Keamanan Obat pada Kehamilan

Menurut FDA
28/07/2016AdminOne comment

Pola penggunaan obat yang aman bagi ibu hamil dan menyusui di Indonesia
belumlah menjadi sebuah pemahaman yang dimengerti dengan baik bukan hanya
bagi masyarakat, melainkan di kalangan tenaga kesehatan itu sendiri. Hal ini
tidaklah mengherankan, pemerintah sendiri, dalam hal ini Kemenkes dan BPOM
sejauh ini memang belum mengeluarkan regulasi atau rilis ilmiah mengenai hal ini.

Secara ilmiah, kita masih berpatokan pada penggolongan keamanan obat pada
kehamilan yang dikeluarkan oleh FDA. FDA (Food and Drug Administration) adalah
Badan POM-nya Amerika Serikat. FDA bertugas mengatur makanan, suplemen
makanan, obat-obatan, produk biofarmasi, transfusi darah, piranti medis, piranti
untuk terapi dengan radiasi, produk kedokteran hewan, dan kosmetik yang beredar
di Amerika Serikat.
Naskah asli dalam bahasa aslinya dapat anda baca disini.
Namun demikian jika anda malas mentranslate, penjelasannya adalah seperti ini,
FDA menggolongkan tingkat keamanan penggunaan obat pada kehamilan dalam 5
kategori yaitu :
1. Kategori A : Studi kontrol pada wanita tidak memperlihatkan adanya resiko
terhadap janin pada kehamilan trimester I (dan tidak ada bukti mengenai resiko
pada trimester selanjutnya), dan sangat rendah kemungkinannya untuk
membahayakan janin. Contoh : Vitamin C, asam folat, vitamin B6, zinc.
Kebanyakan golongan obat yang masuk dalam kategori ini adalah golongan
vitamin, meski demikian terdapat beberapa antibiotik yang masuk dalam
Ketegori A ini
2. Kategori B : Studi pada sistem reproduksi binatang percobaan tidak
memperlihatkan adanya resiko terhadap janin, tetapi studi terkontrol terhadap
wanita hamil belum pernah dilakukan. Atau studi terhadap reproduksi binatang
percobaan memperlihatkan adanya efek samping obat (selain penurunan
fertilitas) yang tidak diperlihatkan pada studi terkontrol pada wanita hamil
trimester I (dan tidak ada bukti mengenai resiko pada trimester berikutnya).
Contoh : acarbose, acyclovir, amiloride, amoxicillin, ampicillin, azithromycine,
bisacodyl, buspirone, caffeine, cefaclor, cefadroxil, cefepime, cefixime, cefotaxime,
ceftriaxone, cetirizine, clavulanic acid, clindamycine, clopidogrel, clotrimazole,
 cyproheptadine, dexchlorpheniramine oral, dicloxaciline, dobutamin, erythromycin,
famotidin, fondaparinux sodium, fosfomycin, glibenclamide + metformin oral, glucagon,
ibuprofen oral, insulin, kaolin, ketamine, lansoprazole, lincomycin, loratadine,
meropenem, metformin, methyldopa, metronidazole, mupirocin, pantoprazole,
paracetamol oral, ranitidine, sucralfat, terbutalin, tetracycline topical, tranexamic acid,
ursodeoxycholic acid, vancomycin oral.
3. Kategori C : Studi pada binatang percobaan memperlihatkan adanya efek
samping pada janin (teratogenik atau embriosidal atau efek samping lainnya)
dan belum ada studi terkontrol pada wanita, atau studi terhadap wanita dan
binatang percobaan tidak dapat dilakukan. Obat hanya dapat diberikan jika
manfaat yang diperoleh melebihi besarnya resiko yang mungkin timbul pada
janin. Contoh : acetazolamide, albendazole, albumin, allopurinol, aminophylin,
amitriptyline, aspirin, astemizol, atropine, bacitracin, beclometasone, betacaroten,
bupivacaine, calcitriol, calcium lactate, chloramphenicol, ciprofloxacin, clidinium
bromide, clobetasol topical, clonidine, cotrimoxazole, codein + paracetamol,
desoximetasone topical, dextromethorphan, digoxin, donepezil, dopamine, enalapril,
ephedrine, fluconazole, fluocinonide topical, gabapentin, gemfibrozil, gentamycin
(parenteral D), griseofulvin, guaifenesin, haloperidol, heparin, hydrocortisone, INH,
isosorbid dinitrate, ketoconazole, lactulosa, levofloxacine, miconazole, nalidixic acid,
nicotine oral, nimodipine, nystatin (vaginal A), ofloxacin, omeprazole, perphenazine,
prazosin, prednisolone, promethazine, pseudoephedrine, pyrantel, pyrazinamide,
rifampicin, risperidone, salbutamol, scopolamine, simethicon, spiramycin,
spironolactone, streptokinase, sulfacetamide opth & topical, theophyline, thiopental
sodium, timolol, tramadol, triamcinolone, trifluoperazine, trihexyphenidil.
4. Kategori D : Terbukti menimbulkan resiko terhadap janin manusia, tetapi
besarnya manfaat yang diperoleh jika digunakan pada wanita hamil dapat
dipertimbangkan (misalnya jika obat diperlukan untuk mengatasi situasi yang
mengancam jiwa atau penyakit serius dimana obat yang lebih aman tidak efektif
atau tidak dapat diberikan). Contoh: alprazolam, amikacin, amiodarone, atenolol,
bleomycin, carbamazepine, chlordiazepoxide, cisplatin, clonazepam,
cyclosphosphamide, diazepam, kanamycin, minocycline,phenytoin, povidon iodine
topical, propylthiouracil, streptomycin inj, tamoxifen, tetracycline oral dan ophthalmic,
valproic acid.
5. Kategori X : Studi pada binatang percobaan atau manusia telah memperlihatkan
adanya abnormalitas janin dan besarnya resiko obat ini pada wanita hamil jelas-
jelas melebihi manfaatnya. Dikontraindikasikan bagi wanita hamil atau wanita
 usia subur. Contoh : alkohol dalam jumlah banyak dan pemakaian jangka
panjang, amlodipin + atorvastatin, atorvastatin, caffeine + ergotamine,
chenodeoxycholic, clomifene, coumarin, danazol, desogestrel + ethinyl estradiol,
dihydroergotamine, ergometrine, estradiol, (+ norethisterone), fluorouracil,
flurazepam, misoprostol, oxytocin, simvastatin, warfarin.

Lebih gampangnya dapat diartikan sebagaimana berikut :

 A= Tidak berisiko
 B= Tidak berisiko pada beberapa penelitian
 C= Mungkin berisiko
 D= Ada bukti positif dari risiko
 X= Kontraindikasi
Doktrin yang masih relevan untuk dipakai hingga kini adalah bahwa : TIDAK ADA
OBAT YANG AMAN UNTUK IBU HAMIL. Penjabaran ilmiah mengenai hal ini
diartikan bahwa penggunaan semua obat pada masa kehamilan harus melalui
dokter (sesuai dengan diagnosa) atau apoteker (sebagai faktor kontrol). Efikasi,
kemanjuran (benefit) vs resiko (risk) adalah pertimbangan utama dalam kita
menggunakan obat khususnya untuk kategori A dan B, sedangkan untuk obat yang
masuk kategori C dan D penggunaannya harus benar-benar melalui pertimbangan
dokter dengan mempertimbangkan manfaat, keselamatan jiwa yang lebih besar
dibandingkan resikonya. Untuk obat dengan kategori X TIDAK BOLEH DIGUNAKAN
pada masa kehamilan.
Darimana kita dapat mengetahui kategori obat tersebut?. Banyak literatur resmi
yang menerangkan obat berada pada kategori A, B, C, D ataukah X. Diantaranya
pada buku MIMS yang hampir pasti menjadi buku pegangan apoteker di apotek.
Daftar kategori obat ini juga dikeluarkan oleh FDA. Jangan asal searching dari
internet dengan sumber yang tidak kredibel. Silakan bertanya pada apoteker anda,
atau pada dokter anda, amankah obat yang anda minum? Jika ya, atau jika dokter
anda menjawab tidak, tanyakan obat anda berada pada kategori apa menurut FDA?
Ingat, keamanan obat pada masa kehamilan adalah sebuah pilihan berdasakan
kondisi pasien secara medis, dan berdasarkan kajian studi ilmiah. Bukan asumsi
pribadi, bukan menurut dokter A, atau menurut dokter B. Sekali lagi adalah evidence
based medicine. Bukan kata si A atau si B.
FDA Pregnancy Categories
FDA Pregnancy Risk Information: An
Update
In 2015 the FDA replaced the former pregnancy risk letter categories (see
below) on prescription and biological drug labeling with new information to
make them more meaningful to both patients and healthcare providers. The
FDA received comments that the old five-letter system left patients and
providers ill-informed and resulted in false assumptions about the actual
meaning of the letters.

The new labeling system allows better patient-specific counseling and

informed decision making for pregnant women seeking medication therapies.
While the new labeling improves the old format, it still does not provide a
definitive “yes” or “no” answer in most cases. Clinical interpretation is still
required on a case-by-case basis.

The Pregnancy and Lactation Labeling Final Rule (PLLR) went into effect on
June 30, 2015; however, the timelines for implementing this new information
on drug labels (also known as the package insert) is variable.

Prescription drugs submitted for FDA approval after June 30, 2015 will use the
new format immediately, while labeling for prescription drugs approved on or
after June 30, 2001 will be phased in gradually. Medications approved prior to
June 29, 2001 are not subject to the PLLR rule; however, the pregnancy letter
category must be removed by June 29, 2018. For generic drugs, if the labeling
of a reference listed drug is updated as a result of the final rule, the
abbreviated new drug application (ANDA) labeling must also be revised.
Labeling for over-the-counter (OTC) medicines will not change, as OTC drug
products are not affected by the new FDA pregnancy labeling.

The A, B, C, D and X risk categories, in use since 1979, are now replaced with
narrative sections and subsections to include:

Pregnancy (includes Labor and Delivery):

 Pregnancy Exposure Registry

  Risk Summary
 Clinical Considerations
 Data

Lactation (includes Nursing Mothers)

 Risk Summary
 Clinical Considerations
 Data

Females and Males of Reproductive Potential

 Pregnancy Testing
 Contraception
 Infertility

The Pregnancy subsection will provide information about dosing and

potential risks to the developing fetus and registry information that collects
and maintains data on how pregnant women are affected when they use the
drug or biological product. Information in drug labeling about the existence of
any pregnancy registries has been previously recommended but not required
until now. Contact information for the registries will also be included, and
pregnant women are encouraged to enroll to help provide data on the effects
of drug use or biologics in pregnancy.

If information for the subsections of Pregnancy Exposure Registry, Clinical

Considerations, and Data is not available, these subsections will be excluded.
The Risk Summary subheadings are always required, even if no data is
available.

The Lactation subsection will replace the “Nursing Mothers” subsection of the
old label. Information will include drugs that should not be used during
breastfeeding, known human or animal data regarding active metabolites in
milk, as well as clinical effects on the infant. Other information may include
pharmacokinetic data like metabolism or excretion, a risk and benefit section,
as well as timing of breastfeeding to minimize infant exposure.

In the subsection entitled Females and Males of Reproductive Potential,

relevant information on pregnancy testing or birth control before, during or
after drug therapy, and a medication’s effect on fertility or pregnancy loss will
be provided when available.
Why Did the FDA Make This Change?
Clinically, many women require drug treatment during pregnancy due to
chronic conditions such as epilepsy, diabetes, hypertension (high blood
pressure), or asthma. To withhold drug treatment would be dangerous for
both mother and baby. In addition, women are having babies at a later age,
which can boost the number of women with chronic conditions. Accessible
and understandable pregnancy and lactation information is important for
women and their health care provider’s to assess risk versus benefit.

The FDA has received requests to improve the decades-old content and
format of pregnancy prescription drug labeling since 1992. According to the
Drug Information Division at the FDA, they obtained input from many affected
groups and held public hearings, advisory committee meetings, and focus
groups to assess the changes. In 2008, the FDA issued the proposed rule and
then opened a docket for public comments.

Clinicians and patients were often confused by the meaning of the pregnancy
risk categories because, according to the FDA, it was overly simplistic, led to
misinformation, and did not adequately address the available information.

Examples of drugs approved since June 30th, 2015 showing various new
pregnancy and lactation subsections in their labels:

 Addyi (flibanserin) - indicated for generalized hypoactive sexual desire

disorder (HSDD) in premenopausal women.
 Descovy (emtricitabine and tenofovir alafenamide fumarate) -
indicated for HIV-1 infection.
 Entresto (sacubitril and valsartan) - indicated for heart failure.
 Harvoni (ledipasvir and sofosbuvir) - indicated for chronic viral
hepatitis C infection (HCV).
 Praluent (alirocumab) - indicated for heterozygous familial
hypercholesterolemia, or patients with atherosclerotic heart disease who
require additional lowering of LDL-cholesterol.
FDA Pregnancy Risk Categories Prior to
2015
In 1979, the FDA established five letter risk categories - A, B, C, D or X - to
indicate the potential of a drug to cause birth defects if used during
pregnancy. The categories were determined by assessing the reliability of
documentation and the risk to benefit ratio. These categories did not take into
account any risks from pharmaceutical agents or their metabolites in breast
milk. In the drug product label, this information was found in the section “Use
in Specific Populations”.

The former pregnancy categories, which still may be found in some package
inserts, were as follows:

Category A

Adequate and well-controlled studies have failed to demonstrate a risk to the

fetus in the first trimester of pregnancy (and there is no evidence of risk in
later trimesters).

Example drugs or substances: levothyroxine, folic acid, liothyronine

Category B

Animal reproduction studies have failed to demonstrate a risk to the fetus and
there are no adequate and well-controlled studies in pregnant women.

Example
drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin

Category C

Animal reproduction studies have shown an adverse effect on the fetus and
there are no adequate and well-controlled studies in humans, but potential
benefits may warrant use of the drug in pregnant women despite potential
risks.

Example drugs: gabapentin, amlodipine, trazodone

Category D

There is positive evidence of human fetal risk based on adverse reaction data
from investigational or marketing experience or studies in humans, but
potential benefits may warrant use of the drug in pregnant women despite
potential risks.

Example drugs: losartan

Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or

there is positive evidence of human fetal risk based on adverse reaction data
from investigational or marketing experience, and the risks involved in use of
the drug in pregnant women clearly outweigh potential benefits.

Example drugs: atorvastatin, simvastatin, methotrexate, finasteride

Related Slideshows
 Breastfeeding & OTC Medication: Safety Tips That You Need To
Know
 OTC Medication Use In Pregnancy: Wise or Worrisome?

Sources:

1. FDA/CDER SBIA Chronicles. Drugs in Pregnancy and Lactation: Improved Benefit-Risk

Information. Accessed August 1, 2019 at
https://www.fda.gov/files/drugs/published/%22Drugs-in-Pregnancy-and-Lactation--
Improved-Benefit-Risk-Information%22-January-22--2015-Issue.pdf
2. FDA Consumer Articles. Pregnant? Breastfeeding? Better Drug Information Is Coming.
Accessed August 1, 2019 at https://www.fda.gov/consumers/consumer-
updates/pregnant-breastfeeding-better-drug-information-coming
3. FDA News Release. FDA issues final rule on changes to pregnancy and lactation
labeling information for prescription drug and biological products. Accessed August
1, 2019 at https://www.fda.gov/drugs/labeling/pregnancy-and-lactation-labeling-
drugs-final-rule
4. Mospan C. New Prescription Labeling Requirements for the Use of Medications in
Pregnancy and Lactation. CE for Pharmacists. The Ohio Pharmacist Foundation.
Accessed August 1, 2019 at
https://cdn.ymaws.com/www.wsparx.org/resource/resmgr/CE_Magazine/WA_0416_St
ate_CE_Lesson.pdf