FDA Approved and Alternative Regimens

MEDICAL ABORTION – APPROVAL IN THE U.S.

What does U.S. FDA approved labeling mean for patients?

The FDA approved label is the official description of a drug product which includes indication (what the drug is used for); who should take it; adverse events (side effects); instructions for uses in pregnancy, children, and other populations; and safety information for the patient. Labels are often found inside drug product packaging. ⁽¹⁾

The FDA approved the Mifeprex (mifepristone) drug application based on the sponsor’s ability to demonstrate, through clinical trials, that its product is safe and effective for medical abortion only under the conditions of use in the approved labeling. ⁽²⁾

Proper labeling of a drug in accordance with FDA’s regulations, underpinned by rigorous data, is a prime concern of the FDA, leading to considerable effort by the FDA and the drug’s sponsor to make sure that product labeling is fully informative on the use of the drug for its intended purpose. ⁽³⁾

When was medical abortion with mifepristone and misoprostol approved in the U.S.?

On September 28, 2000, the United States Food and Drug Administration (FDA) approved a mifepristone (Mifeprex, Danco Laboratories, LLC, New York, NY) and misoprostol regimen for termination of pregnancies up to 49 days from the first day of the woman’s last menstrual period (LMP). ^{(4) (5)}

In the final review for approval, the FDA concluded that termination of an unwanted pregnancy is a serious condition and the drug (mifepristone) can allow patients to avoid a surgical procedure. ⁽²⁾

The approved mifepristone (Mifeprex) regimen for a medical abortion through 49 day’s pregnancy is: ⁽⁵⁾

• Day 1: Mifepristone Administration (provider’s office): 3 tablets of 200 mg of Mifeprex orally at once.
• Day 3: Misoprostol Administration (provider’s office): 2 tablets of 200 mcg of misoprostol orally at once.
• Day 14: Post-Treatment (provider’s office): The patient must return to confirm that a complete termination has occurred. If not, surgical termination is recommended to manage medical abortion treatment failures.

Why is the follow-up visit important for the patient?

It is important that patients understand the need for 2 follow-up visits (Days 3 and 14) with their health care provider and that they have access to a medical care facility in case of an emergency. ⁽⁶⁾

Medical abortion requires the patient to return to their provider’s office for an important follow-up visit about 14 days or before after beginning the treatment to confirm the pregnancy has ended. If it has not ended, there is a chance that there may be birth defects and the potential risk for health complications. ⁽⁷⁾

A surgical procedure is recommended to terminate early pregnancy due to medical abortion treatment failures. ⁽⁸⁾

Does safe mean risk free?

On the basis of scientific data from clinical trials, FDA concluded in 2000 that mifepristone used in combination with oral administration of misoprostol, is safe and effective for the termination of early pregnancy. ⁽⁹⁾

Patients should also understand that safe does not mean risk free; FDA will approve a drug if it determines that the benefits exceed the risks for the approved use. ⁽⁹⁾

The conclusion that benefits exceed risk is based on using the drug as directed by the labeling. When FDA approves a drug, the labeling includes information on benefits and risks and the appropriate dosing regimens. ⁽⁹⁾

The approved dosing regimen includes administration of 600 mg of Mifeprex in a single oral dose. On day three of the regimen, the patient returns to her doctor and, unless abortion has occurred, she takes two-200 mcg tablets of misoprostol orally. ⁽⁹⁾

U.S. FDA APPROVED MEDICAL ABORTION REGIMEN – DOSAGE AND ADMINISTRATION ⁽¹⁰⁾

What is the approved U.S. FDA regimen for mifepristone/misoprostol medical abortion for early pregnancy termination?

The U.S. Food and Drug Administration approved medical abortion regimen for mifepristone and misoprostol for early pregnancy termination includes the following:

Treatment with Mifeprex (mifepristone) and misoprostol for the termination of pregnancy requires three office visits by the patient. Mifeprex (mifepristone) should be prescribed only by physicians who have read and understood the prescribing information. (See DOSAGE and ADMINISTRATION)

Mifeprex (mifepristone) may be administered only in a clinic, medical office, or hospital, by or under the supervision of a physician, able to assess the gestational age of an embryo and to diagnose ectopic pregnancies.

Physicians must also be able to provide surgical intervention in cases of incomplete abortion or severe bleeding, or have made plans to provide such care through others, and be able to assure patient access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary.

Day One: Mifeprex (mifepristone) Administration (provider’s office)

• Patients must read the MEDICATION GUIDE and read and sign the PATIENT AGREEMENT before Mifepristone is administered.
• Three 200 mg tablets (600 mg) of Mifeprex are taken in a single oral dose.

Day Three: Misoprostol Administration (provider’s office)

The patient returns to the health care provider two days after ingesting Mifepristone.

• Unless abortion has occurred and has been confirmed by clinical examination or ultrasonic scan, the patient takes two 200 mcg tablets (400 mcg) of misoprostol orally.
• During the period immediately following the administration of misoprostol, the patient may need medication for cramps or gastrointestinal symptoms (see ADVERSE REACTIONS).
• The patient should be given instructions on what to do if significant discomfort, excessive vaginal bleeding or other adverse reactions occur and should be given a phone number to call if she has questions following the administration of the misoprostol.
• In addition, the name and phone number of the physician who will be handling emergencies should be provided to the patient.

Day 14: Post-Treatment Examination (providers’ office)

• Patients will return for a follow-up visit approximately 14 days after the administration of Mifeprex. This visit is very important to confirm by clinical examination or ultrasonographic scan that a complete termination of pregnancy has occurred.
• Persistence of heavy or moderate vaginal bleeding at this visit could indicate an incomplete abortion.
• Patients who have an ongoing pregnancy at this visit have a risk of fetal malformation resulting from the treatment.
• Surgical termination is recommended to manage medical abortion treatment failures (see PRECAUTIONS, Pregnancy).

Adverse events, such as hospitalization, blood transfusion, ongoing pregnancy, or other major complications following the use of Mifeprex and misoprostol must be reported to Danco Laboratories.

ALTERNATIVE/OFF-LABEL/UNAPPROVED DRUG USE

What is an alternative, unapproved, off-label drug use?

Unapproved drug uses are those that do not appear in a product's U.S. Food and Drug Administration (FDA)-approved labeling and are not approved by the Agency. Such uses commonly are referred to as "off-label," "unapproved," "unlabeled," or "extra-label" uses. ⁽¹¹⁾

A number of evidence-based, alternative, or off-label treatment drug variations have emerged as researchers study other regimens that may prove simpler than the FDA-approved approach and may serve a larger number of patients. ⁽¹²⁾

“If there are substantial safety concerns about approved (FDA) indications and dosages, there is even greater uncertainty with regard to off-label uses.” ⁽¹³⁾

Unapproved drug uses may have negative public health consequences — including exposing patients to unnecessary risks and destroying the incentive for companies to conduct the necessary research to demonstrate that products are safe and effective for these uses. ⁽¹¹⁾

ALTERNATIVE/UNAPPROVED U.S MEDICAL ABORTION REGIMENS

What the FDA stated in its approval letter to the Population Council about alternative uses of misoprostol for medical abortion?

In the FDA’s letter to the Population Council on September 28, 2000 the following statements about Misoprostol Administration for medical abortion were follows: ⁽¹⁴⁾

• Women would not have the option of taking misoprostol on Day 3 at home.
• There was no substantial evidence for safety and efficacy supporting home use of misoprostol.
• Vaginal use of misoprostol, home use of misoprostol using a different regimen with different drug doses are not FDA approved.
• Women need to return to the health care provider on Day 3 for misoprostol, as in the U.S. clinical trial to assure it is being correctly administered.
• Patients need the Day 3 contact at the provider’s office as a reinforcement to return on Day 14 to confirm pregnancy expulsion has occurred.

During mifepristone’s final review process, medical abortion researchers and providers were focused on obtaining the drug’s approval. To not delay the approval process further, medical abortion researchers purposely did not submit any other evidence-based (alternative) regimens for the FDA to review. ⁽¹⁵⁾

Providers Immediately Adopt Unapproved Regimens

Once medical abortion providers had the FDA approval for mifepristone and misoprostol pregnancy termination, abortion researchers set out to increase the gestational age limit, shorten the process, decrease their costs, change the dosing regimen, allow women to administer misoprostol at home (instead of at the provider's clinic) and reduce the number of patient’s return visits back to the clinic. ⁽¹⁵⁾

The FDA-approved regimen, an oral combination of 600 mg mifepristone followed 2 days later by office-based administration of 400 mcg of misoprostol, has been used in only 4% (4 per 100) of abortion provider facilities since its approval in 2000. ⁽¹⁶⁾

The combination of 200 mg mifepristone followed by home use of 800 mcg vaginally administered misoprostol, commonly referred to as the alternative or evidence-based regimen, was used by 83% of facilities. ⁽¹⁶⁾

Providers use repeat dosing of misoprostol to try and improve the success of medical abortion.

Most (71%) clinicians reported advising a repeat dose of misoprostol for a retained sac. NAF's 2005 management recommendations allow for observation and reevaluation of a persistent sac up to approximately 36 days, including the option of repeat misoprostol dosing. ⁽¹⁶⁾

Although common in practice, research has not shown systematically that repeat doses of misoprostol following mifepristone will effect a clear benefit in emptying the uterus. ⁽¹⁶⁾

FDA'S AWARENESS OF PROVIDER'S UNAPPROVED MEDICAL ABORTION REGIMEN USE

What is the FDA saying about the modification of the approved FDA regimen?

FDA is aware that medical abortion providers may be using modified regimens, including prescribing different doses of mifepristone and misoprostol, dosing misoprostol on a different day, and advising the woman that the oral misoprostol tablets may be inserted into the vagina. ⁽⁶⁾

The safety (risks) and effectiveness of alternative (unapproved, modified, evidence-based or off-label) dosing regimens other than the one approved by the FDA, including the use of oral misoprostol that is being administered intra-vaginally to patients, has not been established, evaluated or approved by the FDA. ^{(5) (9)}

PROVIDERS MAKE UNAPPROVED CHANGES TO THE FDA MEDICAL ABORTION REGIMEN

What types of changes did medical abortion providers make to the FDA approved medical abortion regimen with mifepristone and misoprostol?

The most common alterations to the U.S. FDA-approved regimen for medical abortion include^{: (15) (17) (18)}

• The use of Mifepristone and Misoprostol through 9 weeks (63 days) of gestation instead of through 7 weeks (49 days).
• Variations of the doses of Mifepristone (decreased dosage from 600 mg to 200mg).
• Variations of the doses of Misoprostol (increased dosages from 400 mcg to 800 mcg), including repeat dosing of Misoprostol.
• Decreasing the time interval between the Mifepristone and Misoprostol to 6 to 24 hours instead of 48 hours.
• Routes of administration of the Misoprostol (taken by mouth or inserted in the vagina)
• Eliminating the second office visit by providing Misoprostol to the patient to be taken at home instead of returning to the provider.

CONTINUING PREGNANCY & ALTERNATIVE/UNAPPROVED REGIMENS

Do alternative/unapproved medical abortion regimens contribute to the risk of continuing pregnancy?

There is unsettled controversy about the respective efficacy and safety of 200 and 600 mg mifepristone in combination with misoprostol for the termination of pregnancy up to 63 days' gestation. ⁽¹⁹⁾

• Medical abortion regimens substituting 200 mg of mifepristone for the FDA approved 600 mg regimen may result in the risk of medical abortion failure of 1 % more continuing pregnancies. ⁽¹⁹⁾

The available evidence does not support routine substitution of 600 mg by 200 mg mifepristone for the medical termination of pregnancy when used with the approved dose of 400 mcg of oral misoprostol, unless the only relevant outcome is success and unless an excess rate of continuing pregnancies is considered to be only of secondary clinical relevance, which is questionable. ⁽¹⁹⁾

Evidence of Opinion Based Medicine?

Since the introduction of mifepristone at a dosage of 600 mg (600 mg being the originally approved dosage, not 200 mg), no direct comparative studies, powered to demonstrate the difference between dosages with regard to the end point of continuing pregnancy, have been performed. ⁽²⁰⁾

For the women concerned and with respect to the safety of the procedure, the end point is critical. ⁽²⁰⁾

In terms of risk/benefit assessment of the treatment, the conservative approach (approved regimen) is recommended. (2) Whether the risk is that there will be 1000 more or 300 less ongoing pregnancies, it is important that we consider the worst-case scenario for the safety of the women. ⁽²⁰⁾

Hence, some researchers agree that for approved prostaglandin regimens, the debate about which dose of mifepristone to use is over and the current label (FDA approved) reflects the available evidence. ⁽²¹⁾

Whether a possible limited absolute increase in the risk of ongoing pregnancy is compensated for by economical benefits or improved access to services is a political issue that some researchers have excluded to adopt, for fear of crossing the line between evidence- and opinion-based medicine. ⁽²⁰⁾

FATAL SEPSIS & ALTERNATIVE/UNAPPROVED REGIMENS

What has the FDA reported concerning the risk of fatal sepsis and the use of alternative/unapproved regimens?

As of March 2012, the FDA has been informed of the deaths of 11 women (United States, Canada, Europe, Australia) that were associated with sepsis (serious infection involving the bloodstream) following medical abortion with mifepristone and misoprostol. Nine of the fatal sepsis cases reported vaginal misoprostol use, buccal misoprostol use was reported in one case, and one case has not reported the method of misoprostol administration. ^{(6) (22) (23) (24) (25) (26) (34) (35)}

“FDA has concluded the deaths may possibly be related to the use of these medical abortion drugs.”  ⁽⁶⁾  

(See Mifeprex Questions and Answers)

The deaths (See DEATH) of the 11 (eleven) women associated with sepsis after medical abortion, 9 cases tested positive for Clostridium sordellii, 1 case tested positive for Clostridium perfringens,  1 case was reported to be Group A Streptoccocus. ^{(24) (26) (34) (35)}

Clostridium sordellii infections as a result of medically induced abortions have a 100% fatality rate. ⁽²⁷⁾

In terms of the risk and benefit assessment of medical abortion, the conservative approach using the approved regimen is recommended. ⁽²¹⁾

The FDA has issued public health advisories to warn health care professionals about the risks of sepsis in medical abortion and to reinforce use of the approved regimen which does not include the vaginal use of misoprostol. ^{(28) (29)}

OTHER RISKS & ALTERNATIVE/UNAPPROVED REGIMENS

What are the other risks of using alternative medical abortion regimens?

Adverse events, such as hospitalization, blood transfusion, ongoing pregnancy, or other major complications can occur following the use of mifepristone and misoprostol. ⁽⁸⁾

Alternative or off-label mifepristone regimens for pregnancies greater than 49 days gestation resulted in higher incomplete abortion rates. ⁽³⁰⁾

Off-label/alternative mifepristone regimens have shown the use of oral misoprostol resulted in the risk of incomplete abortion in approximately 64 per 1000 women. ⁽³⁰⁾

Off-label/alternative mifepristone regimens using vaginal misoprostol resulted in the risk of incomplete abortion in approximately 21 per 1000 women. ⁽³⁰⁾

The risk of surgical curettage, hospitalization, or intravenous fluid administration was 2 times greater for women at pregnancy greater than 49 days’ gestation than among those less than 49 days’ gestation. ⁽³¹⁾

PLANNED PARENTHOOD’S 2001-2006 MEDICAL ABORTION STUDY

Planned Parenthood’s 2001-2006 Medical Abortion Study and a new alternative use of misoprostol.

From 2001 to March 2006, Planned Parenthood Federation of America (Planned Parenthood) health centers throughout the United States provided medical abortions principally by an alternative/unapproved regimen of 200 mg oral mifepristone, followed 24–48 hours later by 800 mcg vaginal misoprostol. ⁽³²⁾

In late March 2006, analyses of serious uterine infections following medical abortions led Planned Parenthood to change the route of misoprostol administration and to employ additional measures to minimize subsequent serious uterine infections. ⁽³²⁾

In August 2006, Planned Parenthood conducted their own audit of medical abortions with the new alternative/unapproved buccal misoprostol regimen so that patients could be given accurate information about the success rate of the new regimen. ⁽³²⁾

Planned Parenthood concluded; in conjunction with 200 mg of mifepristone, use of 800 mcg of buccal misoprostol up to 59 days of gestation is as effective as the use of 800 mcg of vaginal misoprostol up to 63 days of gestation. ⁽³²⁾

COMMENTS – PLANNED PARENTHOOD’S MEDICAL ABORTION STUDY

Did Planned Parenthood accurately analyze and report their study?

Randomized clinical trials were precisely designed to overcome the multiple biases that plague the observation of the efficacy and safety of treatments in medical practice. ⁽²⁰⁾

Estimates of complications (including continuing pregnancy) of medical abortion made by the Planned Parenthood Federation of America (PPFA) are based on spontaneous reporting, which is always poised by underreporting for different reasons. ⁽²⁰⁾

One of these reasons is a usually high proportion of lost to follow-up patients. ⁽²⁰⁾

A PPFA study in 2005 acknowledged some women with complications may not return to the provider, and as a result, a complication report would not be generated. This could result in an underestimation of the complication rate, depending on the degree of loss to follow-up. ⁽²¹⁾

An audit of PPFA affiliates from 16 facilities averaged 21% (210 per 1000) of patients did not return for the required post-abortion visit to the clinic. ⁽²¹⁾

PPFA corrected their complication estimation by reducing the denominator by 21%, so that the rate of complications would be calculated on the women that actually returned for their required follow–up visit after medical abortion. ⁽²¹⁾

The analysis incorrectly assumes that the risk of complications such as failed medical abortion, continuing pregnancy, heavy bleeding, infection, and death occurred in the same proportion in women who returned to their follow-up visit as compared to women who were lost to follow-up. ⁽²⁰⁾

LEGALITY OF OFF-LABEL/UNAPPROVED DRUG USE

Is off-label drug use legal?

The U.S. Food and Drug Administration (FDA) focuses on market entry for prescription drugs rather than regulating physicians’ prescribing practices, allowing off-label use of medications for indications beyond those formally evaluated by the manufacturer. ⁽³³⁾

Once a drug is approved for marketing, FDA does not generally regulate how, and for what uses, physicians prescribe that drug. A physician may prescribe a drug for uses or in treatment regimens or patient populations that are not listed in the FDA-approved labeling. ⁽¹¹⁾

Although off-label prescribing — the prescription of a medication in a manner different from that approved by the FDA — is legal and common, it is often done in the absence of adequate supporting data. ⁽¹³⁾

Off-label uses have not been formally evaluated, and evidence provided for one clinical situation may not apply to others. ⁽¹³⁾

Off-label prescribing of medications is legal, often thought to be supported by scientific evidence, and common in certain clinical settings^{. (33)}

FDA does not prohibit the dissemination of information to health care professionals. Physicians access information about off-label uses through compendia, journal articles, continuing medical education programs, symposia, and professional meetings. ⁽¹¹⁾

FDA has serious concerns regarding the promotion of indications that have not been reviewed and approved by the Agency. ⁽¹¹⁾

Promotional activities of drug companies and others are substantially motivated by profit and market expansion. ⁽¹¹⁾

The widespread promotion of prescription drugs for uses that have not been determined to be safe and effective by the FDA could be detrimental to the health and safety of the public. ⁽¹¹⁾

PROBLEMS ASSOCIATED WITH OFF-LABEL DRUG USE

What are the problems with off-label drug use?

The fundamental problem with permitting the promotion of off-label uses is that not all off-label uses are safe and effective. ⁽¹¹⁾

Evaluations have shown that off-label use is common but often not supported by strong evidence. ⁽¹³⁾

The drug industry may facilitate off-label use by exploiting areas of ambiguity where policy is permissive, undefined, or not enforced. Besides sponsorship of continuing medical education programs, a key promotional strategy is providing physicians with journal articles about off-label uses. This practice does educate physicians, but it is problematic because “the trials reported are too often of limited quality and industry-sponsored.” ⁽¹³⁾

The only way to know which ones are safe and effective is to collect and analyze the data supporting a finding of safety and efficacy. Because the data on off-label uses have not been collected and analyzed, their promotion raises a number of serious concerns. ⁽¹¹⁾

THE FDA STANDARD & OFF-LABEL DRUG USE

How is the FDA’s efficacy standard undercut with off-label drug use?

Off-label use has potentially negative consequences. It undercuts expectations that drug safety and efficacy have been fully evaluated. ⁽¹³⁾

The efficacy standard requires well-controlled clinical trials, once FDA has made a determination of effectiveness, there can be a high degree of confidence that the drug will work. ⁽¹¹⁾

Permitting the promotion of off-label uses based on studies reported in journal articles or other texts that clearly are an inadequate basis for approval by FDA would undercut the efficacy standard. ⁽¹¹⁾

Eliminating the need for well-controlled studies would be a major setback for the first-rate medical care that the health care system the U.S. provides. ⁽¹¹⁾

Without the requirement to submit clinical studies to prove that drugs are effective for their intended uses, it is far less likely that we would know that these drugs will work for which there is relatively little evidence. ⁽¹¹⁾

RISKS OF OFF-LABEL DRUG USE

What are the risks of off-label drug use?

Widespread promotion of unapproved off-label uses raises significant safety concerns. ⁽¹¹⁾

Although this practice provides a pathway to innovation in clinical practice, it raises key concerns about risks to patients and costs to the health care system. ⁽³³⁾

Unlike medicines prescribed for Food and Drug Administration–approved indications, off-label uses may lack rigorous scientific scrutiny. ⁽³³⁾

Despite sufficient evidence justifying some off-label practices, lack of FDA approval means that off-label uses are not given the same degree of scientific scrutiny as labeled indications. ⁽³³⁾

Scientific evidence documenting the efficacy of off-label uses in routine practice settings commonly falls short of what the drug’s manufacturer would be required to provide the FDA to receive approval for that indication. ⁽³³⁾

The FDA is aware of a number of instances where physicians have used drugs for off-label uses that have resulted in disastrous consequences and death. ^{(9) (11)}

PUBLICATION BIAS & PROMOTION OF OFF-LABEL DRUG USE

Can unapproved off-label drug use promote an unbalanced view?

A significant problem with permitting the promotion of unapproved uses is that physicians may not receive a balanced view of the available information. ⁽¹¹⁾

“It is well documented that there is publication bias.” ⁽¹¹⁾

Studies with favorable results have a greater likelihood of getting published; studies with less favorable results less often get published. ⁽¹¹⁾

There are no incentives to distribute articles, textbook chapters, or other information recommending against a particular use. ⁽¹¹⁾

If the FDA may have evidence that a particular use is unsafe or ineffective, federal confidentiality laws frequently prohibit FDA from disseminating that information. ⁽¹¹⁾

The FDA may be aware of off-label uses about which positive studies appear in the literature and negative data are contained in their files. However, depending on its source, FDA may be unable to use that information to ensure that the medical community has all of the available facts on which to base treatment decisions. ⁽¹¹⁾

Physicians may have access to positive articles about off-label uses and the FDA may be unable to counter those positive articles with any negative information that might be in the FDA files. ⁽¹¹⁾