Thursday, August 10, 2017

Africa Does Not need Melinda Gates' Contraception Project

8 Tools for Coping with Miscarriage

8 Tools for Coping with Miscarriage
http://www.womendeservebetter.com/8-tools-for-coping-with-miscarriage

Emotions You May Feel:
It’s normal to feel an array of emotions after a pregnancy loss. These emotions can range from but are not limited to: sadness, numbness, shock, depression, anger, disbelief, a sense of failure, and vulnerability.

The first thing to remember during this time is that it’s OK to feel these emotions.

Second, the loss of pregnancy isn’t your fault; complications can happen to any woman.

Some women experience physical symptoms while dealing with their emotional distress. You might experience fatigue, trouble sleeping, difficulty concentrating, and loss of appetite. There are hormonal changes that occur after a miscarriage, and this can intensify these emotions.

Some Things You Can Do:
  • Grief and loss are different for everyone, and the time it will take to heal will vary depending on the person. Give yourself time to heal.
  • You may need a chance to process what happened and how you feel. Taking time off of work can be a good way to give yourself time to understand your loss.
  • Sharing your stories with others can actually help you heal with your loss. It may feel painful to talk about, but people can help you not feel alone in this situation. Not everyone will have the right response to your news because he or she hasn’t been through it, but it’s about not keeping the pain to yourself regardless of how someone responds to the news.
  • Try to not close yourself off from others. You don’t have to tell everyone; you can just share your news to a few close friends.
  • Your partner may be coping and reacting in a different way than you are.
  • It’s important to remember that everyone grieves differently. Men, on average, react differently from women when it comes to grief and loss. He may be keeping his feelings inside instead of dealing openly with his loss with others.
Where You Can Get Support:

Tuesday, April 25, 2017

Study finds gender imbalance in children born to Indo-Canadian women

Study finds gender imbalance in children born to Indo-Canadian women
Karen Howlett
http://www.theglobeandmail.com/news/national/study-finds-gender-inbalance-in-children-born-to-indo-canadian-women/article34794700/
Fewer girls than boys are born to Indian women who immigrate to Canada, a skewed pattern driven by families whose mother tongue is Punjabi, according to a new study.
 
One of the most surprising findings of the study, to be published Monday in the Journal of Obstetrics and Gynecology Canada, is that the preference for boys does not diminish, regardless of how long women from India have lived in Canada.
 

“It’s counterintuitive,” said Marcelo Urquia, a research scientist at the University of Manitoba’s Centre for Health Policy and lead author of the study. “We know that the longer immigrants are in Canada, the more likely they are to align to the host country.”

 
But for many Indian immigrants who express a strong desire for sons, the study found, the practice of sex selection remains entrenched. Women who already have two female children are most at risk for abortions in the second trimester, when parents can learn the sex of the fetus. The study builds on previous research led by Dr. Urquia that found a deficit in Canada of more than 4,400 girls over two decades.
 
The latest study shows that women born in India who already have two daughters gave birth to 192 baby boys in Ontario for every 100 girls. The sex ratios are so distorted, they cannot be explained by natural causes, Dr. Urquia said. Across the globe, by comparison, the odds of having a boy over a girl are slightly higher: 107 boys for every 100 girls.
 
The preference for boys among many Indian immigrants reveals underlying gender inequities and will not change without intervention, Dr. Urquia said.
 
Amanpreet Brar, a third-year medical student at the University of Toronto who worked on the study, said gender-selection abortion was talked about openly in India’s Punjab province, where she grew up, but she was surprised to learn that it also happens in Canada.
 
Ms. Brar, who immigrated to Canada with her family when she was 14, remembers the traditional celebration called a Lohri in India for celebrating the birth of a boy.
 
“It was rare to hear about a girl’s birth being celebrated,” she said.
But some steps have been taken in Canada to end gender-based customs and celebrate the birth of girls. In Brampton, Ont., where 40 per cent of the population is South Asian, one hospital has started handing out Ladoos, a sugary Indian sweet, when a baby girl is born, Ms. Brar said. Traditionally in India, Ladoos were just for moms who delivered boys.
 
The study analyzed 46,834 birth records for Indian-born mothers who delivered up to three live births in Ontario hospitals between April, 1993, and March, 2014, and who immigrated to Canada between 1985 and 2012. Mothers who gave birth to twins or triplets were excluded. The study also looked at the mother’s birth place, her mother tongue and how long she had been in Canada.
 
Among all the mothers having their third child, nearly twice as many males were born compared with females if the previous two children were girls. The ratio was even higher among women whose mother tongue was Punjabi: 240 boys to 100 girls. The ratio of males to females did not differ according to when women arrived in Canada.
 
In India, the ratio of male to female newborns varies considerably, with several northern states consistently showing numbers that favour boys, the study says. The practice of sex selection is not widespread across India but it is prevalent, said Kripa Sekhar, executive director of the South Asian Women’s Centre in Toronto.
 
“Many members of the community welcome a girl child,” she said. “It’s a small minority of the community in Canada that still practises this.”
 
A woman has a fundamental right in Canada to decide whether to have an abortion, and should not come under pressure from a spouse or other family members to deliver a male child, Ms. Sekhar said.
 
“This is an issue of choice that is taken away from a woman,” she said. “In many ways it is very abusive.”
 
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Follow on Twitter: @kahowlett


Also on The Globe and Mail



▶ Play


Liberals not opening abortion debate, Justice Minister says (The Canadian Press)

Saturday, January 21, 2017

Some women stay away from Women's March over abortion issue

Bloggers note: the long reach of the PP Abortion industry....

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Some women stay away from Women's March over abortion issue

Melissa Linebaugh was looking forward to taking part in the Women’s March on Washington with her mother and her 9-year-old daughter.

A self-described Christian liberal from Dover, Pa., she was horrified by President Trump’s rhetoric toward women and minorities during the campaign. This was their chance, she thought, to stand with other women in support of a more inclusive and equal world.
Then she read that the organizers had refused to partner with a group of antiabortion feminists. Would she, Linebaugh wondered, be welcome? 

“As liberal as I am,” she said, “my one real issue that I struggle with is abortion.”

She was not alone. Across the United States, many women who oppose abortion decided to stay away from the marches planned in Washington and around the country Saturday. 

Others said that they would march anyway, though in some cases it would be to protest what they see as the outsized influence of abortion providers on the women’s movement.

Not sure of what to do, Linebaugh turned to the march’s Facebook page, where a debate was raging between those who support and those who oppose abortion rights. The vitriol she saw in some of the posts stunned her.

“The pro-life stance reduces women to nothing more than walking incubators,” one defender of abortion rights wrote. 

“The Pro Life movement has tried to destroy Roe v. Wade ever since it was upheld by the Supreme Court!” another wrote, referring to the 1973 decision that legalized the procedure nationwide. “Absolutely they should not be a part of the Women's March.”

Linebaugh was crushed. Why couldn’t these women see that “everybody could be together for the same cause and still have and respect different viewpoints?”

“I sat there and literally cried.”


The ruckus began when the Atlantic reported Monday that the march organizers had recognized the New Wave Feminists, a Dallas-based antiabortion group, as one of hundreds of official partners. Hours later, the organizers issued a statement apologizing for “this error” and dropped the group from the list.

“The Women’s March platform is pro-choice and that has been our stance from day one,” the statement said. 

Destiny Herndon-De La Rosa, head of the New Wave Feminists, said she wasn’t offered an explanation for the reversal but believes that the organizers caved in to pressure from the “pro-choice feminist community.”

“I understand that when you say ‘pro-life,’ people assume bullhorns and bloody fetus signs,” she said, but added that her group takes a very different approach.  

“While we are a pro-life group, we do not work to make abortion illegal,” she said. “We work to make it unthinkable and unnecessary by loving women and serving them well enough that they would never feel the need to turn to abortion.”

Herndon-De La Rosa said she was heartened by an outpouring of support on social media from women who support abortion rights but were disappointed at the organizers’ decision and wanted groups like hers to feel welcome.

When thousands of women take to the streets of the nation’s capital Saturday, she plans to be there, and she has encouraged other women to march too.

“We have so many things in common, fighting domestic abuse and human trafficking and just oppression worldwide,” she said.
Heidi L. Sieck, a cofounder of the #VOTERPROCHOICE campaign who helped put together the march’s policy platform, said, “There was never a moment that this march wasn’t about reproductive freedoms.

Friday, January 20, 2017

ABORTION PILL Now Available as Canada Rolls the dice on women's health


Long-awaited abortion pill Mifegymiso makes Canadian debut

The Globe and Mail

Friday, December 2, 2016

RU-486


RU-486   see the RISKs

recherche-search.gc.ca/rGs/s_r?st=s&s5bm3ts21rch=x&num=10&st1rt=0&langs=eng&cdn=canada&q=,RU-486   

hc-sc.gc.ca/dhp-mps/prodpharma/rds-sdr/drug-med/rds_sdr_mifegymiso_160063-eng.php  


http://hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd-smd-2016-mifegymiso-160063-eng.php#a2

RISKs  this link is printed below see manufactures recommendations
hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd-smd-2016-mifegymiso-160063-eng.php   


use your search engine and type RISK

PrMIFEGYMISO

Contact: tpd-general-dpt-general@hc-sc.gc.ca

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Mifegymiso is located below.

Recent Activity for Mifegymiso

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product’s life cycle. At this time, no PAAT is available for Mifegymiso. When the PAAT for Mifegymiso becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Mifegymiso

Date SBD Issued: 2016/01/08
The following information relates to the original authorization of the new drug submission for Mifegymiso.
Mifepristone 200 mg tablet, oral; Misoprostol 200 µg tablets, buccal
Drug Identification Number (DIN): DIN 02444038
Linepharma International Limited
New Drug Submission Control Number: 160063
On July 29, 2015, Health Canada issued a Notice of Compliance to Linepharma International Limited for the drug product, Mifegymiso.
Mifegymiso (mifepristone tablet/misoprostol tablets) is a composite pack containing one mifepristone 200 mg tablet for oral use and four misoprostol 200 µg tablets for buccal use.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Mifegymiso is favourable for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
  1. What was approved?
  2. Why was Mifegymiso approved?
  3. What steps led to the approval of Mifegymiso?
  4. What follow-up measures will the company take?
  5. What post-authorization activity has taken place for Mifegymiso?
  6. What other information is available about drugs?
  7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Mifegymiso is a combination product containing one mifepristone 200 mg tablet (oral administration) and four misoprostol 200 µg tablets (buccal administration). Mifegymiso was authorized for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle. Mifepristone belongs to the progesterone receptor antagonist therapeutic class, and blocks the progesterone effect on the uterus myometrium and endometrium, rendering the uterus more responsive to prostaglandin stimulation. Misoprostol is a prostaglandin E1 analogue which induces uterine contractions and facilitates the expulsion of the products of conception.
Mifegymiso is not indicated in post-menopausal women.
There are insufficient data with patients less than 15 years old to establish efficacy and safety. Mifegymiso is not indicated in the prepubertal population.
Compared to adults, patients less than 18 years of age reported nausea and pain more frequently.
Mifegymiso is not intended for routine use as a contraceptive.
Prior to prescribing Mifegymiso, physicians must:
  • Ensure that patients have access to emergency medical care in the 14 days following administration of mifepristone.
  • Schedule follow-up 7 to 14 days after patients take mifepristone to confirm complete pregnancy termination.
  • Exclude ectopic pregnancy and confirm gestational age by ultrasound.
  • Counsel each patient on the risks and benefits of Mifegymiso, including bleeding, infection and incomplete abortion.
  • Obtain the patient’s written informed consent to take the drug.
  • Complete the mandatory Mifegymiso education and registration programs.
Mifegymiso is contraindicated for patients with the following conditions:
  • an ectopic pregnancy;
  • an intrauterine device (IUD) in place;
  • unconfirmed gestational age;
  • chronic adrenal failure;
  • on concurrent long-term systemic corticosteroid therapy;
  • haemorrhagic disorders or using concurrent anticoagulation therapy;
  • inherited porphyria;
  • uncontrolled asthma;
  • a known hypersensitivity to mifepristone, misoprostol, other prostaglandins, or any of the excipients used in Mifegymiso.
Mifegymiso was approved for use under the conditions stated in the Mifegymiso Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
The medicinal ingredients in Mifegymiso are mifepristone (one 200 mg tablet) and misoprostol (four 200 µg tablets). In addition to the medicinal ingredient, the mifepristone tablet contains maize starch, povidone K30, microcrystalline cellulose, colloidal silica anhydrous, and magnesium stearate. The misoprostol tablets contain hypromellose, microcrystalline cellulose, sodium starch glycolate, and hydrogenated castor oil.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Mifegymiso approved?

Health Canada considers that the benefit/risk profile of Mifegymiso is favourable for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
Mifegymiso has been shown to be efficacious in terminating a developing intra-uterine pregnancy up to 49 days since the LMP. Data obtained from three pivotal studies support both the efficacy and safety of Mifegymiso and its proposed regimen of 200 mg oral mifepristone followed 24 to 48 hours later by 800 µg buccal misoprostol in pregnant women with a gestational age of 49 days or less. This regimen is well supported through the systematic review of the supportive literature. The mifepristone formulation proposed for the Canadian market was tested in one study and was shown bioequivalent to the formulation used in the two other studies. The mifepristone formulation bridging between the products used in the clinical studies and that proposed for market is considered strong. Bridging of misoprostol was considered robust for regulatory approval based on chemistry, clinical, and regulatory criteria. Many factors were taken into consideration, such as the fact that misoprostol is not a new active substance in Canada, that its efficacy is not sharply dose sensitive (not a critical dose drug), it is a highly soluble and highly bioavailable active molecule formulated as a simple immediate-release tablet, it has a short half-life, and is administered as a single-dose. In addition, the efficacy and safety of the proposed mifepristone and misoprostol combination were further supported in 5,356 patients that used Mifegymiso (200 mg oral mifepristone and 800 µg buccal misoprostol) for the indication of medical termination of pregnancy as reported in an additional post‑market study.
Analysis of the pivotal studies revealed that the average bleeding time was 11.4 days including 2 days of heavy bleeding. The majority of adverse events reported were transient and mild to moderate in severity. The medication causes vaginal bleeding and commonly induced pain and cramping, which required pain medication in some women. The other adverse events more commonly reported were diarrhea, nausea, vomiting, fever/chills, headache, dizziness and weakness. Treatment failure (which was defined as a patient requiring a surgical intervention for any reason, which may include a viable pregnancy, a non-viable persistent pregnancy, persistent bleeding or abdominal pain) was reported in 2% to 4.8% of women. These issues have been addressed through appropriate labelling in the Mifegymiso Product Monograph.
The identified serious safety concerns were the risks of infection and sepsis, the risk of heavy bleeding and the embryotoxicity of Mifegymiso for an ongoing pregnancy (treatment failure) or any immediate subsequent pregnancy. These risks are described in a Serious Warnings and Precautions Box in the Mifegymiso Product Monograph. Patients are warned to expect an immediate return to fertility after Mifegymiso administration. Also, all patients should be followed by a physician 7 to 14 days after taking mifepristone to confirm safety and complete pregnancy termination. Compliance with the drug regimen, the follow-up visit, access to a 24-hour support-line and access to emergency care are important to ensure both safety and efficacy.
A Risk Management Plan (RMP) for Mifegymiso was submitted by Linepharma International Limited to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. The RMP was considered acceptable by Health Canada.
Considering the potential risks associated with Mifegymiso’s conditions of use, Linepharma International Limited agreed to implement the following post-authorization commitments to ensure safe use of the product:
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support-line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card to be provided to each patient by the authorized prescriber.
The Restricted Distribution Program would necessitate that only registered physicians, having successfully completed the education program, would prescribe and provide Mifegymiso to patients, and would supervise the patient’s administration of mifepristone. This measure would minimize the likelihood of incorrect drug intake, and associated health risks, and support the efficacy of the product. This distribution pattern is consistent with the recommended setting in other international jurisdictions in which mifepristone and misoprostol are approved for termination of pregnancy of a gestational age of 49 days or less. In addition, it is the conditions in which Mifegymiso was provided to patients in the three pivotal studies that were used to support the approval decision.
Overall, the benefits of Mifegymiso seen in the pivotal studies are considered to outweigh the potential risks. Mifegymiso has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate conditions of use. Appropriate warnings and precautions are in place in the Mifegymiso Product Monograph to address the identified safety concerns.
Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3. What steps led to the approval of Mifegymiso?

A New Drug Submission (NDS) for Mifegymiso (Control Number 151874) was filed with Health Canada on December 6, 2011. The sponsor submitted a literature-based submission with bioequivalence studies to demonstrate that Mifegymiso was equivalent to the products reported in the literature. A Screening Rejection Letter led to a Request for Reconsideration which resulted in the Director General sending a Decision Letter not accepting the initial submission for review based on missing drug stability data.
On November 14, 2012, a new NDS for Mifegymiso was filed (Control Number 160063). Following review of the submission, an appropriate benefit-risk assessment could not be conducted due to insufficient pivotal efficacy and safety evidence provided and therefore a Notice of Deficiency (NOD) was issued for Mifegymiso on November 5, 2013.
The sponsor submitted a Response to NOD identifying three pivotal studies; however, the clinical package still contained many important uncertainties. Based on the efficacy and safety assessment and important safety data missing from the pivotal studies, as well as lack of information bridging the misoprostol formulation used in the pivotal studies to the formulation submitted for authorization, it was determined that Mifegymiso as submitted did not provide a favourable benefit to risk ratio. The drug submission was considered not acceptable with respect to the safety and efficacy data submitted and reviewed, and a Notice of Non-Compliance (NON) was issued on December 18, 2014.
The sponsor submitted a Response to NON and provided additional evidence, rationales and data stratification to resolve the identified issues and establish the in vivo performance of Mifegymiso (mifepristone and misoprostol). All of the concerns that led to the NON were satisfactorily addressed, and the submission was found to be in compliance with the Food and Drugs Act and Regulations. A Notice of Compliance was issued on July 29, 2015.
Submission Milestones: Mifegymiso
Submission MilestoneDate
Pre-submission meetings:2008/08/29
2010/11/08
2011/03/22
Submission Control Number 151874
Screening
Submission filed:2011/12/06
Screening Deficiency Notice issued:2012/01/27
Response filed:2012/02/28
Screening Rejection Letter issued:2012/04/13
Request for Reconsideration filed:2012/05/11
Reconsideration Decision Letter issued by Director General: 2012/07/30
Submission Control Number 160063
Screening 1
Submission filed:2012/11/14
Screening Acceptance Letter issued:2013/01/11
Review 1
Clinical Evaluation complete:2013/10/22
Biopharmaceutics Evaluation complete:2013/06/26
Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues):2013/11/05
Screening 2
Response filed:2014/02/03
Screening Acceptance Letter issued:2014/03/21
Review 2
Clinical Evaluation complete:2014/12/18
Notice of Non-Compliance (NON) issued by Director General (safety and efficacy issues):2014/12/18
Screening 3
Response filed:2015/03/13
Screening Acceptance Letter issued:2015/04/21
Review 3
Quality Evaluation complete:2015/07/07
Clinical Evaluation complete:2015/07/27
Labelling Review complete:2015/07/27
Notice of Compliance issued by Director General:2015/07/29
The Canadian regulatory decision on the non-clinical and clinical review of Mifegymiso was based on a critical assessment of the Canadian data package. The foreign reviews completed by the Australian Therapeutic Goods Administration were used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4. What follow-up measures will the company take?

As part of the marketing authorization for Mifegymiso, the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support-line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card be provided to each patient by the authorized prescriber.

5. What post-authorization activity has taken place for Mifegymiso?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.
At this time, no PAAT is available for Mifegymiso. When available, the PAAT will be incorporated into this SBD.
For the latest advisories, warnings and recalls for marketed products see MedEffect Canada.

6. What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

Mifegymiso (one mifepristone 200 mg tablet and four misoprostol 200 µg tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.
When mifepristone blocks progesterone receptors, the endometrium can no longer sustain the growing embryo. Without the effect of progesterone, the lining of the uterus breaks down, and bleeding begins. Mifepristone also triggers an increase in prostaglandin levels and dilates the cervix, facilitating abortion. Misoprostol then induces contractions of the smooth muscle fibres in the myometrium, relaxation of the uterine cervix, and evacuation of intrauterine contents.
Mifepristone is a new chemical entity in Canada, although not a first in class, since ulipristal acetate, another progesterone antagonist, was recently approved to treat symptoms of uterine fibroids and as an emergency contraceptive. Misoprostol is not a new chemical entity in Canada, since it was previously approved for the treatment and prevention of gastroduodenal ulcers induced by a nonsteroidal anti-inflammatory drug (NSAID) and for the treatment of duodenal ulcers caused by peptic ulcer disease, at the same dose.
No clinical pharmacology studies were performed by the sponsor, apart from three bioequivalence studies establishing a relationship between Mifegymiso and Mifeprex mifepristone (approved in the United States), Mifegyne mifepristone (approved in Europe), and Cytotec misoprostol (approved in the United States). Instead, published studies provided sufficient information to establish an acceptable pharmacodynamic and pharmacokinetic profile of mifepristone and misoprostol. Mifepristone binds principally to alpha 1-acid glycoprotein in plasma. The primary pathway of mifepristone metabolism is hepatic through the cytochrome P450 (CYP) enzyme CYP3A4 which results in three principal metabolites, which are weakly active toward the progesterone receptor (10-20% affinity compared to the parent drug). The primary pathway of mifepristone excretion is biliary, as 90% of a dose mifepristone was excreted through the faeces. The elimination half-life was reported between 18 to 54 hours in the literature and was reported as 38.4 and 36.5 hours in two bioequivalence studies performed by the sponsor. Misoprostol pharmacokinetic proprieties were based on the approved Canadian product monograph of misoprostol. After absorption, misoprostol is rapidly de-esterified in human plasma to misoprostol acid (the active metabolite). Misoprostol acid is subject to β-oxydation to more polar inactive compounds that are excreted mostly by the kidney (64-73%). Overall, the pharmacology profiles were consistent with the non-clinical findings.
Mifepristone was shown to be a potent antagonist at the progesterone receptor which allows for mifepristone to be used in the medical termination of pregnancy. It also has some affinity for the glucocorticoid receptor and a weak affinity for the androgen receptor, although those are not clinically relevant in women with normal adrenal function at the proposed dosage. Misoprostol is a prostaglandin analogue that binds to the prostaglandin E receptors and stimulates contractility of smooth muscles, including the uterine myometrium. The pharmacodynamic studies also indicated that misoprostol was active when administered by the oral, vaginal, buccal, and sublingual routes. The uterine response appeared to be greater after buccal, vaginal, or sublingual misoprostol than oral misoprostol administration. These differences in misoprostol bioactivity between its varying routes of administration are consistent with the differences in misoprostol clinical efficacy for termination of pregnancy noted in the systematic review of published studies, where buccal, vaginal, or sublingual misoprostol administration had generally a higher efficacy than oral misoprostol. The buccal route of administration proposed by the sponsor for misoprostol administration in Mifegymiso is supported by its efficacy and safety in the pivotal studies.
The sponsor identified three clinical pivotal studies (Study 1, Study 2 and Study 3, discussed in the Clinical Efficacy section and the Clinical Safety section) that were the most representative of the expected performance of Mifegymiso. Because the three studies were conducted by a third-party, it was necessary to demonstrate that the drugs used in these studies were equivalent to the one proposed for marketing approval (Mifegymiso).
Study CAL052015-001 demonstrated that the Linepharma’s mifepristone 200 mg tablets met the recommended standards for bioequivalence in comparison to the Mifeprex 200 mg tablets (marketed in the United States) used in two of the three identified pivotal clinical studies (Study 1 and Study 2), when administered orally in healthy female volunteers under fasting conditions. Linepharma’s mifepristone was used in the Study 3 pivotal study. Therefore, the three pivotal studies were considered to reliably represent the in vivo performance of Linepharma’s mifepristone.
Study JEI308 demonstrated that the Linepharma’s misoprostol 200 µg tablets met the recommended standards for bioequivalence in comparison to Cytotec 200 µg tablets used in two of the three identified pivotal clinical studies (Study 1 and Study 3), when administered orally in healthy female volunteers under fasting conditions. A generic of Cytotec approved in the United States was used in the Study 2 pivotal study. Linepharma’s misoprostol bridging was considered sufficiently robust for regulatory approval. Many factors were taken into consideration, such as it is an active substance with a well-established safety profile in Canada, its therapeutic index is wide, it is highly soluble and bioavailable, it is formulated as a simple immediate-release tablet, it is administered as a single-dose, and it has a short half-life with simple pharmacokinetics. The likelihood of a different buccal bioavailability considering the oral bioequivalence was low. The risk of this hypothetical difference making a clinically meaningful efficacy impact on the Canadian market was considered acceptable, considering the efficacy shown in 5,356 patients enrolled in the Mifegymiso Australian post-market study. Overall, the clinical pharmacological data supported the use of Mifegymiso for the specified indication.
For further details, please refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies with a gestational age up to 49 days was based on two randomized open-label studies and one single-arm study. The inconsistencies in the design of the studies, such as time interval between mifepristone and misoprostol, were addressed in the sponsor’s submission.
The three pivotal studies enrolled a total of 934 patients with a gestational age of 49 days or less. Study 1 reported a rate of completed termination of pregnancy without surgery for the targeted population of 95.2% [number of patients (N) = 146] for buccal misoprostol. Study 2 reported a rate of completed termination of pregnancy without surgery for the gestational age 49 days or less population of 97.3% (N = 214) with buccal misoprostol. Study 3 reported a rate of completed termination of pregnancy without surgery for the targeted population of 98.0% (N = 551) for buccal misoprostol. Together, the efficacy of a 200 mg mifepristone followed by 800 µg buccal misoprostol regimen in the gestational age group of 49 days or less is well supported by the pivotal clinical study package. The efficacy rates were robust considering the minimal effect of different sensitivity analyses and the consistent efficacy in different age, race, and gravidity status. It is noted that two studies were allowing a second dose of misoprostol in case of an incomplete abortion (persistent non-viable pregnancy) at follow-up (Study 2 and Study 3), although data on such a practice indicated that only 8 patients in the buccal misoprostol group with a gestational age of 49 days or less opted for this option (buccally) and 7 (87.5%) of them had successful termination of pregnancy without surgery and one required a subsequent surgical intervention.
Linepharma provided the full description of its secondary endpoints for the three studies, including stratification for gestational age. The median time to expulsion of patients with a gestational age of 49 days or less was between 4 to 5 hours following buccal misoprostol. The average bleeding time was 11.4 days in the buccal group, including about 2 days of heavy bleeding, 4.5 days of normal bleeding, and 5 days of spotting. Patients reported pain perception to be “less pain than expected” in 46.0% of cases and “more than expected” in 25.1% of cases. Bleeding was reported as “more than expected” in 22.3% of patients.
Other regimen parameters not tested in the pivotal studies, such as doses of mifepristone and misoprostol and time interval between mifepristone and misoprostol were resolved by a critical review of the literature, which provided support for the proposed conditions of use negotiated with the sponsor.
In Study 3, 35 patients of less than 18 years of age were included in the study. The rate of patients with successful termination of pregnancy without surgery was 100%. A total of 27 patients of less than 18 years of age and a gestational age of 49 days or less were enrolled in the Australian Authorised Prescriber Program and were administered mifepristone and misoprostol in the currently approved conditions of use. In those patients, 100% had successful termination of pregnancy without surgery. Linepharma presented the outcome of 64 patients with less than 18 years of age enrolled in an Australian post-market study. Among them, 62 (96.9%) had successful termination of pregnancy without surgery. Two women reported persistent vaginal bleeding due to incomplete abortion requiring surgical termination of pregnancy. Based on the data in patients less than 18 years of age, the efficacy in this population is comparable to the adult population.
During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was: “Mifepristone Linepharma 200 mg/GyMiso 200 µg tablets (mifepristone/misoprostol) are indicated in sequential combination in females of childbearing age for medical termination of a developing intra-uterine pregnancy up to 49 days of gestation.”
Following the review of the submission, Health Canada revised the indication to:
“Mifegymiso (mifepristone tablet/misoprostol tablets) is indicated for medical termination of a developing intra-uterine pregnancy with a gestational age up to 49 days as measured from the first day of the Last Menstrual Period (LMP) in a presumed 28-day cycle.”
In the Response to the Notice of Non-Compliance (NON), the sponsor satisfactorily addressed all of the issues stated in the NON and the submission was found to be in compliance with the Food and Drugs Act and Regulations. The clinical pivotal studies along with the bioequivalence studies, and the literature package support the use of Mifegymiso for the specified indication.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Mifegymiso (a combination product of a 200 mg mifepristone tablet and four 200 µg misoprostol tablets) for the purpose of terminating pregnancies of gestational age up to 49 days was based on three pivotal studies and a literature package.
Study 1 was a randomized open-label study conducted in two sites in the United States. It compared the efficacy and safety of 800 µg buccal misoprostol 24 to 72 hours after 200 mg oral mifepristone in 143 women with a gestational age of 49 days or less. The investigators collected adverse events (AEs) based on a list of 8 predefined events. The most frequent AEs were pain (92%), nausea (68%), weakness (56%), dizziness (45%), headache (42%), fever (39%), diarrhea (36%) and vomiting (29%). The concomitant medications list provided by the sponsor indicated that 1.4% of patients took antibiotics prophylactically or as-needed based on symptoms in the buccal misoprostol group.
Study 2 was a randomized open-label study conducted in seven sites in the United States and compared the efficacy and safety of 800 µg buccal misoprostol 24 to 36 hours after 200 mg oral mifepristone in 204 women with a gestational age of 49 days or less. The most frequent AEs were nausea (64%), weakness (46%), chills (37%), dizziness (36%), vomiting (34%), headache (33%) and diarrhea (32%). The concomitant medications list provided by the sponsor indicated that approximately 30% of patients took antibiotics prophylactically or as-needed based on symptoms.
Study 3 was a single-arm prospective study conducted in three sites in Mexico and investigated the efficacy and safety of 800 µg buccal misoprostol 24 to 48 hours after 200 mg oral mifepristone in 551 women with a gestational age of 49 days or less. The most common AEs reported in the study were diarrhea (59%), fever/chills (44%), nausea (31%), vomiting (22%), weakness (20%), headache (12%) and dizziness (13%). The most frequent severe AEs were vomiting (20%), fever/chills (20%) and headache (17%). “Other” AEs were reported and included single cases of anxiety/irritability/depression, dry throat, rash, hypotension, flu, difficulty breathing, hands fell asleep, and hunger.
Vaginal bleeding and abdominal pain were experienced by participants. No deaths occurred during the pivotal studies. Unscheduled visits to the clinic were due mostly to persistent bleeding. Suspected infections were reported at 0-0.21% in the pivotal studies and patients were treated with oral or intravenous antibiotics. Serious AEs included mostly persistent heavy bleeding, but also included single cases of pulmonary embolism, ruptured ectopic pregnancy, and right hip pain that were found unrelated to the study drug. Cases of heavy bleeding requiring an unscheduled clinic visit in the patient population with a gestational age of 49 days or less were reported at rates between 3.3% and 5.5% of patients.
Overall, all missing safety endpoints notified to Linepharma as part of the Notice of Non‑Compliance dated December 18, 2014 were provided and reviewed, providing a complete safety profile of the proposed regimen used in the proposed conditions of use.
The efficacy and safety of Mifegymiso were investigated in patients less than 18 years of age with a pregnancy with a gestational age of 49 days or less (35 in pivotal studies and 91 in post-market studies). The rate of patients less than 18 years of age with successful termination of pregnancy without surgery was 100% in the pivotal studies and 96.9% in the two post-market studies. In post-market studies, two women reported persistent vaginal bleeding due to non-viable pregnancy or gestational sac seen on ultrasound at follow-up and treated by surgical abortion. Based on the data in patients less than 18 years of age, the efficacy and safety in this population are comparable to the adult population. Women less than 18 years of age reported vomiting nearly twice as frequently as women 18 years and older. In addition, patient-reported pain score and the rate of patients reporting “more pain than expected” were higher in patients less than 18 years of age than in adult patients. Bleeding perception compared to expectation was also slightly higher in the pediatric population. The outcome of women less than 18 years of age taking Mifegymiso has been included in the Product Monograph.
Periodic safety update reports were reviewed for Linepharma mifepristone and misoprostol and provided an estimation of Linepharma’s mifepristone use world-wide (216,506 patients) along with adverse drug reactions associated with its use. Linepharma’s misoprostol patient exposure is estimated to be 362,424 patients in France and Australia.
The Australian Authorised Prescriber Program (N = 4,488) and Australian post-market study (N = 8,165) reported a Mifegymiso safety profile consistent with the one observed in the pivotal studies.
Serious risks are described in a Serious Warnings and Precautions Box within the Mifegymiso Product Monograph. Included are the risks of infection and sepsis, bleeding and embryotoxicity for an ongoing pregnancy (treatment failure) or any immediate subsequent pregnancy. Patients are warned to expect an immediate return to fertility after Mifegymiso administration. A warning that all patients should be followed by a physician 7 to 14 days after taking mifepristone to confirm safety and complete pregnancy termination is also included.
The updated labelling, education and distribution programs, along with the Risk Management Plan will help ensure safe use of the product.
Linepharma International Limited has agreed to implement the following post-authorization commitments:
  • a Restrictive Distribution and Administration Program;
  • an Education and Registration Program for Mifegymiso prescribers;
  • a Canadian Phase IV observational study of Mifegymiso safety;
  • a 24-hour support‑line in both English and French for patients taking Mifegymiso;
  • a Patient Consent Form to be provided to each patient by the authorized prescriber;
  • a Patient Medication Information and a Patient Information Card be provided to each patient by the authorized prescriber.
The Restricted Distribution Program would necessitate that only registered physicians, having successfully completed the education program, would prescribe and provide Mifegymiso to patients, and would supervise the patient’s administration of mifepristone. This measure would minimize the likelihood of incorrect drug intake, and associated health risks, and support the efficacy of the product. This distribution pattern is consistent with the recommended setting in other international jurisdictions in which mifepristone and misoprostol are approved for termination of pregnancy of a gestational age of 49 days or less. In addition, it is the conditions in which Mifegymiso was provided to patients in the three pivotal studies that were used to support the approval decision.
Overall, the sponsor addressed the deficiencies and safety concerns noted in the Notice of Deficiency (NOD) and Notice of Non-Compliance (NON). The safety profile of Mifegymiso is considered acceptable and manageable for the medical termination of a developing intra-uterine pregnancy up to 49 days since the first day of the last menstrual period in women of childbearing age.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Non-Clinical Basis for Decision

Mifegymiso is a combination product consisting of a mifepristone tablet and four misoprostol tablets. The non-clinical portion of the Mifegymiso drug submission consisted of two parts. The first part was an overview of non-clinical studies regarding mifepristone and the second part was an overview for misoprostol. There were no non-clinical studies that studied both mifepristone and misoprostol. The non-clinical portion of the submission contained one original study (evaluating mifepristone phototoxicity); all other studies were referenced to published literature and, in the case of mifepristone, to a foreign review. Specifically, the sponsor provided the Australia Therapeutic Goods Administration Summary Basis of Approval (SBoA) for Mifeprex (mifepristone).
Mifepristone
Overall, the non-clinical studies addressed primary and secondary pharmacodynamics, safety pharmacology, pharmacokinetics and toxicology (including single dose, repeated dose, genotoxicity, carcinogenicity, reproductive toxicity, and phototoxicity).
Results of the pharmacodynamic studies showed mifepristone to be a potent antagonist at the progesterone and glucocorticoid receptor and, to a lesser degree, at the androgen receptor. This anti-progesterone activity allows for mifepristone to be used in the medical termination of pregnancy. Results of greatest relevance to the submission showed mifepristone to have anti-ovulatory, anti-fertilization and anti-implantation activity. It also inhibited embryo development and accelerated parturition.
Safety pharmacology studies did not find mifepristone to affect the autonomic nervous, cardiovascular, respiratory or gastrointestinal systems. It also did not show any analgesic/anti-inflammatory or hematological activity. However, it did affect the central nervous system (where there was a potentiation of hexobarbital sleeping time in rodents at oral doses of 10‑100 mg/kg), the genitourinary system (decreased sodium excretion at 10‑100 mg/kg, decreased potassium at 30‑100 mg/kg, increased urine volume at 100 mg/kg) and endocrine activity (slight hypoglycemic effect at 30‑100 mg/kg in fasted rats).
Reproductive and developmental toxicity studies found mifepristone to be embryotoxic and to induce fetal loss in mice, rats and rabbits at doses lower than those proposed for human use (on a mg/kg basis). It is suggested that the embryotoxicity is a consequences of progesterone withdrawal (as progesterone is needed to maintain uterine accommodation during pregnancy), rather than evidence of teratogenicity.
Many of the references were lacking in detail and neither the quality of the studies nor the study data could be assessed independently by Health Canada. However, despite these deficiencies, the non-clinical data was considered acceptable. The reasons being that most adverse effects were seen at doses (mg/kg) that were substantially higher than those expected for humans; in the safety pharmacology studies the adverse effects that were observed were not very severe or serious, and in the repeat-dose toxicology studies the adverse effects could be related to the chronic nature of exposure. In clinical use, the mifepristone indication is for a single dose. This drug has already been on the market throughout the world (including the United States) for over a decade, and, taking the drawbacks of the non-clinical studies into account, adverse effects are better predicted by clinical and/or post-market data.
Misoprostol
The non-clinical documentation supporting the misoprostol application consisted of literature studies. Overall, the non-clinical studies addressed primary pharmacodynamics, safety pharmacology, pharmacokinetics, single and repeat-dose toxicology, genotoxicity, carcinogenicity, and reproductive and developmental toxicity.
Misoprostol is a synthetic analogue of prostaglandin E1. The action of misoprostol as a gastric anti-secretory agent is well‑established. While there is evidence that prostaglandin E2 can cause contraction of uterine strips from pregnant women, there was no non-clinical evidence submitted to support misoprostol as having the same effect. However, clinical data have been provided in the submission to support misoprostol’s effectiveness for uterine expulsion, which compensates for this deficiency.
Reproductive and developmental toxicity studies found pre-natal exposure to misoprostol to decrease the number of implantations and increase resorptions. Teratology studies did not find any evidence of embryotoxicity, foetotoxicity or teratogenicity. However, literature reports suggest a link between misoprostol exposure during pregnancy and congenital malformations, possibly attributed to disturbances in blood supply to the foetus.
Literature reports of congenital malformations observed in humans suggest that humans are more sensitive to misoprostol than mice, rats, or rabbits. However, both pharmacodynamic information (for the specified indication) and pharmacokinetic testing is lacking, making it impossible to determine the differences in sensitivity between animals and humans. Another shortcoming of the non-clinical package for misoprostol is that much of the data is referenced to review articles and therefore lacks the detail necessary to conduct an independent evaluation. However, the shortcomings of this submission can be justified. The reasons being that the same dose of misoprostol is already approved in Canada for chronic use, the indication being sought is of short duration, and there is substantial clinical data available that documents misoprostol use for the specified indication.
In conclusion, the results of the non-clinical studies for mifepristone and misoprostol as well as the potential risks to humans have been included in the Mifegymiso Product Monograph. In view of the intended use of Mifegymiso, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Mifegymiso Product Monograph, approved by Health Canada and available through the Drug Product Database.

Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Mifegymiso has demonstrated that the drug substances, mifepristone and misoprostol, and the drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf‑life is considered acceptable.
Proposed limits of drug-related impurities are considered adequately qualified [i.e. within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies].
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the drug product are not of animal or human origin.