Composition, Pharmacological properties, Pharmacokinetics properties: absorption, distribution, elimination, Therapeutic indications, Dosage and administration, Contraindications, Side effects, Special warnings and precaution for use, Use in single, twin or multiple pregnancies, Teratogenic effects, Nonteratogenic effects, Drug interaction, Lactation, Overdose, Storage condition, Presentation, NAFDAC Registration number, Owner, Marketer and Manufacturer of Misoclear Tablet Medicine for Pregnancy Womb conditions and Ulcer.
Misoclear 200 tablet: Each tablet contains 200 micrograms of Misoprostol
Misoclear (Misoprostol) is a synthetic analogue of naturally occurring prostaglandin E1 and has antisecretory (inhibiting gastric acid secretion) and mucosal protective properties. Mispclear 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.
Being an analogue of prostaglandin E1, Misoclear has an excellent uterotonic effect through the production of uterine contractions. Thus, in many regions of the world it is widely used in obstetrics and gynaecology.
The onset of action for oral absorption is 4-10 minutes after application. Misoprostol is rapidly and almost completely absorbed from the gastro-intestinal tract after oral administration, appearing in the circulation within 90 seconds. Maximum plasma concentration of misoprostol acid is 12± 3 minutes after oral administration of the drug, and the half-life is 20-40 minutes. After a single 400mcg oral dose, peak serum concentration of misoprostol acid (Cmax) is 288 ±144 pg/mL, and time to attain peak concentration (Tmax) is 28±15 minutes. Steady state plasma concentration of misoprostol acid is reached within 49 hours and average about 690pg/mL with misoprostol dosages of 400mcg every 12 hours. Accumulation of misoprostol acid does not occur during continuous administration of the drug. Maximum plasma concentration of misoprostol acid is diminished when the dose is taken with food or with antiacids.
The onset of action for rectal absorption is 7-13 minutes after application. After 40mcg rectal dose, Cmax of misoprostol acid is 202±196pg/mL. The mean Tmax after rectal administration is 40-65 minutes, although it was measured as shorter (20 ± 14 minutes) in one recent study, and the half-life is 20-40 minutes.
Sublingual administration of misoprostol has similar pharmacokinetic properties as oral administration.
Vaginal administration of misoprostol has similar pharmacokinetic properties as rectal administration.
Distribution of misoprostol into human body tissues and fluids has not been fully characterized. Following oral administration of misoprostol in rats, the drug is widely distributed, achieving concentrations in stomach, intestines, liver, blood, and kidneys that are 6-73 times that in plasma. Misoprostol acid is approximately 80-90% bound to serum proteins.
Misoprostol is rapidly metabolized to free misoprostol acid following oral administration. The parent drug has a half-life of 6 minutes in vitro. Plasma concentrations of the free acid and other metabolites of the drug appear to decline in a biphasic manner. Following oral administration of misoprostol in healthy adults, the elimination half-life of the free acid is about 20-40 minutes.
Misoclear is indicated for:
Treatment of duodenal ulcer and gastric ulcer including those induced by nonsteroidal anti-inflammatory drugs (NSAID)
• Prophylaxis of NSAID-induced peptic ulcers
• Prevention of postpartum hemorrhage
• Treatment of postpartum hemorrhage
• Treatment of incomplete abortion and miscarriage
• Treatment of missed abortion in the first trimester
• Treatment for intrauterine fetal death (IUFD)
• Cervical ripening
DOSAGE AND ADMINISTRATION
Treatment of duodenal ulcer, gastric ulcer and NSAID induced peptic ulcer: 800 micrograms (mcg) orally daily in two or four divided doses taken with breakfast and / or each main meal and at bed time. 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 mcg orally 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.
Prevention of postpartum hemorrhage: 600 mcg orally administered immediately after the delivery of the baby and after confirmation that all fetuses have been delivered.
Treatment of postpartum hemorrhage: 1000 mcg rectally significantly reduces the need for additional interventions, especially among women who have not received misoprostol for prevention of PPH. A dose of 800 mcg sublingual misoprostol can also be used.
Treatment of incomplete abortion and miscarriage: A single dose of 600 mcg misoprostol orally. Additional treatment such as antibiotics, IV fluids, and pain killers might be needed depending on the condition of the patient. A dose of 400 mcg sublingual misoprostol is also shown to be effective in recent studies.
Treatment of missed abortion in the first trimester: 800 mcg vaginally or sublingually, every 24 hours for 2 days. Bleeding may persist for up to 1 week. Incomplete abortions are experienced in 5% of the cases and a subsequent evacuation of the uterus might be necessary.
Cervical ripening prior to uterine instrumentation (or cervical priming prior to transcervical procedures): 400 mcg vaginally or orally 3 hours before the procedure.
Induction of labor with dead fetus: Intra Uterine Fetal Death (IUFD) from 13 to 17 weeks: 200 mcg vaginally every 6 to 12 hours for a total of 4 doses. IUFD from 18 to 26 weeks: 100 mcg vaginally every 8 to 12 hours for a total of 4 doses. IUFD beyond 26 weeks: If the cervix is unripe (Bishop score <6), vaginal misoprostol 25-50 mcg is given every 4 hours (up to 6 doses). If the cervix is already ripe (Bishop score ≥6), use the same first dose of 25-50 mcg. If the first dose does not lead to effective contractions the subsequent dose could be doubled to 50 or 100 mcg. The maximum daily dosing should not exceed 600 mcg. If expulsion has not occurred after 24 hours, the same treatment course may be repeated a second time.
Misoclear should not be taken by anyone with a known allergy to prostaglandins.
Misoclear should not be taken to treat or prevent ulcers by pregnant women or women of childbearing potential. When administered to pregnant women Misoclear can cause premature contractions, bleeding, potential birth defects, and, in higher doses than recommended, may cause rupture of the uterus.
Misoprostol is an E1 prostaglandin analogue and so, in contrast to other prostaglandins, it has no significant effect on the lungs or blood vessels (and so can be used in asthmatics). With doses over 400 mcg, diarrhea can occur and some patients experience a brief increase in temperature with shivering. Both effects are dose dependent and settle rapidly without treatment. Patients can experience shivering and pyrexia (usually no more than 38-39 oC) which resolve spontaneously in a few hours.
The most frequent gastrointestinal adverse events are diarrhea (13% of all patients) and abdominal pain (7%). Diarrhea is dose related and usually develops early and is self-limiting. Rare instances of profound diarrhea, leading to severe dehydration have been reported. Patients with an underlying condition, such as inflammatory bowel disease, or those in whom dehydration would be dangerous should be monitored carefully if Misoclear is prescribed. The incidence of diarrhea could be minimized if administering after meals or at bedtime, and by avoiding co-administration of Misoclear with predominantly magnesium containing antacids.
The following gynecological disorders have been reported: spotting (0.7%), cramps (0.6%), hypermenorrhea (0.5%), menstrual disorder (0.3%), and dysmenorrhrea (0.1%). Postmenopausal vaginal bleeding may be related to Misoclear administration. If it occurs diagnostic workup should be undertaken to rule out gynecological pathology.
There are no significant differences in the safety profiles of patients using Misoclear for prevention and treatment of ulcers who are 65 years of age or older compared with younger patients.
The following adverse reactions were reported by more than 1% of the patients receiving Misoclear and may be casually related to the drug: nausea (32%), flatulence (2.9%), headache (2.4%), dyspepsia (2.0%), vomiting (1.3%), and constipation (1.1%).
Mild shivering and pyrexia have been reported when Misoclear has been used for postpartum hemorrhage. These symptoms are transient and typically resolve without intervention. Other rare symptoms are nausea, vomiting, headache, diarrhea, and possibility of skin rashes.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Elderly: The usual dosage may be used.
Renal impairment: Available evidence indicates that no adjustment of dosage is necessary in patients with renal impairment.
Hepatic impairment: Misoclear is metabolized by fatty acid oxidizing systems present in organs throughout the body. Its metabolism and plasma levels are therefore unlikely to be affected markedly in patients with hepatic impairment.
Children: Use of Misoclear in children has not yet been evaluated in the treatment of peptic ulceration or NSAID-induced peptic ulcer disease.
For peptic ulcers: Misoclear should not be used for reducing the risk of NSAID-induced ulcers for women of child bearing potential unless the patient is at high risk of development of or complications from gastric ulcers. In such cases Misoclear may be prescribed if the patient:
• Has had a negative pregnancy serum test within two weeks prior to beginning Misoclear treatment
• Is capable of complying with effective contraceptive measures
• Will be begin Misoclear regimen only on the second or third day after the next normal menstrual period
Twin or Multiple Pregnancies: Misoclear may only be used to prevent or treat postpartum hemorrhage after the delivery of all newborns. In the case of multiple births (twins, triplets. etc.) all fetuses should be delivered before administering Misoclear, as uterine contractions caused by misoprostol would greatly endanger additional fetuses remaining inside the uterus.
Misoprostol and use in pregnancy: If a women is or becomes pregnant while taking this drug to reduce the risk of gastric, duodenal or NSAID-induced ulcers, this drug should be hazard to the fetus.
Teratogenic effects: Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient. This effect is likely to be the result of temporary vascular disruption in the placental fetal unit due to contractions and bleeding caused by misoprostol. Use of misoprostol during the first trimester of pregnancy has been associated with skull defects, cranial nerve palsies, facial malformations, and limb defects. Misoprostol is not fetotoxic or teratogenic in animals at doses 63-625 times the human dose.
Nonteratogenic effects: Misoclear may endanger pregnancy (cause contractions, and may cause bleeding) and thereby cause-harm to the fetus when administered to a pregnant woman. Misoclear produces uterine contractions and expulsion of the products of conception.
Misoclear has not been shown to interfere with the beneficial effects of aspirin on signs and symptoms of rheumatoid arthritis. Misoclear does not exert clinically significant effects on the absorption, blood levels, and antiplatelet effects of the therapeutic doses of aspirin. Misoclear has no clinically significant effect on the kinetics of diclofenac or ibuprofen.
For peptic ulcers: Misoprostol levels in breast milk are negligible and decline rapidly, with a milk elimination half-life of 60-90 minutes. Therefore, Misoclear should not be continuously administered to nursing mothers because the potential excretion of misoprostol acid could cause diarrhea in nursing infants.
For postpartum hemorrhage: Misoprostol enters human milk. Newborns of the mothers that take misoprostol could potentially develop the drug’s side effects. However, the maximum concentration in the breast milk (21 pg/mL peaks at 1 hour, followed by a rapid decline in levels) is much lower than other postpartum oxytocics, namely methylergometrine. After 5 hours of a single oral dose of 600 mcg of misoprostol, the levels in breast milk are immeasurable. Because the levels of misoprostol in breast milk are so small and decline very rapidly, the risk to the infant is minimal with a single dose. When administered for postpartum hemorrhage, misoprostol has no breastfeeding contraindications.
The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of gastrointestinal discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremors, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy.
Store at room temperature (30oC) and protect tablets from humidity. No refrigeration is necessary. Keep Out of children’s reach.
Misoclear 200 Tablet: pack of 3 tablets
NAFDAC No. A4-6446
Marie Stopes International, London, UK
MARIE STOPES INTERNATIONAL NIGERIA
4, Kikuyu Close, Off Nairobi Street,
Off Aminu Kano crescent, Wuse 2, Abuja. Nigeria.
Acme Formulation (P). Ltd.
Roper Road, Nalagarh, Dist. Solan,
Himachal Pradesh – 174101 (India)