Diprostol Diclofenac Sodium and Misoprostol Tablets

Diprostol Tablets 50mg+200mcg Tablets (Diclofenac Sodium & Misoprostol)

Description, Composition, Mechanism of Action, Absorption, Distribution, Metabolism, Elimination, Therapeutic Indications, Dosage and Administration, Adverse Reactions, Contraindications, Gastrointestinal Effects-Risk of GI Ulceration, Renal effects, Hepatic effects, Hematologic effects, Geriatric use, Drug Interactions, Storage, Packaging and Manufacturer of Diprostol Tablet for Arthritis.

 

DESCRIPTION

Diprostol is combination product containing diclofenac sodium, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin E1 analog.

Diclofenac sodium a phenylacetic acid derivative is chemically described as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Its molecular formula is C14H10CI2NO2Na.

Misoprostol is a synthetic, oral prostaglandin E1 analog. Chemically it is described as (±) methyl 11α, 16- dihydroxy-16methyl-9-oxoprost-13E-en-1-oate. The molecular formula is C22H38O5.

 

COMPOSITION

Each tablet contains:

Diclofenac Sodium BP 50mg

Misoprostol 200mcg

 

CLINICAL PHARMACOLOGY

Mechanism of Action

Diclofenac Sodium

The mechanism of action of diclofenac sodium, like other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

 

Misoprostol

It inhibits basal and nocturnal gastric acid secretion through a direct action on the parietal cell. Misoprostol also exerts a mucosal protectant effect that may contribute to its effectiveness in treating ulcers.

 

Pharmacokinetics

Diclofenac Sodium

Absorption

Diclofenac sodium, orally administered, is completely absorbed from the Gltract after fasting.

The diclofenac sodium in Diprostol is in an enteric-coated formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism. Peak plasma levels are achieved in 2 hours.

 

Distribution

Diclofenac sodium is extensively and reversibly bound (99%) to serum albumin.

Diclofenac sodium penetrates synovial fluid where Tmax occurs 2 or 4 hours after plasma Tmax. The synovial fluid elimination half life is at least 3 times greater than that for plasma. Diclofenac sodium is distributed into breast milk but the amount is considered to be too small to be harmful to a breastfed infants. The apparent volume of distribution is 0.12 to 0.17L/kg.

 

Metabolism

Diclofenac sodium undergoes first pass metabolism producing derivatives of diclofenac sodium. These phenolic metabolites are largely inactive, and (along with the parent compound) are mostly converted to glucuronide conjugates.

 

Elimination

In humans about 65% of the drug and its metabolites are eliminated in the urine and the balance through bile in the feces. About 1% of an oral dose is excreted unchanged in urine. The mean terminal drug half-life in plasma is 2 hours after oral doses.

 

Misoprostol

Absorption

Orally administered misoprostol is rapidly and extensively (88%) absorbed. Food and antacids decrease the rate and extent of absorption.

 

Distribution

Misoprostol distribution has not been fully elucidated. It is unknown whether this agent crosses the placenta or is distributed into breast milk, but because it can stimulate uterine contractions, it should not be used during pregnancy.

 

Metabolism

The drug undergoes extensive first-pass metabolism to form the principal and active metabolite misoprostol acid. Portion of this metabolism occurs in the parietal cell.
Misoprostol acid is further metabolized in the body tissues.

 

Elimination

The elimination half-life of misoprostol acid is between 20-40 minutes, but it can be up to 80 minutes in those with renal impairment. Less than 1% of a dose is excreted in the urine as unchanged drug. Approximately 15% of a dose is excreted in the feces, with 74% being excreted in the urine within 7 days.

 

Diclofenac Sodium and Misoprostol

The pharmacokinetics following oral administration of a single dose or multiple doses of diclofenac sodium+misoprostol to healthy subjects under fasting conditions are similar to the pharmacokinetics of the two individual components.

 

THERAPEUTIC INDICATIONS

Diprostol (Diclofenac Sodium+Misoprostol) is indicated for acute and chronic treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis, anlylosing spondylitis and acute musculoskeletal disorders. The misoprostol component of Diprostol is indicated for the prevention of NSAID (nonsteroidal anti- inflammatory drugs, including Aspirin)-induced gastric and duodenal ulcers.

 

DOSAGE AND ADMINISTRATION

Osteoarthritis

The recommended dosage for maximal GI mucosal protection is Diprostol (Diclofenac Sodium+Misoprostol) tablets t.i.d. For patients who experience intolerance, Diprostol b.i.d can be used, but are less effective in preventing ulcers.

 

Rheumatoid Arthritis

The recommended dosage is Diprostol (Diclofenac Sodium+Misoprostol) tablets t.i.d or q.i.d. For patients who experience intolerance, Diprostol (Diclofenac Sodium+Misoprostol) tablets b.i.d can be used but are less effective in preventing ulcers.

 

Ankylosing Spondylitis

The recommended dosage of Diprostol (Diclofenac Sodium+Misoprostol) tablets t.i.d or q.i.d.

 

Acute Musculoskeletal Disorders

The recommended dosage for maximal GI mucosal protection is Diprostol (Diclofenac Sodium+Misoprostol) tablets b.i.d or t.i.d.

 

Special Dosing Considerations

Diprostol, which provides protection against gastric and duodenal ulcers. For gastric ulcer prevention, the 200mcg q.i.d. and t.i.d regimens are more protective than the t.i.d or v.i.d regimens. However, the q.i.d. regimen is less well tolerated than the t.i.d regimen and the b.i.d regimen may be better tolerated than t.i.d in some patients.

Note: The total dose of misoprostol should not exceed 800mcg/day, and no more than 200mcg of misoprostol should be administered at any one time. Doses of diclofenac sodium higher than 150mg/day in osteoarthritis or higher than 225mg/day in rheumatoid arthritis are not recommended.

 

ADVERSE REACTIONS

The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. The following adverse reactions occurred:

 

Gastrointestinal

Abdomen enlarged, esophageal ulceration, gall bladder disorder, glossitis, hematemesis, hiccup and melena.

 

CNS/Psychiatric

Anorexia, anxiety, concentration impaired, depression, hypoesthesia, dry mouth, speech disorder and vertigo.

 

Dermatologic

Angioedema, erythema multiforme, sweating increased and urticaria.

 

Cardiovascular

Palpitation and syncope.

 

Special Senses

Earache, eye pain, taste loss, taste bnormalities, tinnitus and vision abnormal.

 

Hematologic

Leukopenia and thrombocytopenia.

 

Hepatic

Bilirubinemia, abnormal hepatic function, LDH increased and alkaline phosphatase increased.

 

Metabolic

BUN increased and glycosuria.

 

Respiratory

Hyperventilation and sputum increased.

 

Gynecological

Menstrual disorder, intermenstrual bleeding, dysmenorrhea, leukorrhea, and vaginal bleeding.

 

Body as a Whole

Hot flushes, malaise, rigors.

 

Urinary

Dysuria, abnormal urine, hematuria and cystitis.

 

CONTRAINDICATIONS

Diclofenac sodium+misoprostol combination

• Is contraindicated in patients with hypersensitivity to diclofenac sodium or to misoprostol or other prostaglandins.

• Is contraindicated in pregnant women, because its misoprostol component can cause abortion.

• Should not be given to patients who have experienced asthma, urticaria or other allergic-type reactions after taking aspirin or other NSAIDs.

• Is not recommended for use in patients having advanced kidney disease.

• Is not recommended in combination with aspirin and magnesium containing antacids.

• Is not recommended for use in patients with active liver disease.

• Is contraindicated in lactating mother.

 

WARNINGS

Special note for women

Because of the abortifacient property of misoprostol Diprostol is contraindicated for use by pregnant women. Misoprostol may cause miscarriage if given to pregnant women at any time during pregnancy. Miscarriages caused by misoprostol may be incomplete, which could lead to dangerous bleeding, hospitalization, surgery, infertility, or maternal or fetal death. Patients must be advised of the abortifacient property and warned not to give the drug to others.

 

Gastrointestinal Effects-Risk of GI Ulceration, Bleeding and Perforation

Serious GI toxicity, such as inflammation, bleeding, ulceration and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy.

Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms and the steps to take if they occur.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or GI bleeding.

 

PRECAUTIONS

General

Diclofenac sodium+misoprostol combination cannot be used to substitute for corticosteroids or to treat for corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

 

Renal effects

Caution should be used when initiating treatment in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with diclofenac sodium+misoprostol combination.

 

Hepatic effects

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. As with other NSAID containing products, if abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac sodium+misoprostol combination should be discontinued immediately.

 

Hematologic effects

Patients on long-term treatment with NSAIDs, including diclofenac sodium+misoprostol combination should have their hemoglobin or hematocrit checked, if they exhibit any signs or symptoms of anemia. Patients receiving diclofenac sodium+misoprostol combination who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants should be carefully monitored.

 

Fluid Retention and Edema

As with other NSAID containing products, diclofenac sodium+misoprostol combination should be used with caution in patients with a history of cardiac decompensation, hypertension, or other conditions predisposing to fluid retention.

 

Preexisting asthma

Diclofenac sodium+misoprostol combination should be used with caution in patients with pre-existing asthma.

 

Geriatric use

No adjustment of the dose of Diprostol is necessary in the elderly for pharmacokinetic reasons although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.

 

Drug Interactions

Digoxin

Patients receiving digoxin with diclofenac sodium+misoprostol combination should be monitored for possible digoxin toxicity.

 

Antihypertensive agents

NSAIDs can inhibit the activity of anti-hypertensives, including ACE inhibitors. Thus, caution should be taken when administering this with such agents.

 

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious bleeding greater than users of either drug alone.

 

Oral hypoglycemics

Marketing experiences reports, changes in effects of insulin or oral hypoglycemic agents in the presence of diclofenac sodium that necessitated changes in the doses of such agents.

 

Methotrexate and Cyclosporin

Diclofenac sodium+misoprostol combination may increase serum concentrations of methotrexate and increase cyclosporin nephrotoxicity.

 

Lithium

When NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

 

Diuretics

Concomitant therapy of NSAIDs with potassium-sparing diuretics may be associated with increased serum potassium levels.

 

STORAGE

Store below 30°C in a dry place, protect from sun light and moisture.

The expiration date refers to the product correctly stored at the required conditions.

 

HOW SUPPLIED

Diprostol (Diclofenac Sodium+Misoprostol) Tablets are available in alu alu blister pack of 20’s.

 

Manufactured by

Saffron

Pharmaceuticals (Pvt.) Ltd.

19 Km. Sheikhupura Road, Faisalabad-Pakistan.