Methylprednisolone Tablets USP 32mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT
a) Methylprednisolone Tablets USP 2mg Taj Pharma
b) Methylprednisolone Tablets USP 4mg Taj Pharma
c) Methylprednisolone Tablets USP 8mg Taj Pharma
d) Methylprednisolone Tablets USP 16mg Taj Pharma
e) Methylprednisolone Tablets USP 32mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each tablet contains
Methylprednisolone USP 2mg
Excipients     q.s.

b) Each tablet contains
Methylprednisolone USP 4mg
Excipients      q.s

d) Each tablet contains
Methylprednisolone USP 8mg
Excipients            q.s.

e) Each tablet contains
Methylprednisolone USP 16mg
Excipients           q.s.

f) Each tablet contains
Methylprednisolone USP 32mg
Excipients             q.s.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM
Tablet

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Methylprednisolone is indicated for conditions requiring glucocorticoid activity such as:-

1. Endocrine disorders

Primary and secondary adrenal insufficiency

Congenital adrenal hyperplasia

2. Rheumatic disorders

Rheumatoid arthritis

Juvenile chronic arthritis

Ankylosing spondylitis

3. Collagen diseases/arteritis

Systemic lupus erythematosus

Systemic dermatomyositis (polymyositis)

Rheumatic fever with severe carditis

Giant cell arteritis/polymyalgia rheumatica

4. Dermatological diseases

Pemphigus vulgaris

5. Allergic states

Severe seasonal and perennial allergic rhinitis

Drug hypersensitivity reactions

Serum sickness

Allergic contact dermatitis

Bronchial asthma

6. Ophthalmic diseases

Anterior uveitis (iritis, iridocyclitis)

Posterior uveitis

Optic neuritis

7. Respiratory diseases

Pulmonary sarcoid

Fulminating or disseminated tuberculosis (with appropriate anti-tuberculous chemotherapy)

Aspiration of gastric contents

8. Haematological disorders

Idiopathic thrombocytopenic purpura

Haemolytic anaemia (autoimmune)

9. Neoplastic diseases

Leukaemia (acute and lymphatic)

Malignant lymphoma

10. Gastro-intestinal diseases

Ulcerative colitis

Crohn’s disease

11. Miscellaneous

Tuberculous meningitis (with appropriate anti-tuberculous chemotherapy)

Transplantation

 4.2  Posology and method of administration
The dosage recommendations shown in the table below are suggested initial daily doses and are intended as guides. The average total daily dose recommended may be given either as a single dose or in divided doses (excepting in alternate day therapy when the minimum effective daily dose is doubled and given every other day at 8.00 am).

Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see section 4.4).

The initial suppressive dose level may vary depending on the condition being treated. This is continued until a satisfactory clinical response is obtained, a period usually of three to seven days in the case of rheumatic diseases (except for acute rheumatic carditis), allergic conditions affecting the skin or respiratory tract and ophthalmic diseases. If a satisfactory response is not obtained in seven days, re-evaluation of the case to confirm the original diagnosis should be made. As soon as a satisfactory clinical response is obtained, the daily dose should be reduced gradually, either to termination of treatment in the case of acute conditions (e.g. seasonal asthma, exfoliative dermatitis, acute ocular inflammations) or to the minimal effective maintenance dose level in the case of chronic conditions (e.g. rheumatoid arthritis, systemic lupus erythematosus, bronchial asthma, atopic dermatitis). In chronic conditions, and in rheumatoid arthritis especially, it is important that the reduction in dosage from initial to maintenance dose levels be accomplished as clinically appropriate. Decrements of not more than 2 mg at intervals of 7 – 10 days are suggested. In rheumatoid arthritis, maintenance steroid therapy should be at the lowest possible level.

In alternate-day therapy, the minimum daily corticoid requirement is doubled and administered as a single dose every other day at 8.00 am. Dosage requirements depend on the condition being treated and response of the patient.

Elderly patients: 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 (see section 4.4).

Paediatric population: In general, dosage for children should be based upon clinical response and is at the discretion of the physician. 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 (see section 4.4).
Dosage Recommendations:

4.3 Contraindications
Methylprednisolone tablets are contraindicated:

• in patients who have systemic fungal infections
• in patients who have systemic infections unless specific anti-infective therapy is employed
• in patients who have hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

 4.4 Special Warnings and precautions for use
Immunosuppressant Effects/Increased Susceptibility to Infections
Corticosteroids may increase susceptibility to infection, may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

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.

Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

Exposure to measles should be avoided. Medical advice must be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immunoglobulin may be needed.

Similarly corticosteroids should be used with great care in patients with known or suspected parasitic infections such as Strongyloides (threadworm) infestation, which may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. The antibody response to other vaccines may be diminished.

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.

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

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. A systematic review of short-course high-dose corticosteroids did not support their use. However, meta-analyses, and a review have suggested that longer courses (5-11 days) of low-dose corticosteroids might reduce mortality.

Immune System
Because rare instances of skin reactions and anaphylactic/anaphylactoid reactions have occurred in patients receiving corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.

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

Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy. In addition, acute adrenal insufficiency leading to a fatal outcome may occur if glucocorticoids are withdrawn abruptly.
• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.
• Patients repeatedly taking doses in the evening.

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, headache, 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.

Glucocorticoids can produce or aggravate Cushing’s syndrome, therefore glucocorticoids should be avoided in patients with Cushing’s disease.

Particular care is required when considering the use of systemic corticosteroids in patients with hypothyroidism and frequent patient monitoring is necessary.

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

Particular care is required when considering the use of systemic corticosteroids in patients with Diabetes mellitus (or a family history of diabetes) and frequent patient monitoring is necessary.

Psychiatric Effects
Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.

Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Nervous System Effects
Particular care is required when considering the use of systemic corticosteroids in patients with seizure disorders and myasthenia gravis (see myopathy statement in Musculoskeletal Effects section) and frequent patient monitoring is necessary.

There have been reports of epidural lipomatosis in patients taking corticosteroids, typically with long-term use at high doses.

Ocular Effects
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Central serous chorioretinopathy, may lead to retinal detachment.

Particular care is required when considering the use of systemic corticosteroids in patients with glaucoma (or a family history of glaucoma) and ocular herpes simplex as there is a fear of corneal perforation, and frequent patient monitoring is necessary.

Prolonged use 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.

Secondary fungal and viral infections of the eye may also be enhanced in patients receiving glucocorticoids.

.Cardiac Events
Adverse effects of glucocorticoids on the cardiovascular system, such as dyslipidemia and hypertension, may predispose treated patients with existing cardiovascular risk factors to additional cardiovascular effects, if high doses and prolonged courses are used. Accordingly, corticosteroids should be employed judiciously in such patients and attention should be paid to risk modification and additional cardiac monitoring if needed. Low dose and alternate day therapy may reduce the incidence of complications in corticosteroid therapy.

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

Particular care is required when considering the use of systemic corticosteroids in patients with recent myocardial infarction (myocardial rupture has been reported) and frequent patient monitoring is necessary.

Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see section 4.8).

Vascular Effects
Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

Hypertension

Predisposition to thrombophlebitis

Thrombosis including venous thromboembolism has been reported to occur with corticosteroids. As a result corticosteroids should be used with caution in patients who have or may be predisposed to thromboembolic disorders.

Gastrointestinal Effects
High doses of corticosteroids may produce acute pancreatitis.

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

Peptic ulceration.

Fresh intestinal anastomoses.

Abscess or other pyogenic infections.

Ulcerative colitis.

Diverticulitis.

Glucocorticoid therapy may mask peritonitis or other signs or symptoms associated with gastrointestinal disorders such as perforation, obstruction or pancreatitis. In combination with NSAIDs, the risk of developing gastrointestinal ulcers is increased.

Hepatobiliary Effects
Particular care is required when considering the use of systemic corticosteroids in patients with liver failure or cirrhosis and frequent patient monitoring is necessary.

Rarely hepatobiliary disorders were reported, in the majority of these cases, they were reversible after withdrawal of therapy. Therefore appropriate monitoring is required.

Musculoskeletal Effects
An acute myopathy has been reported 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 anticholinergics, such as neuromuscular blocking drugs (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.

Particular care is required when considering the use of systemic corticosteroids in patients with osteoporosis (post-menopausal females are particularly at risk) and frequent patient monitoring is necessary.

Renal and Urinary
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone. Blood pressure and renal function (s-creatinine) should therefore be routinely checked. When renal crisis is suspected, blood pressure should be carefully controlled.

Particular care is required when considering the use of systemic corticosteroids in patients with renal insufficiency and frequent patient monitoring is necessary.

Injury, poisoning and procedural complications
Systemic corticosteroids are not indicated for, and therefore should not be used to treat, traumatic brain injury, a multicenter study revealed an increased mortality at 2 weeks and 6 months after injury in patients administered methylprednisolone sodium succinate compared to placebo. A causal association with methylprednisolone sodium succinate treatment has not been established.

Other
Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternative days. Frequent patient review is required to appropriately titrate the dose against disease activity (see section 4.2).

Patients should carry ‘Steroid Treatment’ cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects (see section 4.5).

Aspirin and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids.

Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Paediatric population: Corticosteroids cause growth retardation in infancy, childhood and adolescence. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo-pituitary-adrenal axis and growth retardation, treatment should be administered where possible as a single dose on alternate days (see section 4.2).

Infants and children on prolonged corticosteroid therapy are at special risk from raised intracranial pressure.

High doses of corticosteroids may produce pancreatitis in children.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

Ingredient warning
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

 4.5 Interaction with other medicinal products and other forms of interaction
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 drugs) have been shown to alter glucocorticoid metabolism by induction (upregulation) or inhibition of the CYP3A4 enzyme.

4.6 Fertility, Pregnancy and lactation
Fertility
Corticosteroids have been shown to impair fertility in animal studies (see section 5.3).

Pregnancy
The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta. In humans, the risk of low birth weight appears to be dose related and may be minimized by administering lower corticosteroid doses.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Infants born to mothers, who have received substantial doses of corticosteroids during pregnancy must be carefully observed and evaluated for signs of adrenal insufficiency. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important.

Since adequate human reproductive studies have not been done with methylprednisolone, this medicinal product, as with all drugs, should be used in pregnancy only after a careful assessment of the benefit-risk ratio to the mother, embryo, foetus or child. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Cataracts have been observed in infants born to mothers undergoing long-term treatment with corticosteroids during pregnancy.

Breast-feeding
Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression. This medicinal product should be used during breast feeding only after a careful assessment of the benefit-risk ratio to the mother and infant.

4.7 Effects on ability to drive and use machines
The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Undesirable effects, such as dizziness, vertigo, visual disturbances and fatigue are possible after treatment with corticosteroids. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

* Not a MedDRA PT

^† Peritonitis may be the primary presenting sign or symptom of a gastrointestinal disorder such as perforation, obstruction or pancreatitis (see section 4.4)

Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Not known (frequency cannot be estimated from the available data)

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (see section 4.4).

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.

 4.9 Overdose
Administration of methylprednisolone should not be discontinued abruptly but tailed off over a period of time. Appropriate action should be taken to alleviate the symptoms produced by any side-effect that may become apparent. It may be necessary to support the patient with corticosteroids during any further period of trauma occurring within two years of overdosage.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Glucocorticosteroids,

Methylprednisolone is a synthetic glucocorticoid and a methyl derivative of prednisolone. Methylprednisolone is a potent anti-inflammatory agent with the capacity to profoundly inhibit the immune system.

Glucocorticoids act primarily by binding to and activating intracellular glucocorticoid receptors. Activated glucocorticoid receptors bind to promoter regions of DNA (which may activate or suppress transcription) and activate transcription factors resulting in inactivation of genes through de-acetylation of histones.

Following corticosteroid administration there is a delay of several hours for the clinical effects resulting from changes in gene expression to be seen.

Other effects not related to gene expression may be more immediate.

Corticosteroids influence the kidney and fluid and electrolyte balance, lipid, protein, and carbohydrate metabolism, skeletal muscle, the cardiovascular system, the immune system, the nervous system, and the endocrine system. Corticosteroids are also critical in the maintenance of function during stress.

5.2 Pharmacokinetic properties
Methylprednisolone pharmacokinetics is linear, independent of route of administration.

Absorption:
Methylprednisolone is rapidly absorbed and the maximum plasma methylprednisolone concentration is achieved around 1.5 to 2.3 hours across doses following oral administration in normal healthy adults. The absolute bioavailability of methylprednisolone in normal healthy subjects is generally high (82% to 89%) following oral administration.

Distribution:
Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg.

The plasma protein binding of methylprednisolone in humans is approximately 77%.

Metabolism:
Corticosteroids are metabolised mainly in the liver but also in the kidney and are excreted in the urine.

In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone.

Metabolism in the liver occurs primarily via the CYP3A4 enzyme. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5.)

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines.

Elimination:
The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 mL/min/kg.

 5.3 Preclinical safety data
Based on conventional studies of safety pharmacology and repeated dose toxicity, no unexpected hazards were identified. The toxicities seen in repeated-dose studies were those expected to occur with continued exposure to exogenous adrenocortical steroids.

Mutagenic potential:
Methylprednisolone has not been formally evaluated for genotoxicity. Studies using structurally related analogues of methylprednisolone showed no evidence of a potential for genetic and chromosome mutations in limited studies in bacteria and mammalian cells.

Carcinogenic potential:
Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m² basis. The clinical relevance of these findings is unknown.

Reproductive toxicity:
Methylprednisolone has not been evaluated in animal fertility studies. Adverse effects on fertility in male rats administered corticosterone were observed and were reversible. Decreased weights and microscopic changes in prostate and seminal vesicles were observed. The numbers of implantations and live foetuses were reduced and these effects were not present following mating at the end of the recovery period.

An increased frequency of cleft palate was observed among the offspring of mice treated during pregnancy with methylprednisolone in doses similar to those typically used for oral therapy in humans.

An increased frequency of cardiovascular defects and decreased body weight were observed among the offspring of pregnant rats treated with methylprednisolone in a dose that was similar to that used for oral therapy in humans but was toxic to the mothers. In contrast, no teratogenic effect was noted in rats with doses <1-18 times those typically used or oral therapy in humans in another study. High frequencies of foetal death and a variety of central nervous system and skeletal anomalies were reported in the offspring of pregnant rabbits treated with methylprednisolone in doses less than those used in humans. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone in pregnancy is unknown. Safety margins for the reported teratogenic effects are unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Lactose
Sucrose
Maize starch
Calcium stearate

6.2 Incompatibilities
Not applicable.

6.3  Shelf life
Bottles – 5 years.
Blister packs – 3 years.

6.4 Special precautions for storage
Store below 25°C.

6.5 Nature and contents of container
High density polyethylene bottles with tamper evident caps. Each bottle contains 30 or 100 tablets.
20-25 micron hard tempered aluminium foil/lacquer, 250 micron opaque polyvinyl chloride film blister. Pack contains 30 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
No special requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Methylprednisolone Tablets USP 32mg Taj Pharma

Package leaflet: Information for the patient

a) Methylprednisolone Tablets USP 2mg Taj Pharma
b) Methylprednisolone Tablets USP 4mg Taj Pharma
c) Methylprednisolone Tablets USP 8mg Taj Pharma
d) Methylprednisolone Tablets USP 16mg Taj Pharma
e) Methylprednisolone Tablets USP 32mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Methylprednisolone is and what it is used for
2. Before you are given Methylprednisolone
3. How you will be given  Methylprednisolone
4. Possible side effects
5. How Methylprednisolone is stored
6. Further Information

1. What Methylprednisolone is and what it is used for
This medicine contains methylprednisolone, which belongs to a group of medicines called steroids. Their full name is corticosteroids. Corticosteroids are produced naturally in your body and are important for many body functions.

Boosting your body with extra corticosteroid such as Methylprednisolone can help if your body cannot produce enough corticosteroid due to problems with your adrenal glands (e.g. adrenal insufficiency).

Corticosteroids can also help following surgery (e.g. organ transplants), injuries or other stressful conditions. These include inflammatory or allergic conditions affecting the:
• brain (e.g. tuberculous meningitis)
• bowel and gut (e.g. Crohn’s disease and ulcerative colitis)
• blood or blood vessels (e.g. leukaemia)
• eye (e.g. optic neuritis, uveitis or iritis)
• joints (e.g. rheumatoid arthritis, rheumatic fever)
• lungs (e.g. asthma, tuberculosis)
• muscle (e.g. dermatomyositis and polymyositis)
• skin (e.g. eczema)

Methylprednisolone may be prescribed to treat conditions other than those listed above. You must talk to a doctor if you are unsure why you have been given this medicine, if you do not feel better or if you feel worse.

2. Before you are given Methylprednisolone
Do not take Methylprednisolone:
▪ If you think you have ever suffered an allergic reaction, or any other type of reaction after being given Methylprednisolone or any of the other ingredients of this medicine (listed in section 6). An allergic reaction may cause a skin rash or reddening, swollen face or lips or shortness of breath.
▪ If you have any serious fungal infection such as a serious fungal infection in your lungs or oesophagus (the tube that connects your mouth with your stomach) or any other infection which is not being treated with an antibiotic or antiviral medicine.
▪ If you have recently had or are about to have any vaccination.

If you get a rash or another symptom of an infection tell your doctor immediately.

Warnings and precautions
Talk to your doctor or pharmacist before taking this medicine if you have any of the following conditions.
Your doctor may have to monitor your treatment more closely, alter your dose or give you another medicine.
• Chickenpox, measles or shingles. If you think you have been in contact with someone with chickenpox, measles or shingles and you have not already had these illnesses, or if you are unsure if you have had them.
• Worm infestation (e.g. threadworm).
• Severe depression or manic depression (bipolar disorder). This includes having had depression before while taking steroid medicines like Methylprednisolone, or having a family history of these illnesses.
• Diabetes (or if there is a family history of diabetes).
• Fits or seizures.
• Glaucoma (increased pressure in the eye) or if there is a family history of glaucoma, or if you have cataracts.
• Contact your doctor if you experience blurred vision or other visual disturbances.
• Viral (e.g. herpes) or fungal eye infection.
• You recently suffered a heart attack.
• Heart problems, including heart failure.
• Hypertension (high blood pressure).
• Hypothyroidism (an under-active thyroid).
• Pancreatitis (inflammation of the pancreas which causes severe pain in the abdomen and back).
• Peritonitis (inflammation of the thin lining (peritoneum) around the gut and stomach).
• Kidney or liver disease.
• Scleroderma (also known as systemic sclerosis, an autoimmune disorder), because the risk of a serious complication called scleroderma renal crisis may be increased. Signs of scleroderma renal crisis include increased blood pressure and decreased urine production.
• Kaposi’s sarcoma (a type of skin cancer).
• Muscle problems (pain or weakness) have happened while taking steroid medicines like Methylprednisolone in the past.
• Myasthenia gravis (a condition causing tired and weak muscles).
• Osteoporosis (brittle bones).
• Pheochromocytoma (a rare tumour of adrenal gland tissue. The adrenal glands are located above the kidneys).
• Skin abscess.
• Stomach ulcer or other serious stomach or intestinal problems.
• Thrombophlebitis – vein problems due to thrombosis (clots in the veins) resulting in phlebitis (red, swollen and tender veins).
• Tuberculosis (TB) or if you have suffered tuberculosis in the past.
• Cushing’s disease (condition caused by an excess of cortisol hormone in your body).
• Brain injury due to trauma (injury).
• Unusual stress.

Other medicines and Methylprednisolone
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, (including medicines you have obtained without a prescription). This could be harmful or affect the way Methylprednisolone or the other medicine works:
• Acetazolamide – used to treat glaucoma and epilepsy.
• Aminoglutethimide or Cyclophosphamide – used for treating cancer.
• Anticoagulants – used to ‘thin’ the blood such as acenocoumarol, phenindione and warfarin.
• Anticholinesterases – used to treat myasthenia gravis (a muscle condition) such as distigmine and neostigmine.
• Antibacterials (such as isoniazid, erythromycin, clarithromycin and troleandomycin).
• Antidiabetics – medicines used to treat high blood sugar.
• Aprepitant or fosaprepitant – used to prevent nausea and vomiting.
• Aspirin and non-steroidal anti-inflammatory medicines (also called NSAIDs) such as ibuprofen used to treat mild to moderate pain.
• Barbiturates, carbamezipine, phenytoin and primidone – used to treat epilepsy.
• Carbenoxolone and cimetidine – used for heartburn and acid indigestion.
• Ciclosporin – used to treat conditions such as severe rheumatoid arthritis, severe psoriasis or following an organ or bone marrow transplant.
• Digoxin – used for heart failure and/or an irregular heartbeat.
• Diltiazem or mibefradil – used for heart problems or high blood pressure.
• Ethinylestridiol and norethisterone – an oral contraceptive.
• Antivirals (such as ritonavir, indinavir) and pharmacokinetic enhancers (such as cobicistat) used to treat HIV infections.
• Ketoconazole or itraconazole – used to treat fungal infections.
• Pancuronium or vecuronium – or other medicines called neuromuscular blocking agents which are used in some surgical procedures.
• Potassium depleting agents – such as diuretics (sometimes called water tablets), amphotericin B, xanthenes or beta2 agonists (e.g. medicines used to treat asthma).
• Rifampicin and rifabutin – antibiotics used to treat tuberculosis (TB).
• Tacrolimus – used following an organ transplant to prevent rejection of the organ.
• Vaccines – tell your doctor or nurse if you have recently had or are about to have any vaccination. You must not have ‘live’ vaccines while using this medicine. Other vaccines may be less effective.

If you are taking long term medication(s)
If you are being treated for diabetes, high blood pressure or water retention (oedema) tell your doctor as he/she may need to adjust the dose of the medicines used to treat these conditions.

Before you have any operation tell your doctor, dentist or anesthetist that you are taking Methylprednisolone.

If you require a test to be carried out by your doctor or in hospital it is important that you tell the doctor or nurse that you are taking Methylprednisolone. This medicine can affect the results of some tests.

Pregnancy and breast-feeding
If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine, as it could slow the baby’s growth. There is a risk of low birth weight of a baby; this risk can be minimised by taking the lowest effective dose of the corticosteroids.

Cataracts have been observed in infants born to mothers treated with long-term corticosteroids during pregnancy.

If you are breast-feeding, ask your doctor or pharmacist for advice, as small amounts of corticosteroid medicines may get into breast milk.

Driving and using machines
Undesirable effects, such as dizziness, vertigo, visual disturbances and fatigue are possible after treatment with corticosteroids. If you are affected do not drive or operate machinery.

Methylprednisolone contains lactose and sucrose
If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking this medicine.

Methylprednisolone Tablets 2 mg contain E123
Methylprednisolone 2mg tablets also contain the colour E123 which can cause allergic reactions.

3. How you will be given Methylprednisolone
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Steroid Cards
Remember to always carry a Steroid Treatment Card. Make sure your doctor or pharmacist has filled out the details of your medicine, including the dose and how long you will require steroid treatment.

You should show your steroid card to anyone who gives you treatment (such as a doctor, nurse or dentist) while you are taking Methylprednisolone, and for 3 months after you stop taking the tablets.

If you are admitted to hospital for any reason always tell your doctor or nurse that you are taking Methylprednisolone. You can also wear a medic-alert bracelet or pendant to let medical staff know that you are taking a steroid if you have an accident or become unconscious.

Adults
The normal daily dose is between 4 mg and 360 mg per day, depending on your condition and how severe it is. Your doctor will prescribe the lowest dose possible.
Your doctor may tell you to take your daily dose all in one go, split your daily dose throughout the day, or take it every other day at 8.00 am.
Swallow the tablets whole with a drink of water.
Do not eat grapefruit or drink grapefruit juice while taking Methylprednisolone.

If you are being given Methylprednisolone because your body cannot make its own corticosteroids, your doctor may also want you to take a second type of steroid to help your salt balance.

Your doctor may prescribe a higher dose at the start of your treatment to bring your condition under control.

When your doctor is happy that your condition has improved your dose will be reduced gradually. Normally the dose will be reduced by not more than 2 mg every 7 to 10 days.

Elderly:
Your doctor may want to see you more regularly to check how you are getting on with your tablets.

Children and adolescents:
Corticosteroids can affect growth in children so your doctor will prescribe the lowest dose that will be effective for your child. Your doctor may tell you to give your child this medicine on every other day.

If you take more Methylprednisolone than you should
It is important that you do not take more tablets than you are told to take. If you accidentally take too many tablets, seek medical attention straight away.

If you forget to take your Methylprednisolone
Wait and take the next dose as normal. Do not take a dose to make up for the forgotten one but tell your doctor or pharmacist what had happened.

Stopping/reducing the dose of your Methylprednisolone
Your doctor will decide when it is time to stop your dose.

You must not stop taking Methylprednisolone suddenly, especially if you:
• have had more than 6 mg Methylprednisolone daily for more than 3 weeks
• have been given high doses of Methylprednisolone (more than 32 mg daily) even if it was only for 3 weeks or less
• have already had a course of corticosteroid tablets or injections in the last year
• already had problems with your adrenal glands (adrenocortical insufficiency) before you started this treatment
• take repeat doses in the evening.

You will need to come off Methylprednisolone slowly to avoid withdrawal symptoms. These symptoms may include itchy skin, fever, muscle and joint pains, runny nose, sticky eyes, loss of appetite, nausea, vomiting, headache, feeling tired, peeling skin and weight loss.

If your symptoms seem to return or get worse as your dose of Methylprednisolone is reduced tell your doctor immediately.

Mental problems while taking Methylprednisolone
Mental health problems can happen while taking steroids like Methylprednisolone (see section 4).
• These illnesses can be serious.
• Usually they start within a few days or weeks of starting the medicine.
• They are more likely to happen at high doses.
• Most of these problems go away if the dose is lowered or the medicine is stopped. However, if the problems do happen they might need treatment.

Talk to a doctor if you (or someone using this medicine) shows any signs of mental problems. This is particularly important if you are depressed, or might be thinking about suicide. In a few cases mental problems have happened when doses are being lowered or stopped.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor will have given you this medicine for a condition which if not treated properly could become serious.

These side effects may occur with certain frequencies, which are defined as follows:
• common: may affect up to 1 in 10 people.
• rare: may affect up to 1 in 1,000 people.
• not known: frequency cannot be estimated from the available data.

In certain medical conditions medicines like Methylprednisolone (steroids) should not be stopped abruptly. If you suffer from any of the following symptoms, seek IMMEDIATE medical attention. Your doctor will then decide whether you should continue taking your medicine:
common
• Burst or bleeding ulcers, symptoms of which are stomach pain (especially if it seems to spread to your back), bleeding from the back passage, black or bloodstained stools and/or vomiting blood.
• Infections. This medicine can hide or change the signs and symptoms of some infections, or reduce your resistance to the infection, so that they are hard to diagnose at an early stage. Symptoms might include a raised temperature and feeling unwell. Symptoms of a flare up of a previous TB infection could be coughing blood or pain in the chest. Methylprednisolone may also make you more likely to develop a severe infection.

not known
• Allergic reactions, such as skin rash, swelling of the face or wheezing and difficulty breathing. This type of side effect is rare but can be serious.
• Pancreatitis, stomach pain spreading to your back, possibly accompanied by vomiting, shock and loss of consciousness.
• Pulmonary embolus (blood clots in the lung), symptoms of include sudden sharp chest pain, breathlessness and coughing up blood.
• Raised pressure within the skull of children (pseudotumour cerebri) symptoms of which are headaches with vomiting, lack of energy and drowsiness. This side-effect usually occurs after treatment is stopped.
• Thrombophlebitis (blood clots or thrombosis in a leg vein), symptoms of which include painful swollen, red and tender veins.

If you experience any of the following side effects, or notice any other unusual effects not mentioned in this leaflet, tell your doctor straight away:

Blood, heart and circulation
common
• High blood pressure, symptoms of which are headaches, or generally feeling unwell.
not known
• Problems with the pumping of your heart (heart failure) symptoms of which are swollen ankles, difficulty in breathing and palpitations (awareness of heart beat) or irregular beating of the heart, irregular or very fast or slow pulse.
• Increased numbers of white blood cells (leukocytosis).
• Low blood pressure.

Body water and salts
common
• Swelling and high blood pressure, caused by increased levels of water and salt content.
• Cramps and spasms, due to the loss of potassium from your body. In rare cases this can lead to congestive heart failure (when the heart cannot pump properly).
not known
• Increased blood urea levels.

Digestive system
not known
• Nausea (feeling sick) or vomiting (being sick).
• Ulcers, inflammation or thrush in the oesophagus (the tube that connects your mouth with your stomach), which can cause discomfort on swallowing.
• Inflammation of the thin lining (peritoneum) around the gut and stomach.
• Indigestion.
• Bloated stomach.
• Abdominal pain.
• Diarrhoea.
• Persistent hiccups, especially when high doses are taken.

Eyes
common
• Damage to the optic nerve or cataracts (indicated by failing eyesight).
rare
• Blurred vision.
not known
• Glaucoma (raised pressure within the eye, causing pain in the eyes and headaches).
• Swollen optic nerve (papilloedema, indicated by sight disturbance).
• Thinning of the clear part at the front of the eye (cornea) or of the white part of the eye (sclera).
• Worsening of viral or fungal eye infections.
• Protruding of the eyeballs (exophthalmos).
• Blurred or distorted vision (due to a disease called chorioretinopathy).

Hepatobiliary disorders
not known
• Increase of liver enzymes. Hormone and metabolic system
common
• Slowing of normal growth in infants, children and adolescents which may be permanent.
• Round or moon-shaped face (Cushingoid facies).
not known
• Irregular or no periods in women.
• Increased hair on the body and face in women (hirsutism).
• Increased appetite and weight gain.
• Abnormal blood level of lipids (e.g. cholesterol and/or fat).
• Diabetes or worsening of existing diabetes.
• Prolonged therapy can lead to lower levels of some hormones which in turn can cause low blood pressure and dizziness. This effect may persist for months.
• The amount of certain chemicals (enzymes) called alanine transaminase, aspartate transaminase and alkaline phosphatase that help the body digest drugs and other substances in your body may be raised after treatment with a corticosteroid. The change is usually small and the enzyme levels return to normal after your medicine has cleared naturally from your system. You will not notice any symptoms if this happens, but it will show up if you have a blood test.
• Accumulation of fat tissue on localised parts of the body, manifesting as different presentations for example back pain or weakness (due to epidural lipomatosis).

Immune system
not known
• Increased susceptibility to infections which can hide or change normal reactions to skin tests, such as that for tuberculosis.

Muscles and bones
common
• Muscle weakness or wasting. not known
• Brittle bones (bones that break easily).
• Broken bones or fractures.
• Breakdown of bone due to poor circulation of blood, this causes pain in the hip.
• Joint pain or joint problems.
• Torn muscle tendons causing pain and/or swelling.
• Muscle pain, cramps or spasms.

Nervous system
Steroids including methylprednisolone can cause serious mental health problems.
These are common in both adults and children. They can affect about 5 in every 100 people taking medicines like methylprednisolone.
• Feeling depressed, including thinking about suicide.
• Feeling high (mania) or moods that go up and down.
• Feeling anxious, having problems sleeping, difficulty in thinking or being confused and losing your memory.
• Feeling, seeing or hearing things which do not exist. Having strange and frightening thoughts, changing how you act or having feelings of being alone.
not known
• Irritability.
• Fits.
• Dizziness, a feeling of dizziness or ‘spinning’.

• Headache.

Skin
common
• Acne.
• Poor wound healing.
• Thinning of skin.
not known
• Stretch marks.
• Bruising.
• Sweating.
• Itchy skin.
• Rash or redness of skin.
• Hives (red itchy swellings).
• Dilation of small blood vessels on the surface of the skin (red spider veins).
• Red, brown or purple, pin point, round spots.
• Brown/purple/red raised patches on the skin or inside the mouth (Kaposi’s sarcoma).

Vascular disorders
not known
• Increased clotting of the blood

Other side effects
not known
• Feeling unwell.
• Feeling tired.
• Accumulation of fluid causing swelling in the body, especially the lower limbs.
• Suppression of reactions to skin tests.

It is important if you are to have a blood test that you tell the doctor or nurse that you have been given treatment with Methylprednisolone.

If you experience any of the side effects listed above tell your doctor straight away.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting effects you can help provide more information on the safety of this medicine.

5. How Methylprednisolone is stored
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date, which is stated on the carton and blister strip after ‘EXP’.
The expiry date refers to the last day of that month.
Keep your blister strips securely in the outer carton.
Store below 25°C.
Do not throw away any medicines via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Further information

What Methylprednisolone contains
The active substance is methylprednisolone.
a) Each tablet contains: Methylprednisolone USP 2mg
b) Each tablet contains: Methylprednisolone USP 4mg
c) Each tablet contains: Methylprednisolone USP 8mg
d) Each tablet contains: Methylprednisolone USP 16mg
e) Each tablet contains: Methylprednisolone USP 32mg
The other ingredients are lactose, sucrose, maize starch and calcium stearate. Methylprednisolone Tablets 2 mg also contains rose colour (E123 and E127).

What Methylprednisolone looks like and contents of the pack
Methylprednisolone Tablets 2 mg are pink, oval and single scored.
Methylprednisolone Tablets 4 mg are white oval and single scored.
It is available in blister packs of 30 tablets and in plastic bottles of 30 or 100 tablets.
Not all pack sizes may be marketed.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com