatic brain injury.

• Other 

Because 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 intermitten therapy should be used. 

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

• Use in children

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

Growth may be suppressed in children receiving long-term daily, divided doses glucocorticoid therapy and use of such regimen should be restricted to the most urgent indication. Alternate day glucocorticoid therapy usually avoids or minimizes these side effects (see DOSAGE AND ADMINISTRATIONS).

• Carcinogenesis, mutagenesis, impairment of fertility

There is no evidence that corticosteroid are carcinogenic, mutagenic or impair fertility. Host defenses are impaired in patient receiving large doses of glucocorticoid and this effect increases susceptibility to fungus infection as well as bacterial and viral infections.

• Pregnancy  

Some animal studies have shown that corticosteroids, when administered to the mother at high doses, may cause fetal malformations.

Adequate human reproductive studies have not been done with corticosteroids. Therefore the use of this drug in pregnancy, nursing mothers or women of childbearing potential requires that the benefits of the drug be carefully weighed against the potential risk to the mother and embryo or fetus. 

Since there is inadequate evidence of safety in human pregnancy, this drug should be used in pregnancy only if clearly needed. Infants born of mothers who have received substantial doses of corticosteroid during pregnancy should be carefully observed for signs of hypoadrenalism. 

Corticosteroids readily cross the placenta. One retrospective study found an increased incidence of low birth weights in infants born of mothers receiving corticosteroid. Although neonatal adrenal insufficiency appears to be rare in infants who were exposed in utero to corticosteroids, those exposed to substantial doses of corticosteroid should be carefully observed and evaluated for signs of adrenal insufficiency.

There are no known effects of corticosteroid on labor and delivery.

• Lactation

Corticoids are excreted in breast milk and mothers taking the drug should not be breast feed.

• Effects on ability to drive and use machines.

The effect of corticosteroids on the ability to drive or use machinery has not been evaluated. 

There is no evidence to suggest that corticosteroids may affect the ability to drive and use machines. No deleterious effects of corticosteroids on driving or operating machinery is expected.

Precautions :

Convulsions have been reported with concurrent use of Methylprednisolone and Cyclosporine. Since concurrent administration of these agents result in a mutual inhibition of metabolism, it is possible that convulsion and other adverse events associated with the individual use of either drug may be more apt to occur.

 

DRUG INTERACTIONS :

Methylprednisolone is a cytochrome P450 enzyme (CYP) substrate and is mainly metabolized by the CYP3A4 enzyme. CYP3A4 is the dominant enzyme of the most abundant CYP subfamily in the liver of adult humans. It catalyzes 6β-hydroxylation of steroids, the essential Phase I metabolic step for both endogenous and synthetic corticosteroids. Many other compounds are also substrates of CYP3A4, some of which (as well as other medicines) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

Table 1. Important drug or substance interactions/effects with Methylprednisolone.

Drug class or type-drug or substance	Interaction/effect
Antibiotic, Antitubercular  – Rifampin	CYP3A4 Inducer
Anticoagulant (oral)	The effect of Methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effects.
Anticonvulsants – Carbamazepine	CYP3A4 Inducers (and substrate)
Anticonvulsants – Phenobarbital – Phenytoin	CYP3A4 Inducers
Anticholinergics – Neuromuscular blockers	Corticosteroids may influence the effect of anticholinergics. An acute myopathy has been reported with the concomitant use of high doses of corticosteroids and neuromuscular blocking drugs (see WARNINGS AND PRECAUTIONS). Antagonism of the neuromuscular blocking effects of Pancuronium and Vecuronium has been reported in patients taking corticosteroids. This interaction may be expected with all competitive neuromuscular blockers.
Antiemetic – Aprepitant – Fosaprepitant	CYP3A4 Inhibitors (and substrates)
Antifungal – Itraconazole – Ketoconazole	CYP3A4 Inhibitors (and substrates)
Calcium channel blocker – Diltiazem	CYP3A4 Inhibitors (and substrates)
Contraceptives (oral) – Ethinylestradiol/Norethindrone	CYP3A4 Inhibitors (and substrates)
– Grapefruit juice	CYP3A4 Inhibitors
Immunosuppresant – Cyclosporine	CYP3A4 Inhibitors (and substrates) Mutual inhibition of metabolism occurs with concurrent use of Cyclosporine and Methylprednisolone, which may increase the plasma concentrations of either or both drugs. Therefore, it is possible that adverse events associated with the use of either drug alone may be more likely to occur upon coadministration.  Convulsions have been reported with concurrent use of Methylprednisolone and Cyclosporine.
Immunosuppresant  – Cyclophosphamide  – Tacrolimus	CYP3A4 Substrates
Macrolide antibacterial – Clarithromycin – Erythromycin	CYP3A4 Inhibitors (and substrates)
Macrolide Antibacterial – Troleandomycin	CYP3A4 Inhibitors
NSAIDs (Nonsteroidal anti-inflammatory drugs) – High dose Aspirin (Acetylsalicyclic acid)	There are increased incidence of gastrointestinal bleeding and ulceration when corticosteroid are given with NSAIDs. Methylprednisolone may increase the clearance of high-dose Aspirin. This  decreased in Salicylate serum levels could lead to an increased risk of Salicylate toxicity when Methylprednisolone is withdrawn.
Antivirals – HIV Protease Inhibitors	CYP3A4 Inhibitors (and substrates) Protease inhibitors such as Indinavir and Ritonavir, may increase plasma concentrations of corticosteroids. Corticosteroids may induce the metabolism of HIV-protease inhibitor resulting in reduced plasma concentrations.

Note :

• CYP3A4 Inhibitors : Drugs that inhibit CYP3A4 activity generally decrease hepatic clearance and increase the plasma concentration of CYP3A4 substrate medications, such as Methylprednisolone. In the presence of a CYP3A4 inhibitor, the dose of Methylprednisolone may need to be titrated to avoid steroid toxicity. 
• CYP3A4 Inducers : Drugs that induce CYP3A4 activity generally increase hepatic clearance, resulting in decreased plasma concentrations of medications that are substrates for CYP3A4. Co-administration may require an increase in Methylprednisolone dosage to achieve the desired result.
• CYP3A4 Substrates : In the presence of another CYP3A4 substrate, the hepatic clearance of Methylprednisolone may be inhibited or induced, with corresponding dosage adjustments required. It is possible that adverse events associated with the use of either drug alone may be more likely to occur with co-administration.
• Non – CYP3A4 – Mediated Effects : Other interactions and effects that occur with Methylprednisolone are described in Table 1 above. Table 1 provides a list and descriptions of the most common and/or clinically important drug interactions or effects with Methylprednisolone.

 

ADVERSE REACTIONS : 

• Infections and infestations : Latent infections becoming active, masking of infections, opportunistic infection.
• Immune system disorders : Drug hypersensitivity (including anaphylactic reaction and anaphylactoid reaction), suppression of reactions to skin tests. 
• Endocrine disorders : Cushingoid, hypopituitarism, suppression of pituitary-adrenal axis. Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness. 
• Metabolism and nutrition disorders : Alkalosis hypokalaemic, fluid retention, glucose tolerance impaired, increased appetite (which may result in weight increased), increased requirements for insulin or oral hypoglycemic agents in diabetics, metabolic acidosis, manifestation of latent of diabetes mellitus, sodium retention. 
• Psychiatric disorders : Abnormal behaviour, affective disorder (including affect lability, depressed mood, euphoric mood, psychological dependence, suicidal ideation), anxiety, confusional state, insomnia, irritability, mental disorders, mood swings, personality change, psychic derangements, psychotic behaviour, psychotic disorders (including mania, delusion, hallucination and schizophrenia).
• Nervous system disorders : Amnesia, cognitive disorders, convulsions, dizziness, headhache, intracranial pressure increased (with papilloedema [benign intracranial hypertension]) pseudomotor cerebri, seizures. 
• Eye disorders : Cataract subcapsular, exophthalmos, glaucoma, posterior subcapsular cataracts.
• Ear and labyrinth disorders : Vertigo.
• Cardiac disorders : Cardiac failure congestive (in susceptible patients).
• Vascular disorders : Hypertension, hypotension.
• Respiratory, thoracic and mediastinal disorders : Hiccups.
• Gastrointestinal disorders : Abdominal distension, abdominal pain, diarrhoea, dyspepsia, gastric haemorrhage, intestinal perforation, nausea, oesophagitis, oseophagitis ulcerative, pancreatitis, peptic ulcer (with possible peptic ulcer perforation and peptic ulcer haemorrhage), perforation of the bowel.
• Skin and subcutaneous tissue disorders : Angioedema, ecchymosis, facial erythema, hirsutism, hyperhidrosis, petechiae, pruritus, rash, skin atrophy, skin striae, thin fragile skin, urticaria, increased sweating. 
• Musculoskeletal and connective tissue disorders : Arthralgia, aseptic necrosis, growth retardation, muscle atrophy, muscular weakness, myalgia, myopathy, neuropathic arthropathy, osteonecrosis, osteoporosis, pathologic fracture, suppression of growth in children. 
• Reproduction system and breast disorders : Menstruation irregular.
• General disorders and administration site conditions : Fatigue, impaired healing, malaise. 

A steroid ‘withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of glucocorticoids. This syndrome includes symptoms such as : Anorexia, nausea, vomiting, lethargy, headhache, fever, joint pain, desquamation, myalgia, weight loss, and/or hypotension. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels. 

• Investigations : Alanine aminotransferase increased (ALT, SGPT), aspartate aminotransferase increased, blood potassium decreased, carbohydrate tolerance decreased, intraocular pressure increased, urine calcium increased. 
• Metabolic : Negative nitrogen balance due to protein catabolism. The following additional reaction have been reported following oral as well as parenteral therapy and other allergic, anaphylactic or hypersensitivity reactions. 
• Injury, poisoning and procedural complications : Spinal compression fracture, tendon rupture (particularly of the Achilles tendon). 

 

PRESENTATION :

Methylprednisolone Tablet 4 mg Box, 10 blister @ 10 tablet

Reg. No. GKL0602339210A1

 

STORAGE :

STORE BELOW 30°C

 

ON MEDICAL PRESCRIPTION ONLY

 

Manufactured by :  

BERNOFARM

Sidoarjo – Indonesia