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she may experience and have direct access to the treatment centre by telephone or local 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 Clinical efficacy of early medical abortion is defined as complete abortion without surgical an increased incidence of cleft palate was seen at a single oral dose of 30 mg/kg in mice (28 and intervention, regardless of the reason for the intervention, which may include continuing The following risks related to the medical method must be taken into account and explained to 170 times the recommended human dose, on a mg/m2 body surface area basis, respectively). pregnancy, missed or incomplete abortion, prolonged or heavy vaginal bleeding or a woman’s GyMiso®, misoprostol 200 microgram tablet A study of 966 patients with pregnancies up to 63 DA, randomized to 200 mg mifepristone The non-negligible risk of failure, which occurs in up to 7% of cases, makes follow up mandatory Australian Approved Name (AAN): Misoprostol - Women should be informed that due to the risk of failure of the medical method of followed 24-36 hours later by 800 micrograms of misoprostol orally or buccally, reported efficacy in order to check that the expulsion is completed. Up to 49 days about 1% will have continuing pregnancy termination and to the unknown risk to the fetus, follow-up is mandatory (see rates of 91.3% for the oral and 96.2% for the buccal group (RR 0.95, 95%CI 0.92¬0.98, pregnancies, the rest needing curettage for other reasons. Special Warnings and Precautions for Use). p=0.003). When patients at 43-49 days gestation were considered, efficacy rates were not significantly different according to route of administration, 94.7% for the oral and 96.4% for the - Should a failure of the medical method be diagnosed at follow-up (viable ongoing buccal group. This study allowed a repeat dose of misoprostol if abortion had not occurred by pregnancy), and should the patient still agree, pregnancy termination should be completed The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of 10 to 16 days after Mifepristone Linepharma and GyMiso® intake) which may be heavy. Bleeding Clinical trials have reported efficacy rates varying from 89-98% with oral misoprostol in doses occurs in almost all cases and is not in any way proof of complete expulsion. Persistent bleeding Should the patient wish to continue with her pregnancy, she should be appropriately counseled of 400 to 800 micrograms 24-48 hours after mifepristone. Varying results are likely due in part can be the consequence of incomplete expulsion. Bleeding can be large enough to necessitate a as to the risk of birth defects. In that event of continuation of the pregnancy, careful ultra- to varying follow up and intervention practices. Some studies reported higher efficacies when a blood transfusion and to lead to a significant decrease in haemoglobin levels. sonographic monitoring of the pregnancy should be carried out. repeat dose of misoprostol was offered at a varying time interval (1-14 days) after the first dose. The patient should be informed not to travel far away from the prescribing centre as long as For patients up to 49 days gestation clinical trials have consistently reported efficacy rates of at complete expulsion has not been recorded. She will receive precise instructions as to whom she least 93% using 800 micrograms misoprostol orally in single or divided doses or 800 micrograms should contact and where to go, in the event of any problems emerging, particularly in the case Misoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active buccally 24-48 hours after 200 mg mifepristone, when a follow up dose could be used. and is excreted in breast milk. GyMiso® should not be administered to breastfeeding mothers because the excretion of misoprostol acid could cause undesirable effects such as diarrhoea in White, flat round tablet with ‘ML’ debossed on one side and ‘200’ on the other side. Most studies that have reported mifepristone and oral misoprostol regimens in women after 49 Follow-up must take place within a period of 14 to 21 days after administration of Mifepristone days gestation have found significantly lower efficacy rates at later gestations, often less than Linepharma and GyMiso® to verify by the appropriate means (clinical examination, ultrasound Each tablet contains 200 micrograms of misoprostol as a 1% dispersion of 90%; for this reason oral misoprostol should not be used in medical abortion regimens after scan, or beta-hCG measurement) that expulsion has been completed and that vaginal bleeding misoprostol¬hypromellose. Misoprostol is a clear, colourless or yellowish oily liquid. 49 days gestation. Such a decline has not been observed using buccal misoprostol to 63 days. has stopped. In case of persistent bleeding (even light) beyond this follow-up, the disappearance GyMiso® contains the following excipients: hypromellose, cellulose - microcrystalline, sodium of bleeding should be checked within a few days. Limited data are available for use of misoprostol in women under 18 years of age. There is no starch glycollate type A and castor oil - hydrogenated. relevant use of misoprostol in the prepubertal paediatric population in the indication. If an ongoing pregnancy is suspected, a further ultrasound scan may be required to evaluate its GyMiso® 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 Persistence of vaginal bleeding at this point could signify incomplete abortion, or an unnoticed There is no relevant use of misoprostol in the elderly population in the indication. extra-uterine pregnancy, and appropriate treatment should be considered. In the event of an Pharmacotherapeutic group: Other gynecological medicines – prostaglandins. ATC code: ongoing pregnancy diagnosed after follow-up, termination by another method will be offered to Genotoxicity Misoprostol has been evaluated in tests for mutagenicity in bacterial, yeast and mammalian cells: Misoprostol is a synthetic analogue of prostaglandin E1. At the recommended dosages, • Known hypersensitivity to misoprostol (or any prostaglandin) or to any of the excipients; Since heavy bleeding requiring haemostatic curettage occurs in up to 5 % of cases during and for clastogenicity in vitro (Chinese hamster ovary cells) and in vivo (mouse bone marrow misoprostol induces contractions of the smooth muscle fibers in the myometrium and relaxation • Contraindication to medical abortion (see Product Information of Mifepristone Linepharma 200 the medical method of pregnancy termination, special care should be given to patients with micronucleus test). No evidence of genotoxicity was observed.
of the uterine cervix. The uterotonic properties of misoprostol should facilitate cervical opening haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical - Known or suspected hypocoagulation diseases, treatment with anticoagulants; or the surgical method should be decided with specialised consultants according to the type of haemostatic disorder and the level of anaemia. In the event of an early termination of pregnancy, the combination of GyMiso® used in a The potential carcinogenicity of misoprostol has been evaluated in both mice and rats. There sequential regimen after mifepristone leads to an increase in the success rate and accelerates was no evidence of an effect of misoprostol on tumour occurrence or incidence in rats receiving oral doses up to 2.4 mg/kg/day for 24 months. Similarly, there was no effect of misoprostol on As with other types of abortion, cases of serious bacterial infection, including very rare cases of tumour occurrence or incidence in mice receiving oral doses up to 16 mg/kg/day for 21 months. Pharmacodynamic studies in early pregnancy have found an increase in uterine tone around 8 fatal septic shock, have been reported following the use of mifepristone and misoprostol. No These doses are at least 27 times the recommended human dose, on a mg/m2 body surface minutes after oral and 40 minutes after buccal misoprostol, with sustained contractions achieved causal relationship between these events and the use of mifepristone and misoprostol has been by a mean of around 90 minutes and uterine activity peaking prior to 5 hours. Following oral Misoprostol (or mifepristone) should not be administered if an intrauterine contraceptive device established. Treating doctors evaluating a patient who is undergoing a medical abortion should be administration uterine activity rises earlier than other routes, but is lower overall. Pretreatment alert to the possibility of this rare event. In particular, a sustained fever of 38C or higher, severe with mifepristone has previously been shown to increase uterine contractility in response to abdominal pain, or pelvic tenderness in the days after a medical abortion may be an indication Because of its abortive properties, GyMiso® should not be used by a woman with a viable There are no known effects of misoprostol on laboratory tests. 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 misoprosotol may be 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 The serum protein binding of misoprostol acid was not affected by indomethacin, ranitidine, Rare serious cardiovascular accidents have been reported following administration of (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking misoprostol. digoxin, phenylbutazone, warfarin, diazepam, methyldopa, propranolol, triamterene, cimetidine, When administered orally, misoprostol is rapidly absorbed and metabolized. Peak concentrations prostaglandins including misoprostol. For this reason women with risk factors for cardiovascular Very rarely, deaths have been reported in patients who presented without fever, with or without paracetamol, ibuprofen, chlorpropamide and hydrochlorothiazide. With salicylic acid (300 around 1.1 ng/mL were reached about 15 minutes after a 400 microgram dose in the fasting disease or established cardiovascular disease should be treated with caution. abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, microgram/mL), the protein binding of misoprostol was lowered from 84 to 52% which is not state. Plasma concentrations of its main degradation metabolite, misoprostol acid, reach their and general malaise. Most of these deaths occurred in women who used vaginally administered considered clinically significant since the binding of misoprostol acid is not extensive and its peak of 2 - 2.5 ng/mL after a 2 microgram/kg oral dose within approximately 30 minutes and Epileptic seizures have been reported with prostaglandins and prostaglandin analogues misoprostol however other forms of administration have been reported. No causal relationship rapidly decline thereafter. As a result, uterine contractility increases and then plateaus after about administered by routes other than oral and this possibility should be borne in mind in patients between mifepristone and misoprostol use and an increased risk of infection or death has been one hour. Absorption is almost complete, measured at levels between 64 - 73% from urinary established. Clostridium sordellii and other infections such as Streptococcus and other bacteria In laboratory studies, misoprostol has no significant effect on the cytochrome P450 linked data. While not compared directly with oral administration, buccal administration has been found have also been reported very rarely following childbirth (vaginal delivery and caesarian section), hepatic mixed function oxidase system, and therefore should not affect the metabolism of to result in peak concentrations comparable to those following vaginal administration, which have Bronchospasm may occur with some prostaglandins and prostaglandin analogues. The possibility and in other gynaecologic and non-gynaecologic conditions. Reviews have estimated overall theophylline, warfarin, benzodiazepines or other drugs normally metabolized by this system. No been found in turn to be lower and later than those for oral administration. should be borne in mind in patients with a history of asthma.
serious infection rates after medical abortion at less than 1%. 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- Serum protein binding of labeled misoprostol acid was studied in man and was similar in young During clinical trials, pregnancies occurred between embryo expulsion and the resumption of (81-88%) and elderly (81-89%) subjects. Accumulation in erythrocytes was not seen. Special warnings and precautions for use related to the combination of GyMiso® with Mifepristone menses. To avoid the potential exposure of a subsequent pregnancy to GyMiso®, it is recommended Linepharma, should also be followed (see Mifepristone Linepharma 200 mg tablet Product that conception be avoided during the next menstrual cycle. Reliable contraceptive precautions should therefore commence as early as possible after administration of GyMiso®. The most frequent undesirable effects which are observed during treatment with misoprostol Metabolism of misoprostol to misoprostol acid is rapid with no intact misoprostol found in plasma Medical termination of a developing intra-uterine pregnancy: consistent with an in vitro half-life of 6.4 minutes for de-esterification of misoprostol in human In fertility studies in rats in which treated females were mated with treated males, increased • Gastrointestinal disorders: nausea (transient and mild), vomiting, diarrhea, abdominal pain. plasma at 37ºC. Elimination of misoprostol and its metabolites is also rapid with a plasma Ectopic pregnancy should be excluded and gestation confirmed prior to medical abortion. 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 This method requires the involvement of the woman who should be informed of the requirements also increased at 10 mg/kg/day (114 times the recommended human dose, on a mg/m2 basis). • Reproductive system disorders: very frequent uterine contractions observed in the hours following misoprostol intake; vaginal bleeding, sometimes heavy and prolonged when The liver is the primary site of metabolism and between 1-4% of misoprostol acid is excreted used with mifepristone for medical termination of pregnancy (see Special Warnings and - The necessity to combine treatment with Mifepristone Linepharma Misoprostol has no known drug interactions. No induction of the hepatic cytochrome P-450 - The need for follow-up within 14 to 21 days after intake of Mifepristone Linepharma and Use of misoprostol has been associated with birth defects. In a few cases where misoprostol • General disorders: headache, dizziness, and chills and fever. GyMiso® in order to confirm that the abortion is complete 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 - The non-negligible risk of failure (see Clinical Trials) of the medical method which may cranial nerves (hypomimia, abnormalities in suckling, deglutition, and eye movements). To date, Because castor oil is an excipient, digestive symptoms (nausea, vomiting, abdominal pain) can a risk of malformation cannot be excluded. - On discharge from the treatment centre all women should be provided with appropriate Reproductive toxicity studies in animals showed embryotoxicity (increased resorptions) with oral medications as necessary and be fully counseled regarding the likely signs and symptoms doses of 1 mg/kg/day in rabbits, 10 mg/kg/day in rats, and 20 mg/kg in mice when treatment The adverse events reported with mifepristone and a prostaglandin analogue, classified according Bleeding is an almost constant part of the procedure, whatever the prostaglandin analogue to frequency and system organ class, are summarized as shown in Table 1. 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 Table 1: Adverse Events for the Combined Use of Mifepristone 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 Licensed from Linepharma (France). GyMiso® is a registered trademark of HRA Pharma, France, 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 GyMiso® administration to ensure that expulsion is complete with no Very common (≥ 1/10) Common (> 1/100 to < 1/10) persisting bleeding and (ii) until follow-up has taken place, the woman remains close to a facility Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG) 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 sordellii 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 The prescriber must ensure that consent and treatment of the patient is in accordance with the without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, appropriate state or territory legislation. 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. Medical termination of early pregnancy of up to 49 days of gestation, in combination with Adverse Events reported with mifepristone, classified as “Uncommon” (≥ 1/1000 to < 1/100) are • GyMiso® must be administered 36 to 48 hours after the oral intake of mifepristone. • Reproductive System and Breast disorders: Haemorrhagic shock, Salpinitis. • G yMiso® 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 • Infections and Infestations: Infection later by another two tablets. GyMiso® 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. • Skin and Subcutaneous Tissue Disorder: Skin Rash/ Pruritus No dosage adjustment of misoprostol is necessary with renal or hepatic insufficiency when Adverse Events reported with mifepristone, classified as “Rare” (≥ 1/10000 to < 1/1000) and “Very Rare” (<1/10000*) are summarized as shown below: There are no data available on the effect of food intake on the absorption of misoprostol. • Gastro Intestinal Disorders: Gastric Bleeding Misoprostol should be taken 2 hours before or 2 hours after a meal. Refer also to Contraindicatons, Precautions and Special Warnings and Precautions For Use. • Nervous System Disorders: Epilepsy, Neurogenic Tinnitus • Reproductive System and Breast Disorders: Bilateral adnexal mass, Intrauterine adhesion, Ovarian cyst rupture, Breast abscess, Haematosalpynx, Uterine rupture 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 • General disorders and administration site conditions: Anaphylaxis, Periorbital edema • Infections and infestations: Toxic Shock Syndrome Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnoea, abdominal pain, diarrhea, fever, palpitations, hypotension or bradycardia. Hypertension and • Vascular Disorders: Superficial Thrombo-phlebitis, Hypotension tachycardia have also been reported following overdoses. Overdose in pregnancy has resulted in • Cardiac Disorders: Myocardial infarction, Induced Adam-Stokes Syndrome There is no specific antidote. Treatment should be symptomatic and supportive. Consider • Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm, Induced bronchial asthma 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 • Skin and Subcutaneous tissue disorders: Urticarial reaction, Toxic Epidermal necrolysis 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. • Pregnancy Puerperium and perinatal conditions: Hydatiform mole, Ectopic pregnancy, For information on the management of overdose, contact the Poisons Information Centre on 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, GyMiso®, misoprostol 200 microgram tablets are packaged in dual-faced aluminium blisters Thrombocytopenia , Induced systemic lupus erythematosus and presented in a box of four white, round, flat tablets with ML on one side and 200 on the • Renal and urinary disorders: Renal Failure • Neoplasms Benign, Malignant and Unspecified: Elevated alpha-feto protein, Elevated Do not use after the expiry date printed on the outer packaging. Store below 25°C in the original packaging. • Musculoskeletal and Connective Tissue Disorders: Limb spasm

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