LABELING
The Agency recommends that labeling reflect the
data from PK/PD studies in pregnancy and, if known, dosing recommendations
during pregnancy. The labeling would reflect the data pertaining to the effect
of pregnancy on the PK and PD obtained from studies conducted. If no studies
were conducted, the Agency recommends that the labeling indicate that the impact
of pregnancy was not studied. If the PK/PD is altered during pregnancy,
the appropriate description of such and recommendations for dosing should be
stated in labeling.
The various permutations of intrinsic drug
characteristics and the effect of pregnancy on drug performance preclude precise
specification of how such drugs would be labeled. The following comments offer
general suggestions on labeling.
A. Clinical Pharmacology 1. Pharmacokinetics Subsection
It is recommended that this section include information
pertinent to pregnancy such as:
·
Disposition of parent drug and metabolites, if
applicable
·
Effects of pregnancy on protein binding of parent drug
and metabolites, if applicable
·
Effects of changes in urinary pH or other special
situations (e.g., tubular secretion inhibited by probenecid)
2. Special Populations Subsection
It is recommended that
this section recapitulate, in brief, the PK changes found in pregnancy and, if
needed, dosing adjustments for pregnant patients. This information should be
based on the studies performed as described in this guidance. Reference should
be made to the PRECAUTIONS/PREGNANCY and the DOSAGE AND ADMINISTRATION
sections. The following text provides examples of possible wording for these
sections.
The simplest situation involves drugs for which
pregnancy has little or no effect on PK:
The disposition
of [Drug X] was studied in [number of] pregnant patients [in y trimester
or from a through b weeks gestation]. Pregnancy has little or no influence on
[Drug X] pharmacokinetics and no dosing adjustment is needed.
This should be followed by a brief summary of
the PK/PD data (e.g., mean, range).
Similarly, for drugs whose PK is influenced by
pregnancy, the statement similar to the following can be modified as appropriate
and in accordance with what is known about the drug (e.g., active or toxic
metabolite) and from the studies performed in accordance with this guidance:
The disposition
of [Drug X] was studied in [number of] pregnant patients [in y trimester
or from a through b weeks gestation]. Elimination of the drug (and metabolite,
if applicable) is significantly changed during pregnancy. Total body clearance
of (unbound, if applicable) [Drug X]/metabolite was reduced/increased in
pregnant patients compared to [healthy postpartum women, the same women prior to
pregnancy or c weeks postpartum]. The terminal half-life of [Drug X]/metabolite
is [prolonged/decreased] by Y-, and Z- fold in second and third trimesters,
respectively. Protein binding of [Drug X]/metabolite [is/is not]
affected by pregnancy. The [drug/metabolite accumulates/does not accumulate] in
pregnant patients on chronic administration resulting in increased/decreased
plasma levels of drug/metabolite. The pharmacologic response [is/is not]
affected by pregnancy. The dosage/dosing interval should be
[decreased/increased] in pregnant patients receiving [Drug X] (see DOSAGE
AND ADMINISTRATION).
B. Precautions/Pregnancy In addition to standard labeling for use in
pregnancy, including Pregnancy Category, a brief statement regarding PK/PD in
pregnancy would be included in the PRECAUTIONS/PREGNANCY section with cross
reference to DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections. If
PK studies in pregnancy were not conducted, the Agency recommends that the
labeling indicate that.
C. Dosage and Administration As appropriate, the following information could
be included:
·
A statement describing the relationship between the
drug’s clearance and pregnancy
·
A statement describing how the dose would be adjusted
during pregnancy, for example:
The dose of [Drug X] should be [increased/decreased by
_____%] during pregnancy.
·
A statement describing how the dose would be adjusted
in the postpartum time period in nonlactating women, specifying the time period
studied (e.g., 2 weeks postpartum)
·
The dosing adjustment regimen can alternatively be
represented in tabular format, for example:
|
Group |
Dosage (mg) |
Frequency |
|
1st trimester |
x |
Every y hours |
|
2nd trimester |
|
|
|
3rd trimester |
|
|
|
Postpartum
(specify time) |
|
|
|
Standard adult dose |
|
|
The influence of
pregnancy on [Drug X] pharmacokinetics is
sufficiently small that no dosing adjustment is needed.
|
