In Canada, the medication abortion pills are packaged and sold as Mifegymiso. Mifegymiso comes in an outer white box, containing two smaller boxes: a green box containing mifepristone 200 mg (MIFE) and an orange box containing misoprostol 800 mcg (MISO) (four small tablets of 200 mcg each)^[10].

MIFE is a progesterone receptor modulator. It is a potent anti-progestin that also exhibits strong antiglucocorticoid and weak antiandrogenic properties. It blocks progesterone receptors in early pregnancy, which leads to endometrial degeneration, synthesis of prostaglandins, and decline in beta- human chorionic gonadotropin (βhCG) secretion. These events promote cervical dilation and facilitate the onset of bleeding^[10].

MISO is a potent synthetic prostaglandin E1 that induces cervical ripening and uterine contractions, which cause the pregnancy tissues to leave the body^[10].

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MIFE is metabolized by CYP3A4 and is also an irreversible competitive inhibitor of CYP3A4 and, to a lesser extent, of CYPs 1A, 2B, 2D6 and 2E1. As MIFE binds CYP irreversibly and is slowly eliminated from the body, caution should be taken when MIFE is administered with drugs that are CYP3A4 substrates and have narrow therapeutic range^[10].

Drug interactions of importance in the clinical setting that may alter the metabolism of MIFE include^[10]:

• CYP3A4 inducers (glucocorticoids, macrolide antibiotics, rifampicin, carbamazepine, benzodiazepines, barbiturates, St. John’s wort).
• CYP3A4 inhibitors (cimetidine, ketoconazole, erythromycin, chloramphenicol, spironolactone, secobarbital, grapefruit juice).

MIFE has antiglucocorticoid activity; it may temporarily decrease the efficacy of corticosteroid therapy, including inhaled corticosteroids^[10].

As for MISO, there is no known drug interactions. Oral ingestion with food or antacids may decrease oral bioavailability^[10].

MIFE taken orally shows non-linear pharmacokinetics. It is rapidly absorbed and distributed, reaching peak concentrations after 0.75 hours. It is 94-99% plasma-bound and is metabolized by CYP enzymes, mainly CYP3A4. Elimination is relatively slow with a half-life ranging between 83 and 90 hours^[10].

MISO's pharmacokinetic profile varies substantially depending on the route of administration^[10]:

• Buccal: time to first uterine contraction is 67 minutes, sustained for about 90 minutes and begins to decline at 5 hours after administration. The uterine response appears similar to that of vaginal administration, with less inter-individual variability.
• Vaginal: time to first uterine contraction is 82 minutes for dry tablets and 98 minutes for moistened tablets, sustained activity is attained at 106 minutes and 128 minutes, respectively, and uterine activity begins to decline at five hours after administration.
• Sublingual: tablets are absorbed through the mucosa within 20 minutes and MISO reaches peak serum concentration at 30 minutes. First-pass metabolism is avoided.

Efficacy:

• MIFE / MISO is highly effective. The risk of ongoing pregnancy is 0.9% for pregnancies up to 49 days of gestation and 3.1% for pregnancies up to 70 days of gestation^[10].
• According to SOGC’s protocol for the provision of medication abortion via telemedicine, the patient should take a first dose of misoprostol buccally or vaginally 24-48 hours after taking mifepristone^[7].
• In addition, patients with gestational age 63 days or less should take the second dose of misoprostol if no bleeding occurs within the first 24 hours after the first misoprostol dose or as instructed by the clinician. Patients with a gestational age over 63 days should take a second dose of misoprostol 4 hours after the first dose^[7].

Side Effects and Complications^[10]:

• Very common (≥ 10%): Nausea, vomiting, diarrhea, dizziness, headache, chills / fever, weakness, fatigue, gastric discomfort, abdominal pain, vaginal bleeding, spotting, uterine contractions or cramping.
• Common (1-10%): Fainting, light or moderate gastrointestinal cramping, prolonged post-abortion bleeding, endometritis, breast tenderness, heavy bleeding (may or may not require surgical termination of pregnancy).
• Uncommon (0.1-1%): Arrhythmia, hemorrhagic shock, salpingitis, heavy bleeding requiring IV fluids or blood transfusion, infection, hot flushes, hypotension, bronchospasm, skin rash / pruritus.

Indication:

MIFE / MISO is indicated by Health Canada for pregnancy termination up to 63 days as counted from the first day of the last menstrual period (LMP) in a presumed 28-day cycle. The Society of Obstetricians and Gynaecologists of Canada indicates safe use up to 70 days after LMP. There is no absolute lower gestational age limit^[5].

Contraindications^[6]:

• Ectopic pregnancy
• Chronic adrenal failure
• Inherited porphyria
• Uncontrolled asthma
• Hemorrhagic disorder or concurrent anticoagulant therapy
• Anemia (Hb level < 9.5 g/dL)
• Long-term systemic corticosteroid therapy
• Allergy or hypersensitivity to product ingredients
• IUD in situ (no longer a contraindication once removed)
• Serious systemic illnesses such as liver disease, cardiac disease, renal failure and seizure disorders (these illnesses should be evaluated individually)
• Uncertain gestational age
• Decisional uncertainty

Breastfeeding / Chestfeeding^[6]:

Oral MISO is excreted into human breast milk in small amounts which are rapidly eliminated. No interruption of breastfeeding or chestfeeding is necessary when misoprostol is given by any route.

Gestational Age > 63 days

The Society of Obstetricians and Gynaecologists of Canada and the National Abortion Federation both endorse medication abortion (MA) with MIFE / MISO up to 70 days after LMP. They also recommend a second dose of MISO 800mcg four hours after the first dose of MISO 800mcg to increase the effectiveness of MA^[5,13].

The Society of Obstetricians and Gynaecologists of Canada also recommends a MIFE / MISO regimen from 70-84 days gestational age, with mifepristone 200mg followed in 24-48 hours with two doses of MISO 800mcg (buccal or vaginal), 4 hours apart.

The effectiveness decreases as the gestational age approaches 70 days. Prescribers should counsel patients that this is off-label use, that there is a possibility of expelling and seeing an intact fetus, and that there are higher rates of bleeding and incomplete or failed abortion.

Patients between 15 to 18 years of age

Data is insufficient to establish efficacy and safety in patients younger than 15 years old. However, in patients aged between 15 and 18 years, safety and efficacy have been demonstrated with vomiting and pain being reported more frequently than in adults^[11]. Thus, special considerations for patients in this age range can include counselling to prepare them for vomiting and pain, as well as psychosocial supports through the medication abortion process.

Prescribers will provide clinical assessments prior to prescribing MIFE / MISO. With the new guideline by SOGC for the provision of medical abortion via telemedicine (MA), prescribers may eliminate blood work or ultrasound, or both, to ensure timely provision of MA^[7].

• Gestational age is determined using medical history, urine or serum βhCG test, or ultrasound. Ultrasound is not required to determine gestational age, unless people seeking abortion are uncertain of their last menstrual period^[6,7].
• Ectopic pregnancy is ruled out using medical history to screen for risk factors and symptoms. Ultrasound is recommended if there are significant risk factors or symptoms suggestive of ectopic pregnancy^[6,7].
• Guideline on Rhesus testing and administration varies:
  • SOGC’s Guideline on Prevention of RhD Alloimmunization: Rh administration is suggested for non-sensitized Rh D-negative individuals who have experienced threatened, spontaneous, or induced abortion after 12 weeks gestation^[21].
  • The Society of Family Planning: Rh testing is not recommended prior to 12 weeks gestations for spontaneous, medications, or uterine aspiration abortion^[8].
• Complete blood count to measure hemoglobin level is indicated if there is an increased risk of anemia; otherwise, it is unnecessary^[7].
• Routine prophylactic antibiotics are not required; screen-and-treat is the preferred management strategy and it is performed by the prescriber^[6].