Arthrotec (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmacia, Ltd. (United Kingdom)

Group Company

PFIZER (USA)

ATC Code

M01AB55 (Diclofenac in combination with other drugs)

Active Substances

Diclofenac (Rec.INN registered by WHO)

Misoprostol (Rec.INN registered by WHO)

Dosage Forms

	Arthrotec	Tablets 50 mg+200 mcg: 20 pcs.
		Tablets 75 mg+200 mcg: 20 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex, with an engraving on one side in the form of four “A” characters arranged in a circle, and on the other – “Searle” and “1411”.

Excipients: methylhydroxypropylcellulose, aerosil, microcrystalline cellulose, crospovidone, hydrogenated castor oil, lactose, corn starch, povidone (K-30), magnesium stearate, cellulose acetate phthalate, diethyl phthalate.

10 pcs. – blisters (2) – cardboard packs.

Tablets white or almost white, round, biconvex, with an engraving on one side in the form of four “A” characters surrounding the number “75”, and on the other – “Searle” and “1421”.

Excipients: methylhydroxypropylcellulose, aerosil, microcrystalline cellulose, crospovidone, hydrogenated castor oil, lactose, corn starch, povidone (K-30), magnesium stearate, cellulose acetate phthalate, diethyl phthalate.

10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

NSAID in combination with a synthetic analogue of prostaglandin E₁

Pharmacotherapeutic Group

NSAID

Pharmacological Action

Arthrotec is a combination of diclofenac sodium – an NSAID with anti-inflammatory and analgesic properties and misoprostol – a synthetic analogue of prostaglandin E₁ that protects the gastrointestinal mucosa.

The mechanism of action of diclofenac sodium is associated with its ability to non-selectively inhibit COX-1 and COX-2.

Misoprostol is a synthetic analogue of prostaglandin E₁ that enhances the action of factors involved in the protection of the gastric and duodenal mucosa.

Misoprostol maintains gastric mucosal blood supply, reduces pepsin and hydrochloric acid secretion in the stomach, and promotes bicarbonate formation in the duodenum.

Pharmacokinetics

The pharmacokinetics of diclofenac and misoprostol in combination is similar to the pharmacokinetics of these drugs when taken as separate tablets.

T_max – time to reach maximum concentration

No pharmacokinetic interaction is observed between these two substances. After repeated administration of Arthrotec, accumulation of diclofenac, misoprostol, or misoprostol acid does not occur.

Indications

Symptomatic treatment

• Rheumatoid arthritis;
• Osteoarthritis;
• Ankylosing spondylitis;
• Acute musculoskeletal pain syndrome.

ICD codes

Dosage Regimen

Orally during meals, without chewing; tablets should not be broken or dissolved.

Arthrotec is recommended to be used in the following doses

Osteoarthritis, rheumatoid arthritis

Tablets containing a dose of 50 mg/200 mcg – 1 tab. 2-3 times/day; tablets containing a dose of 75 mg/200 mcg – 1 tab. 2 times/day.

Ankylosing spondylitis

Tablets containing a dose of 50 mg/200 mcg – 1 tab. 2-3 times/day; tablets containing a dose of 75 mg/200 mcg – 1 tab. 2 times/day.

Acute musculoskeletal pain syndrome

Tablets containing a dose of 50 mg/200 mcg – 1 tab. 2-3 times/day; tablets containing a dose of 75 mg/200 mcg – 1 tab. 2 times/day.

Adverse Reactions

Mainly adverse reactions from the gastrointestinal tract have been registered, the frequency of which is >1%: abdominal pain, constipation, diarrhea, duodenitis, dyspepsia, belching, esophagitis, flatulence, gastritis, nausea and vomiting.

Abdominal pain and diarrhea are usually transient and mild or moderate.

In addition, such adverse reactions as dizziness, headache, insomnia, skin itching, hemorrhagic rash, gastrointestinal bleeding and perforation have been registered. Changes in laboratory parameters were also detected: increased alkaline phosphatase levels, decreased hematocrit and increased ALT levels.

In women receiving Arthrotec, adverse reactions from the mammary glands and genital organs were noted: breast pain, dysmenorrhea, intermenstrual bleeding, menorrhagia, menstrual cycle disorders, cramping lower abdominal pain, vaginal spotting (including bleeding in postmenopausal women), vaginitis.

During post-marketing surveillance, the following adverse reactions were additionally identified: allergic reactions (including anaphylaxis and angioedema), skin reactions (including rash and bullous eruptions), mood changes, shortness of breath, hepatitis, interstitial nephritis, pancreatitis, acute renal failure, stomatitis, thrombocytopenia, urticaria, anemia, epidermal necrolysis.

In very rare cases, blurred vision, vivid dreams, as well as reactions from the skin and mucous membranes have been reported during therapy with diclofenac/misoprostol.

In cases of misoprostol use by pregnant women, the following adverse events were noted: abnormal uterine contractions, uterine bleeding, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death, congenital malformations.

Contraindications

• Active gastrointestinal bleeding;
• Pregnancy and lactation;
• Hypersensitivity to diclofenac sodium, misoprostol or any other ingredient of the drug, to other NSAIDs, including acetylsalicylic acid, as well as to other prostaglandins;
• “aspirin” asthma, hematopoietic disorders.

Data on the safety and efficacy of Arthrotec in children under 18 years of age are not available.

With caution anemia, bronchial asthma, congestive heart failure, arterial hypertension, porphyria, elderly age, history of erosive and ulcerative lesions of the gastrointestinal tract, hepatic or renal failure, heart disease, fluid retention in the body, dehydration.

Use in Pregnancy and Lactation

Arthrotec is contraindicated in pregnant women because Misoprostol causes uterine contractions and can provoke miscarriages, premature birth and fetal death. When using misoprostol, fetal malformations may occur. Diclofenac can cause premature closure of the ductus arteriosus.

Misoprostol should not be prescribed to nursing mothers, since the possible excretion of misoprostol acid in milk can cause diarrhea in the infant. It is not known whether this drug is excreted in breast milk. However, since many drugs are excreted in breast milk, and also due to the possibility of infants developing adverse reactions to Diclofenac/Misoprostol, either breastfeeding should be discontinued or the use of this drug should be stopped.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in renal insufficiency.

Pediatric Use

Data on the safety and efficacy of Arthrotec in children under 18 years of age are not available.

Geriatric Use

Use the drug with caution in elderly patients.

Special Precautions

In patients receiving NSAID therapy, including Arthrotec, serious adverse reactions from the gastrointestinal tract, such as bleeding, ulceration and perforation, have been registered.

Doctors and patients should be aware of the potential for ulceration, even in the absence of gastrointestinal symptoms.

NSAIDs, including Arthrotec, should be prescribed with caution to patients with a history of or active gastrointestinal diseases, such as ulcer, bleeding, inflammatory bowel disease.

Women of childbearing potential should not start therapy with Arthrotec until pregnancy has been ruled out, and they should use reliable contraceptive measures throughout the entire therapy period. If pregnancy is planned, this drug should be discontinued.

During therapy with Arthrotec, liver function should be periodically monitored. If Arthrotec is prescribed to patients with impaired liver function, treatment should be carried out under constant medical supervision.

Caution should also be exercised in patients with kidney damage, liver disease or heart disease, since the use of NSAIDs, including Diclofenac/ Misoprostol, can lead to impaired renal function. Caution is required at the beginning of treatment of patients with dehydration. The lowest possible dose should be used and renal function should be regularly monitored.

In patients receiving NSAIDs, including Arthrotec, fluid retention and edema have also been noted. Therefore, caution should be exercised when prescribing Arthrotec to patients with a history of chronic heart failure, as well as in conditions predisposing to fluid retention.

NSAIDs, including Diclofenac, increase platelet aggregation time. Misoprostol does not enhance the effect of diclofenac on platelet activity.

Arthrotec weakens inflammation; it may reduce the severity of symptoms that allow the diagnosis of infectious diseases, for example, fever.

In patients aged 65 years and older, the adverse reaction profile of diclofenac/ misoprostol is similar to that in younger patients, with the only clinically significant difference being that patients 65 years and older are more susceptible to the adverse effects of diclofenac/ misoprostol on the gastrointestinal tract.

Overdose

Toxic doses of Arthrotec have not been established. However, overdose symptoms due to the components of this drug have been described: nausea, vomiting, abdominal pain, bleeding, confusion, drowsiness, decreased muscle tone.

Clinical symptoms indicating an overdose of misoprostol are: tremor, convulsions, shortness of breath, abdominal pain, diarrhea, fever, palpitations, arterial hypotension, bradycardia.

Treatment for acute overdose includes gastric lavage. Forced diuresis may also be effective, since metabolites of diclofenac and misoprostol are excreted in the urine. The effect of dialysis on the elimination of diclofenac (whose plasma protein binding is 99%) and misoprostol acid (plasma protein binding less than 90%) has not yet been precisely established. Oral administration of activated charcoal helps reduce the absorption of diclofenac/misoprostol.

Drug Interactions

Diclofenac is displaced by acetylsalicylic acid from its binding sites with albumin, which leads to a decrease in the concentration of diclofenac in plasma, as well as a decrease in its maximum plasma concentration and a decrease in the AUC value. In this regard, simultaneous use of diclofenac/misoprostol and acetylsalicylic acid is not recommended.

In patients receiving digoxin and Diclofenac simultaneously, elevated digoxin levels were recorded. Therefore, patients receiving digoxin and Diclofenac/Misoprostol simultaneously should be under medical supervision to detect toxic effects of digoxin.

NSAIDs may weaken the natriuretic effect of diuretics. Since when used simultaneously with potassium-sparing diuretics, an increase in serum potassium levels may be observed, in such cases it is necessary to monitor the level of this indicator. Caution should be exercised when prescribing diclofenac/misoprostol simultaneously with the above drugs.

A number of NSAIDs have been found to interact with oral anticoagulants, although it has been noted that Diclofenac does not interact with warfarin-type anticoagulants. When taking indirect anticoagulants (warfarin) with NSAIDs, the risk of gastrointestinal bleeding increases. In this regard, patients receiving anticoagulants of this type simultaneously with diclofenac/misoprostol should be under observation so that, if necessary, the dose of the anticoagulant can be adjusted.

NSAIDs may reduce the effect of antihypertensive agents, including ACE inhibitors. When diclofenac/misoprostol is prescribed simultaneously with ACE inhibitors, renal function may worsen.

Diclofenac does not impair glucose metabolism in healthy people; moreover, when diclofenac is used simultaneously with oral hypoglycemic agents, the effect of the latter does not change. However, there are reports of changes in the effect of such drugs when taken simultaneously with NSAIDs. Therefore, Arthrotec should be prescribed with caution to patients receiving insulin or oral hypoglycemic agents.

Caution should be exercised when prescribing methotrexate simultaneously with NSAIDs, including Arthrotec, since NSAIDs can increase the plasma level of methotrexate.

Diclofenac reduces the renal clearance of lithium and increases the plasma concentration of lithium. Therefore, Arthrotec should be prescribed with caution to patients receiving lithium.

Antacids may slow the absorption of diclofenac. Magnesium-containing antacids may exacerbate diarrhea associated with misoprostol use.

Cyclooxygenase inhibitors, such as Diclofenac, due to their effect on renal prostaglandins, may enhance the nephrotoxicity of cyclosporine.

Storage Conditions

List B. In a dry place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf life – 3 years. Do not use after the date indicated on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.