MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

DATE:                        February 2, 2004

TO:                              Paul Seligman, M.D., M.P.H., Acting Director

                                    Anne Trontell, M.D., M.P.H., Deputy Director

                                    Office of Drug Safety

Immediate Office, HFD-400

 

THROUGH:                Mark Avigan, M.D., C.M., Director

                                    Office of Drug Safety

                                    Division of Drug Risk Evaluation, HFD-430

 

FROM:                        Marilyn Pitts, Pharm.D., Safety Evaluator

                                    Claudia B. Karwoski, Pharm.D., Safety Evaluator Team Leader

                                    Office of Drug Safety

                                    Division of Drug Risk Evaluation, HFD-430

 

SUBJECT:                  PID D030417

                                    Drug:  Isotretinoin

                                    Topic: Pregnancy Exposures

 

 

EXECUTIVE SUMMARY

 

This document summarizes a review of pregnancy exposure data reported to FDA in women treated with isotretinoin. The goal of this review was to compare isotretinoin pregnancy exposure data during the year prior to the implementation of the enhanced Isotretinoin Risk Management Program (Pre-RMP) to the first year of implementation of the enhanced RMP (Post-RMP).

It is important to keep in mind that the data for these analyses are primarily based on spontaneous reporting to passive surveillance systems such as AERS and are subject to reporting bias. It is possible for instance, that there was an increase in the reporting of pregnancies in the Post-RMP year, due to publicity around the implementation of the RMP. Additionally spontaneous reports are variable in quality and completeness; as such, lack of information does not necessarily indicate lack of compliance with the RMP. Furthermore, experience of pregnancy failures may not represent general experience of isotretinoin users.

 

The review of the pregnancy exposure data comparing the Pre-RMP to the Post-RMP period can by summarized as follows:

 

·       Pregnancies occurred throughout isotretinoin treatment for both Pre-RMP and Post-RMP periods. Although more pregnancies occurred during the first month of isotretinoin use compared to other months (~15-19%), the aggregate number of pregnancies that occurred after the first month of isotretinoin therapy was greater than in the first month (~42-53%).

·       The number of days of exposure to isotretinoin following conception has not changed between the Pre-RMP or Post-RMP periods.

·       There has been no improvement in baseline pregnancy testing (49.6% and 50% for Pre-RMP and Post-RMP, respectively) and only a slight improvement in monthly pregnancy testing (35.4% and 39.1% for Pre-RMP and Post-RMP, respectively) and in the use of at least one method of birth control (53.5% and 58.3% for Pre-RMP and Post-RMP, respectively) among patients who became pregnant during the Pre-RMP period versus the Post-RMP period.

 

Although the actual reason that the pregnancies occurred could not be delineated from the cases in the series, some common themes were identified and could account for the pregnancy failures. These are summarized below:

 

·        Twenty-one women were not using any form of contraception when the exposed pregnancy occurred or chose abstinence as a means of contraception and then went on to engage in unprotected sexual intercourse.

·        Only 15% of women reporting birth control information reported use of “appropriate” birth control consisting of two methods, at least one of which was a primary method. 

·        Thirty-eight percent (38%) of women who reported using at least one form of contraception reported non-compliance with their chosen method of contraception. Non-compliant women either discontinued use of birth control early, missed doses of their oral contraceptive, or used contraception inconsistently.

 

The outcome of the pregnancy is unknown in almost half of all the pregnancy cases reviewed. As would be expected, this percentage is higher in the Post-RMP cases where outcomes may not yet have occurred or been reported. Sixty-seven percent (113/160) of those that reported pregnancy outcome information elected to terminate the pregnancy. Twenty-nine women delivered a live born infant and a small number of these cases reported a congenital anomaly.

 

In summary, the number of pregnancy exposures has not decreased appreciably and may have increased relative to the overall decrease in use of isotretinoin in the year following the implementation of the enhanced Isotretinoin Risk Management Program. Our review of a number of parameters comparing the Pre-RMP to the Post-RMP suggest minimal or no improvement with the implementation of the RMP. However, it should be emphasized that pre-specified pregnancy exposure metrics were not defined and that the experience of pregnancy failures may not represent general experience of isotretinoin users.

 

METHODS

All pregnancy cases submitted to the Agency after April 1, 2001 from the following sources were reviewed[2]:

 

 

Inclusion Criteria

 

Cases were included if they met the following criteria:

 

 

RESULTS

 

Eight hundred and eight (808) cases from all sources were reviewed. Four hundred eighty-three cases were excluded for the following reasons:

 

1.         GENERAL SUMMARY INFORMATION

 

Three hundred twenty-five pregnancy exposures from all sources met the inclusion criteria.

The following table provides general information about the pregnancy exposures.

 

Table 1. General Information Regarding Pregnancy Exposures

 

Pre-RMP

Post-RMP

Unknown

Number of pregnancy exposures

127

120

78

 

During isotretinoin

95 (74.8%)

87 (72.5%)

67 (85.9%)

 

Within 30 days after isotretinoin

31 (24.4%)

31 (25.8%)

7 (9%)

 

Indeterminate

1 (0.8%)

2 (1.7%)

4 (5.1%)

Trimester exposed

 

 

 

 

First

123

112

28

 

First and second

1

0

0

 

Unknown

3

8

50

Age (years)

n=111

n=101

n=27

 

Mean

22.7

24.1

25

 

Median

24

23

24

 

Range

14-36

14-42

15-50

 

One hundred twenty-seven cases were determined to have occurred during the year prior to the implementation of the enhanced RMP (Pre-RMP). One hundred twenty cases were determined to have occurred during the first year of implementation of the enhanced RMP (Post-RMP). Seventy-eight cases could not be categorized because the conception date was not reported and could not be estimated. The majority of the pregnancy exposures in all three categories occurred during the use of isotretinoin and during the first trimester of pregnancy. There was no difference in the median age of the women among all three categories.

1.1       Pregnancy Exposures by Report Source

 

Table 2 shows the pregnancy cases by report source. Pregnancy cases are voluntarily reported either directly to the manufacturers or to the FDA. They may also be reported via the Isotretinoin Patient Surveys.

 

Table 2.  Report Source of Pregnancy Exposure Reports included in analysis

                          Source

Pre-RMP   

Post-RMP             

Unknown Conception Date

Total

Slone

SI/Degge

25

0

20

12

0

6

45

18

Total Isotretinoin Survey

25

32

6

63

Direct to Manufacturer

99

86

72

257

Direct to FDA

3

2

0

5

Total Cases

127

120

78

325

 

 

We attempted to determine whether any particular source provided more complete and better quality data (e.g. isotretinoin survey versus directly to manufacturer). Table 3 shows the number of data elements completed in the pregnancy exposure reports, stratified by source of the report. 

 

Table 3.  Report Data Elements completed in Pregnancy Exposure Cases included in analysis

                          Source

Pre-RMP

(n=127)

Post-RMP  (n=120)

Unknown      (n=78)

Overall

Total Isotretinoin Survey

Range: 6 to 11, median=8 (n=5)

Range: 3 to 11, median 7 (n=32)

Range: 3 to 6, median=4 (n=6)

Range: 3 to 11, median=7 (n=63)

Direct to Manufacturer

Range: 1 to 11, median=6 (n=99)

Range: 1 to 11, median=6 (n= 86)

Range: 0 to 6, median=1 (n=72)

Range: 0 to 11, median=5 (n=257)

Direct to FDA

Range: 3 to 5, median= 4 (n=3)

Range: 3 to 9, median=6 (n=2)

 

------

Range: 3 to 9, median=4 (n=5)

 

The data elements that were assessed included:

 

 

Overall, reports submitted by the patient surveys contained more data elements (median = 7) than reports submitted either by the manufacturer (median = 5), or reports submitted directly to the FDA (median = 4). It is not clear whether greater attempts for follow-up information occur in those pregnancy cases reported to the patient surveys.

 

It is important to note that the data elements assessed in these reports do not directly measure compliance with Isotretinoin Risk Management Program parameters as listed in the Hoffmann-La Roche, 1 Year Report on the S.M.A.R.T. Program[3] which include the following: 

 

 

1.2       Pregnancy Cases by Quarter

 

Cases by the conception date quarter for both Pre-RMP and Post-RMP cases were examined.  Analysis of the number of pregnancies by quarter for the Post-RMP year was performed to determine whether there has been a decline in the number of cases over time after the implementation of the RMP (Table 4). In addition a comparison of each Post-RMP quarter relative to the same Pre-RMP quarter was made (Table 5). 

 

Table 4. Isotretinoin Pregnancy Cases by Quarter for the Post-RMP Periods as a Percentage of Total

 

Pregnancies (% of total)

Quarter 1

26 (22%)

Quarter 2

29 (24%)

Quarter 3

19 (16%)

Quarter 4

19 (16%)

Unknown*

27 (23%)

*actual quarter conception occurred could not be determined in all Post-RMP cases

 

There were fewer cases reported during the last two quarters of the Post-RMP period compared to the first two quarters. It’s not clear whether this decrease is due to improved compliance with the enhanced RMP over time, less follow-up time compared to earlier quarter, and/or whether this decline will continue into the second year following implementation of the RMP.

 

Table 5. Isotretinoin Pregnancy Cases by Quarter

 

Quarter 1

(Apr 1 – Jun 30)

Quarter 2

(Jul 1 –  Sep 30)

Quarter 3

(Oct 1 –    Dec 31)

Quarter 4

(Jan 1 – Mar 31)

Pre-RMP (n = 110)*

37

27

18

28

Post-RMP (n = 93)*

26

29

19

19

Percent Change from Pre-RMP to Post-RMP

- 30%

+ 7%

+ 5.5%

- 32%

*actual quarter conception occurred could not be determined in all Pre-RMP and Post-RMP cases

 

When each Post-RMP quarter was compared to the same Pre-RMP quarter, variations in all examined quarters were found.  Variations between the quarters ranged from increased reporting of pregnancies by 7% in the second quarter to decreased reporting by 32% in the fourth quarter. The variations between quarters were not necessarily reflected by the change in use patterns over that same time frame (Table 6). Please see the Drug Utilization Review[4] for more comprehensive isotretinoin usage information.

 

Table 6. Isotretinoin Prescriptions Dispensed by Quarter (in thousands)

 

Quarter 1

(Apr 1 – Jun 30)

Quarter 2

(Jul 1 –  Sep 30)

Quarter 3

(Oct 1 –    Dec 31)

Quarter 4

(Jan 1 – Mar 31)

Pre-RMP

377

338

394

398

Post-RMP

295

248

293

325

Percent Change from Pre-RMP to Post-RMP

- 22%

- 27%

- 26%

- 18%

US Data Source: IMS Health, IMS National Prescription Audit Plus™; for 4/01 to 3/03; accessed November 7, 2003.

 

1.3       Estimated Timing of Conception

 

The following table shows the estimated timing of conception relative to the isotretinoin treatment course.  This was based on the most recent treatment course around the pregnancy.

 

Table 7. Estimated timing* of conception in women that became pregnant during isotretinoin treatment

Treatment Month

Pre-RMP

(n=95)

Post-RMP

(n=87)

Unknown (n=67)

All cases (n=249)

Prior to treatment**

12 (12.6%)

7 (8%)

1 (1.5%)

20 (8.0%)

During 1st month

18 (18.9%)

13 (14.9%)

1 (1.5%)

32 (12.9%)

During 2nd month

7 (7.3%)

7 (8 %)

0

14 (5.6%)

During 3rd month

7 (7.3%)

7 (8 %)

2 (3%)

16 (6.4%)

During 4th month

8 (8.4%)

15 (17.2%)

1 (1.5%)

23 (9.2%)

During 5th month

7 (7.3%)

5 (5.7%)

0

12 (4.8%)

During 6th month

8 (8.4%)

5 (5.7%)

0

13 (5.2%)

> 6 months

3 (3.1%)

7 (8 %)

1 (1.5%)

11(4.4%)

Indeterminate

25 (26.3%)

21 (24.1%)

61 (91%)

107 (43%)

*Based on isotretinoin start date to conception or positive pregnancy test; assuming a 30 day treatment period

** Percentage is based on the number of when who became pregnant during isotretinoin treatment; percentage is lower if applied to women who became pregnant during and within 30 days of discontinuation of isotretinoin.

 

For the 249 patients (of 325 total) that became pregnant during isotretinoin therapy, there were more reported pregnancies in the first month of isotretinoin therapy relative to subsequent individual months (15-19%); however the aggregate number of pregnancies that occurred after the first month of isotretinoin therapy was greater (~42-53%).

 

1.4       Days Exposure to Isotretinoin Following Conception

 

The following tables show the days of exposure to isotretinoin following conception. This is based on the estimated conception date to the day that isotretinoin was discontinued. 

 

Table 8. Days Exposure to Isotretinoin Following Conception

 

Pre-RMP

Post-RMP

Unknown

Range

Mean

Median

1 to 91 days

19.1 days

17 days

(n=71)

1 to 52 days

19.3 days

17 days

(n=54)

3 to 105 days

26.1 days

14 days

(n=8)

 

There was no difference in mean and median number of days exposed to isotretinoin following conception between the Pre-RMP and Post-RMP year.  The following table shows these same data in ranges of days.

 

Table 9. Days Exposure to Isotretinoin Following Conception

 

Pre-RMP

Post-RMP

Unknown

<7 days

15 (15.7%)

11 (12.6%)

2 (3%)

7 to 14 days

18 (18.9%)

9 (10.3%)

2 (3%)

15 to 30 days

27 (28.4%)

21 (24.1%)

2 (3%)

> 30 days

11 (11.6%)

13 (14.9%)

2 (3%)

Number of days exposure unknown

24 (25.2%)

33 (38%)

59 (88%)

Total number during isotretinoin

95

87

67

 

The percentage of pregnant patients exposed to isotretinoin for greater than two weeks has not changed from Pre-RMP to Post-RMP (40%; 38/95 and 39%; 34/87, for Pre-RMP and Post-RMP periods, respectively).

 

2.         PREGNANCY TESTING

 

2.1       Baseline Pregnancy Testing Prior to Starting Isotretinoin

 

Two (urine or serum) baseline pregnancy tests, prior to starting isotretinoin therapy are mandated in the product label.

 

An evaluation of how often any baseline pregnancy testing was performed before starting isotretinoin therapy was performed.  Any baseline pregnancy testing is defined as pregnancy testing occurring before starting isotretinoin therapy.  Information on the type of pregnancy test (urine or serum) was inconsistently reported, therefore making it impossible to reliably determine the type of pregnancy test that occurred.  A comparison of Pre-RMP data with Post-RMP data was made. 

 

Table 10. Baseline Pregnancy Testing while using Isotretinoin

 

Pre-RMP                                 n = 127

Post-RMP

n = 120

Any Baseline Pregnancy Test

63 (49.6%)

60 (50%)

 

> 2 Baseline Tests

18

23

No Baseline Test Taken

4 (3.2%)

2 (1.7%)

Not Reported

60 (47.2%)

58 (48.3%)

 

Sixty-three (49.6%) Pre-RMP and 60 (50%) Post-RMP cases reported having at least one baseline pregnancy test before starting isotretinoin therapy. For those cases reporting baseline pregnancy testing, we found that slightly more than one-quarter (29%, 18/63) of the Pre-RMP cases, and more than one-third (38%, 23/60) of the Post-RMP cases reported at least two baseline pregnancy tests. 

 

Four Pre-RMP cases (3.2%, 4/127)) and two (1.7%, 2/120) Post-RMP cases reported having no baseline pregnancy testing performed and 60 (47.2%, 60/127) Pre-RMP and 58 (48.3%, 58/120) Post-RMP cases did not report whether or not baseline pregnancy testing had been performed.

 

2.2       Pregnancy Testing During Isotretinoin Therapy

 

The isotretinoin product label requires a pregnancy test each month prior to the female patient receiving an isotretinoin prescription. 

 

An evaluation of compliance with pregnancy testing during isotretinoin treatment was performed. A comparison Pre-RMP data with Post-RMP data was made. 

 

 

 

 

Table 11. Pregnancy Testing During Isotretinoin Therapy

 

Pre-RMP                           n = 127

Post-RMP                         n = 120

At Least One Pregnancy Test During Isotretinoin Therapy

45 (35.4%)

47 (39.1%)

No Pregnancy Test During Isotretinoin Therapy

4 (3.2%)

2 (1.7%)

Pregnancy Testing Not Reported

78 (61.4%)

71 (59.2%)

 

·       Overall, 45 (35.4%) Pre-RMP cases and 47 (39.1%) Post-RMP cases reported at least one pregnancy test during isotretinoin use. 

·       Four (3.2%) Pre-RMP and 2 (1.7%) Post-RMP cases reported having no pregnancy testing during isotretinoin therapy. 

·       Additionally, 78 Pre-RMP (61.4%) cases and 71 (59.2%) Post-RMP cases did not report whether or not any pregnancy testing occurred during isotretinoin therapy.  Of note 31 cases overall reported using isotretinoin for less than 30 days and may not have been eligible for pregnancy testing during treatment.

 

3.         SUMMARY OF PATIENTS WHO BECAME PREGNANT PRIOR TO STARTING ISOTRETINOIN

 

3.1       Baseline Pregnancy Testing

 

A careful examination of the cases involving the 20 women who were pregnant prior to starting therapy with isotretinoin was performed. Sixteen of the 20 women reportedly received some pregnancy testing. The other four cases did not mention whether baseline pregnancy testing was conducted.

 

Of the 16 women who reportedly received baseline pregnancy testing, nine reported two or more baseline pregnancy tests, six reported “a” baseline pregnancy test, and the number of baseline tests was unknown in one case. The results of the pregnancy tests were negative in eight patients and positive in three. The results were unknown in the remaining five patients.

 

The following describe the circumstances of the three with positive pregnancy results:

 

3.2       Compliance with Label Recommendations

 

An evaluation of the isotretinoin treatment start date in relation to first day of the last menstrual period (LMP) and baseline pregnancy testing among patients who were pregnant prior to initiating therapy with isotretinoin was performed. The product label states that the second test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy.  Sixteen of the 20 cases provided LMP dates.

 

Table 12. LMP, Baseline Pregnancy (BL Preg) Testing, and Isotretinoin Start dates among 20 patients already pregnant prior to initiating isotretinoin

Pre/Post RMP

LMP

BL Preg

test date*

Isotretinoin start date

Days b/n BL Preg Test and isotretinoin start

Days b/n LMP and isotretinoin start

Pre

NR

Oct 1

Oct 1

0

Unable to determine

Pre

NR

Aug 10

Aug 10

0

Unable to determine

Pre

Jan 18

NR

Mar 5

Unable to determine

46

Pre

Feb 8

NR

Mar 15

Unable to determine

35

Pre

Mar 5

Feb 13

Feb 27

14

NA§

Pre

Mar 8

NR

Apr 1

Unable to determine

23

Pre

Apr 20

NR

Jul 27

Unable to determine

98

Pre

Jun 3

Jul 26

Jul 27

1

54

Pre

Jul 6

May 16

Jul 31

76

25

Pre

Aug 18

Aug 30

Sep 4

5

17

Pre

Aug 20

Sep 7

Sep 17

10

27

Pre

Sep 17

Oct 23

Oct 24

1

37

Post

NR

Dec 15

Dec 15

0

Unable to determine

Post

Jan 2

NR

Feb 3

Unable to determine

32

Post

Feb 4

in Jan

Feb 25

30+

21

Post

Feb 5

Feb 7

Feb 20

13

15

Post

Mar 28

NR

Apr 23

Unable to determine

26

Post

Sep 11

Sep 25

Sep 30

5

19

Post

Dec 24

Dec 29

Jan 15

17

22

Unk

NR

NR

NR

Unable to determine

Unable to determine

* Date is based on confirmatory or only baseline pregnancy test reported; in four women dates for the baseline pregnancy testing was not provided.

§ patient had menses during pregnancy

 

Only two reported a baseline pregnancy test during the LMP, both during the Post-RMP period.  Seven of the 20 patients began isotretinoin therapy within 5 days of the baseline pregnancy test, however not in conjunction with the LMP. Moreover, none of the 16 patients (with an LMP date reported) started isotretinoin within two weeks of their LMP. Although the label does not instruct to start within a specified period of time around the LMP, it does state that the baseline pregnancy test should be conducted during the first five days of menses immediately preceding isotretinoin therapy, and that the prescription for isotretinoin should be dispensed within 7 days of the “qualification date” or confirmatory pregnancy test. It is perhaps the lack of specific instructions that may be a source of confusion to both practitioners as well as patients.

 

 

 

4.         CONTRACEPTIVE USE

 

4.1       Contraceptive Use during Isotretinoin Therapy

 

Isotretinoin’s product label requires that female patients commit to two forms of effective birth control, at least one of which must be a primary form, unless absolute abstinence is chosen, or the patient has undergone a hysterectomy.

 

An evaluation of contraceptive use by patients reporting isotretinoin associated pregnancies was performed.  A comparison of Pre-RMP data with Post-RMP data was made. 

 

Table 13. Contraceptive Use with Isotretinoin

 

Pre-RMP                          

n = 127

Post-RMP                        

n = 120

Any Birth Control Method

68 (53.5%)

70 (58.3%)

·     One Method (any)

(One Method - primary[5])

50

(44)

61

(54)

·     Two Methods (any)

(Two methods – 1 primary)

18

(14)

9

(7)

No Birth Control Used/abstinence

15 (11.8%)

6 (5%)

Not Reported

44 (34.6%)

44 (36.7%)

 

The percentage of patients reporting any contraceptive use was about the same Pre-RMP and Post-RMP; however the percentage reporting no contraceptive use decreased during the Post-RMP year (11.8% and 5% for Pre-RMP and Post-RMP cases, respectively).

 

Of those reporting any contraceptive use, the following was noted:

 

Forty-four cases each (Pre-RMP 34.6%, Post-RMP 36.7%) did not report whether or not contraception was used during the time of isotretinoin use.

 

4.2       Contraceptive Compliance during Isotretinoin Therapy

 

Of the patients reporting contraceptive use, there were 32 Pre-RMP and 35 Post-RMP cases that provided information concerning contraceptive compliance during isotretinoin therapy.  The majority of cases (82.1%; 23/28 Pre-RMP, and 80%; 28/35 Post-RMP) reported non-compliance with their chosen contraceptive methods.  Five cases in each category reported contraceptive failure.  There were two Post-RMP cases reporting both contraceptive failure and non-compliance.

 

Table 14. Contraceptive Compliance

 

Pre-RMP                       

Post-RMP                           

Any Compliance Statement

28

35

Non-compliant

23

28

Contraceptive Failure

5

5

Contraceptive Failure and non-compliant

-----

2

 

Non-compliance refers to patients that discontinued use of contraceptive methods prior to label recommendations (during use and 30 days following isotretinoin discontinuation), or those that missed doses or otherwise inconsistently used contraceptive methods.  Contraceptive failure is defined as those patients that reported “contraceptive failure”.  Some examples of contraceptive failure included:

 

 

5.         OUTCOME DATA

 

Both pregnancy outcome and fetal outcome data for all 325 cases was tallied. Although these data are stratified by RMP period, any enhancements to the Isotretinoin RMP are unlikely to affect the pregnancy or fetal outcomes during these two periods.

 

5.1       Pregnancy Outcomes

 

The table below provides a summary of the pregnancy outcomes by RMP category.

 

 

 

 

 

Table 15. Pregnancy Outcomes

 

Pre-RMP

(n=127)

Post-RMP

(n=120)

Unknown

(n=78)

Total

(n=325)

Delivery

18

7

4

29

Spontaneous abortion/ectopic pregnancy

15

6

2

23

Elective Abortion

47

48

18

113

Unknown (lost to FU, pregnancy ongoing)

47 (37%)

59 (49%)

54 (69%)

160 (49%)

 

The outcome of the pregnancy is unknown in almost half of all pregnancy cases (160/325). As would be expected, this percentage is higher in the unknown and in the Post-RMP cases where outcomes may not yet have occurred been reported. About 35% of patients in the series elected to terminate their pregnancy. Nine percent (29/325) of patients delivered a live born infant.

 

The table below provides a breakdown of the 165 known pregnancy outcomes by time of isotretinoin exposure.

 

Table 16. Pregnancy Outcome by time of isotretinoin exposure

 

Delivery

SAB/ectopic*

Elective Abortion

After discontinuation

 

 

 

15 to 30 days

10

2

5

7 to 14 days

3

2

5

< 7 days

1

1

3

During isotretinoin

 

 

 

< 7  days

5

4

5

7 to 14 days

4

3

14

15 to 30 days

2

2

29

> 30 days

1

5

11

Number of days exposed unknown

3

4

41

Total

29

23

113

*Spontaneous abortion and ectopic pregnancies

 

It appears that the longer the patient was exposed to isotretinoin following conception, the greater the tendency of the patient to terminate the pregnancy.

 

5.2       Fetal Outcomes

 

Twenty-nine patients reported delivery of a liveborn infant. Twenty reported normal babies (at time of reporting) of which four were born prematurely (2 to 5 weeks). Another mother had premature labor that was successfully stopped. In another case a mother with a history of epilepsy experienced seizure activity during pregnancy. Her pregnancy was further complicated by polyhydraminos, cord entanglement, small subchorionic hemorrhage, and decreased fetal movement but she subsequently delivered a normal baby. There was also another infant in whom a septal defect was noted in utero. Following birth, the infant underwent echocardiography which ruled out a defect.

 

Seven reported some type of abnormality and the fetal outcome in the remaining two was unknown. The mothers in three of the seven infants with an abnormality discontinued isotretinoin 15 to 25 days prior to conceiving. One infant developed gastroschisis and undescended testicles both events that required surgery. The other was a male infant who developed bilateral hydrocele and moulding of the anterior fontanel. In the third, an ultrasound in utero showed a small spot on the fetal heart. The mother delivered a female infant but no follow-up regarding a possible cardiac anomaly was provided.

 

The mothers in the remaining four infants that developed an abnormality conceived during isotretinoin therapy. Anomalies of the heart were reported in two cases, kidney in one case, and facial anomalies and retardation in one case. All four cases are briefly summarized below.

 

The patterns of isotretinoin embryopathy are characteristic malformations involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations include microtia/anotia, micrognathia, cleft palate, conotruncal heart defects and aortic-arch abnormalities, thymic defects, retinal or optic-nerve abnormalities, and central nervous system malformations.[7] Cognitive deficits in more than half the children exposed in utero have also been reported in follow-up studies to 5 years of age.[8]

 

DISCUSSION

 

The data for these analyses are primarily based on spontaneous reporting to passive surveillance systems such as AERS and are subject to reporting bias. It is possible for instance, that there was an increase in the reporting of pregnancies in the Post-RMP year, due to publicity around the implementation of the RMP. Additionally spontaneous reports are variable in quality and completeness; as such, lack of information does not necessarily indicate lack of compliance with the RMP. Furthermore, experience of pregnancy failures may not represent general experience of isotretinoin users.

 

Although there were no prespecified metrics agreed upon regarding any of these data, experience from pregnancy failures may help guide future RMP efforts to further reduce pregnancy exposures.

 

Review of the pregnancy exposure data comparing the Pre-RMP to the Post-RMP period can by summarized as follows:

 

·       Pregnancies occurred throughout isotretinoin treatment for both Pre-RMP and Post-RMP periods. Although more pregnancies occurred during the first month of isotretinoin use compared to most other months (15-19%), the aggregate number of pregnancies that occurred after the first month of isotretinoin therapy was greater (~42-53%).

·       The number of days of exposure to isotretinoin following conception has not changed between the Pre-RMP or Post-RMP periods.

·       There has been no improvement in baseline pregnancy testing (49.6% and 50% for Pre-RMP and Post-RMP, respectively) and only a slight improvement in monthly pregnancy testing (35.4% and 39.1% for Pre-RMP and Post-RMP, respectively) and in the use of at least one method of birth control (53.5% and 58.3% for Pre-RMP and Post-RMP, respectively) among patients who became pregnant during the Pre-RMP period versus the Post-RMP period.

 

Although the actual reason that the pregnancies occurred could not be delineated from the cases in the series, some common themes were identified and could account for the pregnancy failures. These are summarized below:

 

·        Twenty-one women were not using any form of contraception when the exposed pregnancy occurred or chose abstinence as a means of contraception and then went on to engage in unprotected sexual intercourse.

·        The majority of women describe using only one method of birth control. Only 15% of women reporting birth control information reported use of “appropriate” birth control consisting of two methods, at least one of which was a primary method.

·        Fifty-one of 138 women (38%) who reported using at least one form of contraception reported non-compliance with their chosen method of contraception. Non-compliant women either discontinued use of contraception early, missed doses of their oral contraceptive, or used contraception inconsistently.

 

The outcome of the pregnancy is unknown in almost half of all the pregnancy cases reviewed. As would be expected, this percentage is higher in the Post-RMP cases where outcomes may not yet have occurred or been reported. Sixty-seven percent (113/160) of those that reported pregnancy outcome information elected to terminate the pregnancy. Nine percent (29/325) of patients delivered a live born infant and a small number of these cases reported a congenital anomaly.

 

CONCLUSION

 

The number of pregnancy exposures has not decreased appreciably and may have increased relative to the overall decrease in use of isotretinoin in the year following the implementation of the enhanced Isotretinoin Risk Management Program. Our review of a number of parameters comparing the Pre-RMP to the Post-RMP suggest minimal or no improvement with the implementation of the RMP. However, it should be emphasized that pre-specified metrics were not defined and that experience of pregnancy failures may not represent general experience of isotretinoin users.

 

 

 



[1] See Isotretinoin Utilization Review, pg 30.

[2] Source:  Adverse Event Reporting System, Request for Information – Roche Submission: September 18, 2003, Ranbaxy Submission: November 18, 2003, and Genpharm Submission: November 17, 2003.

 

[3] Hoffmann-La Roche submission–General Correspondence: 1 Year Report on the SMART Program, June 30, 2003

[4] See Isotretinoin Utilization Review, pg 30.

[5] Primary methods of contraception: oral contraceptives, implantable hormones, injectable hormones, hormonal patch, intrauterine devices, hormonal vaginal contraceptive ring, sterilization (male, female)

[6] Secondary methods of contraception:  diaphragms, latex condoms, cervical cap,

[7] Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Broun JT, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313:837-41.

[8] Teratology Society. Recommendations for isotretinoin use in women of childbearing potential. Teratology 1991;44:1-6.