MISOPROSTOL TABLET

NAME OF THE MEDICINAL PRODUCT

Misoprostol Tablet 200mcg

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 micrograms misoprostol.

PHARMACEUTICAL FORM
Tablet White to off-white hexagonal tablets scored both sides, engraved SEARLE 1461 on one side for oral administration.

CLINICAL PARTICULARS

Therapeutic indications
Misoprostol is indicated for the healing of duodenal ulcer and gastric ulcer including those induced by nonsteroidal anti-inflammatory drugs (NSAID) in arthritic patients at risk, whilst continuing their NSAID therapy. In addition, Misoprostol can be used for the prophylaxis of NSAID-induced ulcers.

Posology and method of administration

Posology

Adults
Healing of duodenal ulcer, gastric ulcer and NSAID-induced peptic ulcer: 800 micrograms daily in two or four divided doses taken with breakfast and / or each main meal and at bedtime.

Treatment should be given initially for at least 4 weeks even if symptomatic relief has been achieved sooner. In most patients ulcers will be healed in 4 weeks but treatment may be continued for up to 8 weeks if required. If the ulcer relapses further treatment courses may be given.

Prophylaxis of NSAID-induced peptic ulcer: 200 micrograms twice daily, three times daily or four times daily. Treatment can be continued as required. Dosage should be individualised according to the clinical condition of each patient.

Renal impairment: Available evidence indicates that no adjustment of dosage is necessary in patients with renal impairment.

Hepatic impairment: Misoprostol is metabolised by fatty acid oxidising systems present in organs throughout the body. Its metabolism and plasma levels are therefore unlikely to be affected markedly in patients with hepatic impairment.

Elderly
The usual dosage may be used.

Paediatric population
Use of Misoprostol in children has not yet been evaluated in the treatment of peptic ulceration or NSAID-induced peptic ulcer disease.

CONTRAINDICATION
Misoprostol is contraindicated:

  • In women who are pregnant, or in whom pregnancy has not been excluded, or who are planning a pregnancy as misoprostol increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception. Use in pregnancy has been associated with birth defects.
  • In patients with a known hypersensitivity to misoprostol or to any other component of the product, or to other prostaglandins.

SPECIAL PRECAUTIONS & WARNINGS

Women of childbearing potential should not be started on misoprostol until pregnancy is excluded, and should be fully counselled on the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, use of the product should be discontinued.

In such patients it is advised that Misoprostol should only be used if the patient:

  • takes effective contraceptive measures
  • has been advised of the risks of taking Misoprostol if pregnant

Gastrointestinal bleeding, ulceration, and perforation have occurred in NSAID-treated patients receiving misoprostol. Physicians and patients should remain alert for ulceration, even in the absence of gastrointestinal symptoms, and, where appropriate, endoscopy and biopsy should be carried out before use to ensure that malignant disease is absent in the upper gastrointestinal tract. These investigations and any others considered necessary by the clinician should be repeated at appropriate intervals for follow-up purposes.

Symptomatic responses to misoprostol do not preclude the presence of gastric malignancy.

Misoprostol should be used with caution in patients with conditions that predispose them to diarrhoea, such as inflammatory bowel disease. To minimise the risk of diarrhoea, misoprostol should be taken with food, and magnesium-containing antacids should be avoided.

Misoprostol should be used with caution in patients in whom dehydration would be dangerous. These patients should be monitored carefully.

The results of clinical studies indicate that Misoprostol does not produce hypotension at dosages effective in promoting the healing of gastric and duodenal ulcers. Nevertheless, Misoprostol should be used with caution in the presence of disease states where hypotension might precipitate severe complications, e.g. cerebrovascular disease, coronary artery disease or severe peripheral vascular disease including hypertension.

There is no evidence that Misoprostol has adverse effects on glucose metabolism in human volunteers or patients with diabetes mellitus.

Interaction with other medicinal products and other forms of interaction

Concomitant administration of NSAIDs and misoprostol in rare cases can cause a transaminase increase and peripheral oedema.

Misoprostol is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system. In specific studies no clinically significant pharmacokinetic interaction has been demonstrated with antipyrine or diazepam. A modest increase in propranolol concentrations (mean approximately 20% in AUC, 30% in Cmax) has been observed with multiple dosing of misoprostol. In extensive clinical studies no drug interactions have been attributed to Misoprostol. Drug interaction studies with misoprostol and several NSAIDs showed no clinically significant effect on the kinetics of ibuprofen, diclofenac, piroxicam, aspirin, naproxen or indomethacin.

Magnesium-containing antacids should be avoided during treatment with misoprostol as this may worsen the misoprostol-induced diarrhoea.

Fertility, pregnancy and lactation

Pregnancy
Misoprostol is contraindicated in women who are pregnant because it induces uterine contractions and is associated with abortion, premature birth, foetal death and birth defects. First trimester exposure to misoprostol is associated with a significantly increased risk of two birth defects: Möbius sequence (i.e. palsies of cranial nerves VI and VII) and terminal transverse limb defects. Other defects including
arthrogryposis have been observed.

Very Common: ≥ 1/10 (>10%)
Common: ≥ 1/100 and < 1/10, (>1% and <10%)
Uncommon: ≥ 1/1000 and < 1/100, (>0.1% and <1%)
Rare: ≥ 1/10,000 and < 1/1000, (>0.01% and <0.1%)
Very Rare: < 1/10,000, (<0.01%)
Not Known
Immune System Disorder

Not Known

Anaphylactic reaction
Nervous System Disorders

Common

Dizziness, headache
Gastrointestinal Disorders

Very common

Common

Diarrhoea*

Abdominal pain*, constipation, dyspepsia, flatulence, nausea, vomiting

Skin and Subcutaneous Tissue Disorders

Very Common

Rash
Pregnancy, puerperium, and perinatal conditions

Not Known

Amniotic fluid embolism, abnormal uterine contractions, foetal death, incomplete abortion, premature birth, retained placenta, uterine rupture, uterine perforation
Reproductive System and Breast Disorders

Uncommon

Rare

Not Known

Vaginal haemorrhage (including postmenopausal bleeding), intermenstrual bleeding, menstrual disorder, uterine cramping

Menorrhagia, dysmenorrhoea

Uterine haemorrhage

Congenital, Familial and Genetic Disorders

Not Known

Birth defects
General Disorders and Administration Site Conditions

Not Known

Uncommon

Chills

Pyrexia

The risk of uterine rupture increases with advancing gestational age and with prior uterine surgery, including Caesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

Breast-feeding
Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. Misoprostol should not be administered to nursing mothers because the excretion of misoprostol acid could cause undesirable effects such as diarrhoea in nursing infants.

Effects on ability to drive and use machines
Misoprostol can cause dizziness. Patients should be cautioned about operating machinery and driving.

UNDESIRABLE EFFECTS
The Adverse reaction terms were then categorised utilising the incidence rate as follows:

* Diarrhoea and abdominal pain were dose-related, usually developed early in the course of therapy, and were typically self-limiting. Rare instances of profound diarrhoea leading to severe dehydration has been reported.

Diarrhoea can be minimised by using single doses not exceeding 200 micrograms with food and by avoiding the use of predominantly magnesium containing antacids when an antacid is required.

The pattern of adverse events associated with Misoprostol is similar when an NSAID is given concomitantly.

Clinical trials:

In clinical trials, over 15,000 patients and subjects received at least one dose of misoprostol. Adverse reactions involved primarily the gastrointestinal system.

Diarrhoea and abdominal pain were dose-related, usually developed early in the course of therapy, and were typically self-limiting. Rare instances of profound diarrhoea leading to severe dehydration have been reported.

The profile for adverse reactions with >1% incidence was similar for subacute (four to twelve weeks duration) and long- term (up to one year) clinical trials.

The safety of long-term (greater than 12 weeks) administration of misoprostol has been demonstrated in several studies in which patients were treated continuously for up to one year. This includes no adverse or unusual change in the morphology of gastric mucosa, as determined by gastric biopsy.

Special populations:

There were no significant differences in the safety profile of misoprostol in patients who were 65 years of age or older, compared with younger patients.

The use of misoprostol in children has not been evaluated.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Overdose
Signs and symptoms of overdose

The toxic dose of misoprostol in humans has not been determined. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhoea, fever, palpitations, hypotension, or bradycardia.

Treatment of overdose

Because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage. In cases of overdose, standard supportive measures should be adopted as required.

In clinical trials patients have tolerated 1200 micrograms daily for three months without significant adverse effects.

 Pharmacological properties

Pharmacodynamic properties

Pharmacotherapeutic group: prostaglandins, ATC code: A02BB01.

Misoprostol is an analogue of naturally occurring prostaglandin E1 which promotes peptic ulcer healing and symptomatic relief.

Mechanism of action
Misoprostol protects the gastroduodenal mucosa by inhibiting basal, stimulated and nocturnal acid secretion and by reducing the volume of gastric secretions, the proteolytic activity of the gastric fluid, and increasing bicarbonate and mucus secretion.

Pharmacokinetic properties

Misoprostol is rapidly absorbed following oral administration, with peak plasma levels of the active metabolite (misoprostol acid) occurring after about 30 minutes. The plasma elimination half-life of misoprostol acid is 20-40 minutes. No accumulation of misoprostol acid in plasma occurs after repeated dosing of 400 micrograms twice daily.

Preclinical safety data

In single and repeat-dose studies in dogs, rats and mice at multiples of the human dose, toxicological findings were consistent with the known pharmacological effects of the E-type prostaglandins, the main symptoms being diarrhoea, vomiting, mydriasis, tremors and hyperpyrexia. Gastric mucosal hyperplasia was also observed in the mouse, rat and the dog. In the rat and the dog the hyperplasia was reversible on discontinuation of misoprostol following one year of dosing. Histological examination of gastric biopsies in humans has shown no adverse tissue response after up to one year’s treatment. In studies of fertility, teratogenicity and peri/post-natal toxicity in rats and rabbits there were no major findings. A decrease in implantations and some pup growth retardation was observed at doses greater than 100 times the human dose. It was concluded that misoprostol does not significantly affect fertility, is not teratogenic or embryotoxic and does not affect rat pups in the peri/post-natal period.

Misoprostol was negative in a battery of 6 in vitro assays and one in vivo test to assess mutagenic potential. In carcinogenicity studies in the rat and mouse it was concluded that there was no risk of carcinogenic hazard.

Pharmaceutical particulars

List of excipients
Microcrystalline cellulose
Sodium starch glycolate (Type A)
Hydrogenated castor oil
Hypromellose

Incompatibilities

Not applicable.

Shelf life

3 years.

Special precautions for storage
Do not store above 30°C. Store in the original package to protect from moisture.

Nature and contents of container

Cold-formed aluminium blister packs of 56, 60, 112, 120 or 140 tablets.

Not all pack sizes may be marketed.

Special precautions for disposal and other handling

No special requirements.

MARKETING AUTHORISATION HOLDER

TAJ PHARMA CIS LTD.
Marksistsky lane 6, office 221, Moscow, 109147, Russia

MANUFACTURER:

Manufactured in India by:
TAJ PHARMACEUTICALS LTD,
220, Mahagujarat Ind. Estate,  Moraiya,

Tal. Sanand , Dist. Ahmedabad,

Gujarat, INDIA.

What is in this leaflet
1) What Misoprostol is and what it is used for
2) What you need to know before you take Misoprostol
3) How to take Misoprostol
4) Possible side effects
5) How to store Misoprostol
6) Contents of the pack and other information

1.What  Misoprostol is and what it is used for
·Misoprostol tablets contain misoprostol which is similar to a chemical substance called ‘prostaglandin’ which your body produces naturally. Prostaglandins are produced in the stomach and intestine and help to protect the lining. Misoprostol belongs to a group of medicines known as ‘anti-ulcer agents’.
·The Misoprostol tablets may help prevent you getting ulcers in your stomach or the part it empties into, called the duodenum. These ulcers could be caused by taking non-steroidal anti inflammatory drugs (NSAIDs) like diclofenac and naproxen. The way NSAIDs work means they reduce the amount of prostaglandins in your stomach and intestine. This can cause indigestion and lead to ulcers forming. The Misoprostol tablets will replace these prostaglandins and help to protect your stomach and intestine, so you can continue getting benefit from your NSAID. Misoprostol also reduces acid and increases bicarbonate in your stomach secretions.
· Misoprostol can also be used to heal existing ulcers.

2) What you need to know before you take Misoprostol

Misoprostol may not be suitable for everyone. Please read the following list carefully to see if any of these apply to you. Consult your doctor if you are not sure.

Do not take Misoprostol
·if you are allergic to misoprostol or any of the other ingredients of this medicine, or other prostaglandin medicines.
·if you are pregnant or trying to become pregnant because it may cause a miscarriage, premature· birth or birth defects.
· if you are breastfeeding (as this may give your baby diarrhoea).

Warnings and precautions
Talk to your doctor or pharmacist before taking Misoprostol. Tell your doctor if you have any of the following conditions to help him or her decide if Misoprostol is suitable for you:
·heart disease
·  low or high blood pressure, or any disease of the blood vessels
·  inflammatory bowel disease
·  prone to dehydration
If you are a younger woman who has not yet gone through the menopause, your doctor will have only prescribed Misoprostol if he is satisfied you are at high risk of developing ulcers from your NSAID medicine.

Other medicines and Misoprostol
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
You can take Misoprostol with most medicines without any problems. If you use an antacid (something to reduce acid in the stomach) you should avoid antacids with magnesium in them as these may make diarrhoea worse.
If you are taking any medicines for a heart condition, please consult your doctor. Use with NSAIDs in rare cases can result in swelling of feet or hands and an increase in liver enzymes. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
If you are a younger woman who has not yet gone through the menopause, your doctor will have only prescribed Misoprostol if he is satisfied you are at high risk of developing ulcers from your NSAID medicine. Your doctor will make you aware of the risks if you do become pregnant.
Misoprostol can cause a miscarriage or damage to your womb, so it is very important to use reliable contraception while taking this medicine. The risk of damage to your womb is greater in the later stages of pregnancy, and if you have had a previous Caesarean delivery or have given birth to five or more children. If you want to try for a baby, tell your doctor as you will have to stop taking Misoprostol and use a different treatment.
Misoprostol should not be taken by pregnant women and in women planning a pregnancy. Do not breastfeed while taking Misoprostol.

Driving and using machines
Dizziness has been reported after taking Misoprostol. Be cautious when driving or operating machinery until you know how the medicine affects you.

3) How to take Misoprostol

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
You should take Misoprostol with food.
Misoprostol is suitable only for adults aged 18 years and over.

To heal ulcers in your stomach or duodenum You should normally take two 200 microgram Misoprostol tablets twice a day with food. Alternatively you can take one Misoprostol tablet four times a day, at regular intervals with food. Treatment will usually last for 4 weeks, but may be extended up to 8 weeks.
If your ulcers are not completely healed after this period, further treatment may be given.

To prevent ulcers when taking NSAID medicines
You should usually take one 200 microgram tablet, two, three or four times a day. Your doctor will adjust your dose to suit you.
You will need to continue to take Misoprostol as long as is needed to protect your stomach or gut, and must keep taking the tablets until your doctor advises you to stop.

If you take more Misoprostol than you should
If you take too many tablets, contact your doctor or accident and emergency department straight away.

If you forget to take Misoprostol
If you forget to take a dose of your tablets, take them as soon as you remember. But if it is almost time for your next dose, do not take the tablet(s) you have missed.
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. Most of these don’t happen very often, are not serious and will often wear off after a while. If you are worried about any side effects, then talk to your doctor.
Stop taking the tablets and get emergency medical help immediately if you have any of the symptoms below which could represent an allergic reaction:
·swelling of the face, lips, tongue or throat (angioedema)
·  difficulty in breathing
·  swelling of the extremities (hands and feet)
If you get any of the following symptoms, tell your doctor immediately:
·prolonged heavy or painful bleeding
·  abnormal contractions of the womb

 The following side effects have been reported with Misoprostol:
Very common: may affect more than 1 in 10 people
·skin rashes
·  diarrhea
Diarrhoea is the most common problem and is occasionally severe. You have less chance of getting diarrhoea if you take Misoprostol with food. If you use an antacid (something to reduce acid in the stomach) you should avoid antacids with magnesium in them as these may make diarrhoea worse. Your pharmacist can help you choose a suitable antacid.

Common: may affect up to 1 in 10 people  ·dizziness
·headache  stomach pain
·  constipation
·  wind
·  indigestion
·  feeling or being sick

 Uncommon: may affect up to 1 in 100 people  ·fever
·  irregular periods
·  periods problems
·  severe uterine pain
·  some older women may have vaginal bleeding even though they have gone through the menopause

Rare: may affect up to 1 in 1,000 people  ·cramping
Not known: frequency cannot be estimated from the available data
·allergic reactions, including swelling of the hands and feet, face, lips, tongue or throat and
· which may cause great difficulty in breathing  prolonged heavy or painful bleeding
·  chills
·  high temperature
·  abnormal contractions of the womb
·  bleeding from the womb
·  tearing of the tissues in the womb
·  placenta remaining in the womb after birth, termination or miscarriage
·  amniotic fluid (the fluid which surrounds the baby when pregnant) entering the mother’s
· bloodstream causing an allergic reaction  incomplete miscarriage and premature birth
·  foetal death and birth defects

 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. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine

5) How to store Misoprostol

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.
Do not store above 30ºC. Keep the blister in the outer carton.
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.

  1. Further Information

What Misoprostol contains
The active substance is misoprostol. Each Misoprostol tablet contains 200 micrograms (mcg) of misoprostol.
– The other ingredients are microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil, and hypromellose (E464).

What Misoprostol looks like and the contents of the pack
Misoprostol tablets are white to off white hexagonal tablets scored on both sides and engraved ‘SEARLE 1461’ on one side. The tablets are packed in aluminium foil blisters in boxes containing 56, 60, 112, 120 or 140 tablets.
Not all pack sizes may be marketed

Manufactured by:
Taj Pharmaceuticals Limited
220, Mahagujarat Ind. Estate, Moraiya, Tal. Sanand, Dist. Ahmedabad, Gujarat, INDIA

Marketing Authorization Holder:
Regal sun co., Ltd.Myanmar

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