Products Information - Misoprost tablets

 Name of the Medicine: Misoprost tablets

Active Ingredient and concentration: misoprostol 200 microgram as misoprostol HPMC 1% dispersion. (Applicant Name: Multipharma for pharmaceutical and chemicals) Manufacturer: DBK for pharmaceuticals industries "D BK pharma"

Description

White, plain flat round tablets, scored from one side. Each tablet contains 200 micrograms of misoprostol as a 1% misoprostol HPMC. Misoprostol is a clear, colourless or yellowish oily liquid. Misoprost tablets contains the following excipients: microcrystalline cellulose, sodium starch glycolate and magnesium stearate.

Pharmacology

Pharmacodynamic properties

Pharmacotherapeutic group: Other gynecological medicines - prostaglandins. ATC Misoprostol is a synthetic analogue of prostaglandin E1. At the recommended dosages, misoprostol induces contractions of the smooth muscle fibers in the myometrium and relaxation of the uterine cervix. The uterotonic properties of misoprostol should facilitate cervical opening and evacuation of intrauterine debris. In the event of an early termination of pregnancy, the combination of Misoprost tablets used in a sequential regimen after mifepristone leads to an increase in the success rate and accelerates the expulsion of the conceptus. Pharmacodynamic studies in early pregnancy have found an increase in uterine tone around 8 minutes after oral and 40 minutes after buccal misoprostol, with sustained contractions achieved by a mean of around 90 minutes and uterine activity peaking prior to 5 hours. Following oral administration uterine activity rises earlier than other routes, but is lower overall. Pretreatment with mifepristone has previously been shown to increase uterine contractility in response to misoprostol.

Pharmacokinetic properties

Absorption

When administered orally, misoprostol is rapidly absorbed and metabolized. Peak concentrations around 1.1 ng/ml, were reached about 15 minutes after a 400 microgram dose in the fasting state. Plasma concentrations of its main degradation metabolite, misoprostol acid, reach their peak of 2 - 2.5 ng/mL after a 2 microgram/kg oral dose within approximately 30 minutes and rapidly decline thereafter. As a result, uterine contractility increases and then plateaus after about one hour. Absorption is almost complete, measured at levels between 64 - 73% from urinary data. While not compared directly with oral administration, buccal administration has been found to result in peak concentrations comparable to those following vaginal administration, which have been found in turn to be lower and later than those for oral administration.

Distribution

Serum protein binding of labeled misoprostol acid was studied in man and was similar in young (81-88%) and elderly (81-89%) subjects. Accumulation in erythrocytes was not seen.

Metabolism and excretion

Metabolism of misoprostol to misoprostol acid is rapid with no intact misoprostol found in plasma consistent with an in vitro half-life of 6.4 minutes for de-esterification of misoprostol in human plasma at 37°C. Elimination of misoprostol and its metabolites is also rapid with a plasma elimination half-life of 35 minutes. The liver is the primary site of metabolism and between 1-4% of misoprostol acid is excreted in the urine. Misoprostol has no known drug interactions. No induction of the hepatic cytochrome P-450 enzyme system has been observed.

Indications

Misoprost tablets is indicated in females of childbearing age for the medical termination of a developing intrauterine pregnancy in sequential combination with a mifepristone 200 mg tablet, up to 49 days of gestation.

Contraindications

• Known hypersensitivity to misoprostol (or any prostaglandin) or to any of the excipients;
• Contraindication to medical abortion including:
  • Known or suspected hypocoagulation diseases, treatment with anticoagulants;
  • Uncertainty about pregnancy age;
  • Suspected ectopic pregnancy;
• Contraindication to mifepristone.

Precautions

Misoprostol should not be administered if an intrauterine contraceptive device is present: it should be removed first. Because of its abortive properties, Misoprost should not be used by a woman with a viable pregnancy and who intends to carry that pregnancy to term. Uterine hyperstimulation and rupture have been reported beyond the first trimester when much lower dosage of misoprostol may be required. Rare serious cardiovascular accidents have been reported following administration of prostaglandins including misoprostol. For this reason women with risk factors for cardiovascular disease or established cardiovascular disease should be treated with caution. Epileptic seizures have been reported with prostaglandins and prostaglandin analogues administered by routes other than oral and this possibility should be borne in mind in patients with a history of epilepsy. Bronchospasm may occur with some prostaglandins and prostaglandin analogues. The possibility should be borne in mind in patients with a history of asthma.

Special warnings and precautions for use

Special warnings and precautions for use related to the combination of Misoprost with Mifepristone should also be followed.

Medical termination of a developing intra-uterine pregnancy

Ectopic pregnancy should be excluded and gestation confirmed prior to medical abortion. This method requires the involvement of the woman who should be informed of the requirements of the medical method, which involves:

• The necessity to combine treatment with Mifepristone
• The need for follow-up within 14 to 21 days after intake of Mifepristone and Misoprost tablet in order to confirm that the abortion is complete
• The non-negligible risk of failure (see Clinical Trials) of the medical method which may require termination by another method
• On discharge from the treatment center all women should be provided with appropriate medications as necessary and be fully counseled regarding the likely signs and symptoms she may experience and have direct access to the treatment center by telephone or local access.

The following risks related to the medical method must be taken into account and explained to the woman:

Failures

The non-negligible risk of failure, which occurs in up to 7% of cases, makes follow up mandatory in order to check that the expulsion is completed. Up to 49 days about 1% will have continuing pregnancies, the rest needing curettage for other reasons.

Bleeding

The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of 10 to 16 days after Mifepristone and Misoprostol intake) which may be heavy. Bleeding occurs in almost all cases and is not in any way proof of complete expulsion. Persistent bleeding can be the consequence of incomplete expulsion. Bleeding can be large enough to necessitate a blood transfusion and to lead to a significant decrease in haemoglobin levels. The patient should be informed not to travel far away from the prescribing center as long as complete expulsion has not been recorded. She will receive precise instructions as to whom she should contact and where to go, in the event of any problems emerging, particularly in the case of very heavy vaginal bleeding. Follow-up must take place within a period of 14 to 21 days after administration of Mifepristone and Misoprostol to verify by the appropriate means (clinical examination, ultrasound scan, or beta-hCG measurement) that expulsion has been completed and that vaginal bleeding has stopped. In case of persistent bleeding (even light) beyond this follow-up, the disappearance of bleeding should be checked within a few days. If an ongoing pregnancy is suspected, a further ultrasound scan may be required to evaluate its viability. Persistence of vaginal bleeding at this point could signify incomplete abortion, or an unnoticed extra-uterine pregnancy, and appropriate treatment should be considered. In the event of an ongoing pregnancy diagnosed after follow-up, termination by another method will be offered to the woman. Since heavy bleeding requiring haemostatic curettage occurs in up to 5% of cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialized consultants according to the type of haemostatic disorder and the level of anaemia.

Infection

As with other types of abortion, cases of serious bacterial infection, including very rare cases of fatal septic shock, have been reported following the use of mifepristone and misoprostol. No causal relationship between these events and the use of mifepristone and misoprostol has been established. Treating doctors evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event. In particular, a sustained fever of 38°C or higher, severe abdominal pain, or pelvic tenderness in the days after a medical abortion may be an indication of infection. A high index of suspicion is needed to rule out sepsis (from e.g. Clostridium sordellii or other species e.g. Streptococcus) if a patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking misoprostol. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. Most of these deaths occurred in women who used vaginally administered misoprostol however other forms of administration have been reported. No causal relationship between mifepristone and misoprostol use and an increased risk of infection or death has been established. Clostridium sordellii and other infections such as Streptococcus and other bacteria have also been reported very rarely following childbirth (vaginal delivery and caesarian section), and in other gynaecologic and nongynaecologic conditions. Reviews have estimated overall serious infection rates after medical abortion at less than 1%.

Effects on fertility

During clinical trials, pregnancies occurred between embryo expulsion and the resumption of menses. To avoid the potential exposure of a subsequent pregnancy to Misoprost, it is recommended that conception be avoided during the next menstrual cycle. Reliable contraceptive precautions should therefore commence as early as possible after administration of Misoprost. In fertility studies in rats in which treated females were mated with treated males, increased pre-implantation losses were observed with misoprostol at oral doses greater than 1 mg/kg/day (11 times the recommended human dose, on a mg/m2 basis). Post-implantation loss was also increased at 10 mg/kg/day (114 times the recommended human dose, on a mg/m2 basis).

Use in pregnancy

Use of misoprostol has been associated with birth defects. In a few cases where misoprostol was self-administered (orally or vaginally) in order to induce an abortion, the following deleterious effects of misoprostol have been suggested: malformations of limbs, of foetal movements and of cranial nerves (hypomimia, abnormalities in suckling, deglutition, and eye movements). To date, a risk of malformation cannot be excluded. Reproductive toxicity studies in animals showed embryotoxicity (increased resorptions) with oral doses of 1 mg/kg/day in rabbits, 10 mg/kg/day in rats, and 20 mg/kg in mice when treatment occurred during the period of organogenesis. An increased incidence of skeletal abnormalities was observed with an oral dose of 1 mg/kg/day in rabbits (possibly due to maternal toxicity) while an increased incidence of cleft palate was seen at a single oral dose of 30 mg/kg in mice (28 and 170 times the recommended human dose, on a mg/m2 body surface area basis, respectively).

Consequently:

• Women should be informed that due to the risk of failure of the medical method of pregnancy termination and to the unknown risk to the fetus, follow-up is mandatory (see Special Warnings and Precautions for Use).
• Should a failure of the medical method be diagnosed at follow-up (viable ongoing pregnancy), and should the patient still agree, pregnancy termination should be completed by another method.
• Should the patient wish to continue with her pregnancy, she should be appropriately counseled as to the risk of birth defects. In that event of continuation of the pregnancy, careful ultra-sonographic monitoring of the pregnancy should be carried out.

Use during lactation

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

Paediatric use

Limited data are available for use of misoprostol in women under 18 years of age. There is no relevant use of misoprostol in the prepubertal paediatric population in the indication.

Use in the elderly

There is no relevant use of misoprostol in the elderly population in the indication.

Effect on laboratory tests

There are no known effects of misoprostol on laboratory tests.

Interactions with other medicines

The serum protein binding of misoprostol acid was not affected by indomethacin, ranitidine, digoxin, phenylbutazone, warfarin, diazepam, methyldopa, propranolol, triamterene, cimetidine, paracetamol, ibuprofen, chlorpropamide and hydrochlorothiazide. With salicylic acid (300 microgram/mL), the protein binding of misoprostol was lowered from 84 to 52% which is not considered clinically significant since the binding of misoprostol acid is not extensive and its elimination half-life is very short. In laboratory studies, misoprostol has no significant effect on the cytochrome P450 linked hepatic mixed function oxidase system, and therefore should not affect the metabolism of theophylline, warfarin, benzodiazepines or other drugs normally metabolized by this system. No drug interactions have been attributed to misoprostol in extensive clinical trials. As such, other drugs would be unlikely to interfere with misoprostol's metabolism in either normal or hepatically-impaired patients.

Adverse effects

The most frequent undesirable effects which are observed during treatment with misoprostol are the following:

• Gastrointestinal disorders: nausea (transient and mild), vomiting, diarrhea, abdominal pain.
• Reproductive system disorders: very frequent uterine contractions observed in the hours following misoprostol intake; vaginal bleeding, sometimes heavy and prolonged when used with mifepristone for medical termination of pregnancy (see Special Warnings and Precautions for Use)
• General disorders: headache, dizziness, and chills and fever.

The adverse events reported with mifepristone and a prostaglandin analogue, classified according to frequency and system organ class, are summarized as shown in Table 1.

Table 1: Adverse Events for the Combined Use of Mifepristone and a Prostaglandin Analogue

MedDRA System Organ Class	Adverse events (frequency)
	Very common (≥ 1/10)	Common (> 1/100 to < 1/10)
Gastro-intestinal disorders	Nausea Vomiting Diarrhoea Dizziness Gastric discomfort Abdominal pain
Nervous system disorders	Headache
Reproductive system and breast disorders	Vaginal bleeding Uterine spasm	Prolonged post-abortion bleeding Spotting Severe haemorrhage Endometritis Breast tenderness Heavy bleeding
General disorders and administration site conditions	Fatigue Chill / fever	Fainting

Adverse Events reported with mifepristone, classified as "Uncommon" (≥ 1/1000 to < 1/100) are summarized as shown below:

• Reproductive System and Breast disorders: Haemorrhagic shock, Salpingitis.
• Infections and Infestations: Infection
• Vascular Disorders: Hot flush
• Skin and Subcutaneous Tissue Disorder: Skin Rash/ Pruritus

Adverse Events reported with mifepristone, classified as "Rare" (≥ 1/10000 to < 1/1000) and "Very Rare" (<1/10000*) are summarized as shown below:

• Gastro Intestinal Disorders: Gastric Bleeding
• Nervous System Disorders: Epilepsy, Neurogenic Tinnitus
• Reproductive System and Breast Disorders: Bilateral adnexal mass, Intrauterine adhesion, Ovarian cyst rupture, Breast abscess, Haematosalpinx, Uterine rupture
• General disorders and administration site conditions: Anaphylaxis, Periorbital edema
• Infections and infestations: Toxic Shock Syndrome
• Vascular Disorders: Superficial Thrombophlebitis, Hypotension
• Cardiac Disorders: Myocardial infarction, Induced Adam-Stokes Syndrome
• Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm, Induced bronchial asthma
• Skin and Subcutaneous tissue disorders: Urticarial reaction, Toxic Epidermal necrolysis
• Pregnancy Puerperium and perinatal conditions: Hydatiform mole, Ectopic pregnancy, Amniotic band syndrome, Gestational trophoblastic tumor, Uteroplacental apoplexy
• Hepatobiliary disorders: Abnormal liver function tests, Hepatic failure, Hepatorenal failure
• Blood and lymphatic system disorders: Thrombotic thrombocytopenic purpura, Thrombocytopenia, Induced systemic lupus erythematosus
• Renal and urinary disorders: Renal Failure
• Neoplasms Benign, Malignant and Unspecified: Elevated alpha-feto protein, Elevated carcinoembryonic antigen*
• Musculoskeletal and Connective Tissue Disorders: Limb spasm
• Eye Disorders: Ophthalmoplegia*
• Psychiatric Disorders: Mania*

\Including occasional case reports*

Bleeding is an almost constant part of the procedure, whatever the prostaglandin analogue used, and at any pregnancy term, although it is usually more abundant when pregnancy age increases. It can occur after mifepristone alone. When heavy, it usually reflects incomplete abortion and is observed in approximately 3 to 12% of cases, depending on the pregnancy age and the prostaglandin analogue used, and needs specific treatment. It can necessitate a blood transfusion in 0.5 to 1 percent of cases. It can be prolonged for several days after prostaglandin analogue administration and sometimes leads to a decrease in hemoglobin levels. This potentially severe complication justifies that after intake (i) follow-up takes place approximately 14 to 21 days after mifepristone and Misoprost administration to ensure that expulsion is complete with no persisting bleeding and (ii) until follow-up has taken place, the woman remains close to a facility where she can be treated at any moment in case of severe or prolonged bleeding.

Infectious complications, including Clostridium sordellii toxic shock appear extremely rare but can lead to fatal outcome. A high index of suspicion is needed to rule out sepsis (from e.g. Clostridium sordelli or other species e.g. Streptococcus) if a patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhoea) more than 24 hours after taking misoprostol. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, haemoconcentration, and general malaise. Most of these deaths occurred in women who used vaginally administered misoprostol. No causal relationship between mifepristone and misoprostol use and an increased risk of infection or death has been established.

The issue of the outcome of persisting pregnancy in the case of failure of the medical method remains incompletely solved; a risk of malformation attributable to mifepristone or to prostaglandin analogues such as misoprostol cannot be excluded, and women should be adequately counseled in such a situation. Another fact to take into consideration is the possibility of a pregnancy persisting in the form of an ectopic pregnancy, since evidence suggests that the method does not appear able to terminate an ectopic pregnancy.

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: epvic.pvcenter@eda.mohp.gov.eg

Dosage and administration

Medical termination of early pregnancy of up to 49 days of gestation, in combination with Mifepristone 200 mg tablet.

• Misoprost tablets must be administered 36 to 48 hours after the oral intake of mifepristone.
• Misoprost tablets dosage is 800 micrograms, i.e. 4 tablets in a single intake, orally, or if preferred taken as two doses of 400 micrograms, i.e. two tablets taken orally followed two hours later by another two tablets. Misoprost tablets may be taken buccally i.e: kept between the cheek and the gum for 30 minutes before any fragments being swallowed with water.
• A repeat dose of misoprostol may be offered after 1-7 days if abortion has not occurred.
• No dosage adjustment of misoprostol is necessary with renal or hepatic insufficiency when administered at the recommended doses.
• There are no data available on the effect of food intake on the absorption of misoprostol.
• Misoprostol should be taken 2 hours before or 2 hours after a meal.

Refer also to Contraindications, Precautions and Special Warnings and Precautions for Use.

Overdosage

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 micrograms have been tolerated, with only symptoms of gastrointestinal discomfort reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhea, fever, palpitations, hypotension or bradycardia. Hypertension and tachycardia have also been reported following overdoses. Overdose in pregnancy has resulted in uterine contractions with fetal death. There is no specific antidote. Treatment should be symptomatic and supportive. Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal may reduce absorption of misoprostol if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.

Presentation and storage conditions

Misoprost tablets Pack: Carton box containing 1, 2 (Al/Al) strips, each of 10 tablets and with inner leaflet. Keep out of the reach of children. Do not use after the expiry date printed on the outer packaging. Store in a temperature not exceeding 30 °C in the original packaging, in a dry place.

Shelf life: 3 years

 

   

     

About the Author

     

Dr. Ahmad Baker, PharmD

     

He is a senior pharmacist and health educator with extensive experience in the Middle East and North Africa region. Through his writing, Dr. Ahmad aims to empower communities by providing reliable, evidence-based health information. With expertise in clinical pharmacy and regulatory affairs, he strives to offer unique insights into healthcare and simplify complex medical concepts, making them accessible to everyone.

   

   

         

 

 

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