Enrollment

REBETOL®
(ribavirin)
CRIXIVAN®
(indinavir sulfate)
ISENTRESS®
(raltegravir)
GARDASIL®
[Quadrivalent Human Papillomavirus (Types 6,11,16,18) Recombinant Vaccine]
JANUVIA®
(sitagliptin phosphate)
JANUMET®
(sitagliptin/metformin HCl)
MAXALT®
(rizatriptan benzoate)
SINGULAIR®
(montelukast sodium)
VARICELLA ZOSTER VIRUS-CONTAINING VACCINES


 

The Pregnancy Registry for JANUVIA and JANUMET receives voluntary reports from healthcare providers or from women/family members/friends about women who inadvertently (before knowing they were pregnant) or purposefully (knowingly took the drug to control their diabetes) used JANUVIA or JANUMET during pregnancy. The women are enrolled and their pregnancies are followed. Outcomes are obtained from participating clinicians.

JANUVIA and JANUMET have been assigned FDA Pregnancy Category B.

Sitagliptin Phosphate
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats. Placental transfer of sitagliptin administered to pregnant rats and rabbits was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Because there have been no adequate and well-controlled studies in pregnant women and because animal reproduction studies are not always predictive of human response, JANUVIA and JANUMET should be used during pregnancy only if clearly needed.

Literature Review

Prevalence of Type 2 Diabetes during Pregnancy: U.S. prevalence of type 2 diabetes has increased by 33% from 1990 to 1998 and by 70% among women of childbearing age (30-39 years).1 The true prevalence of type 2 diabetes in pregnancy is difficult to measure because populations with pregestational diabetes include patients with type 1 or gestational diabetes, making estimation of the true frequency of various maternal and fetal complications difficult. Moreover, the proportion of type 1 and type 2 diabetes varies in different maternity populations depending on ethnic mix, with type 2 diabetes being more prevalent among ethnic minority groups.1 A US population-based prevalence study estimated that 0.2-0.5% of all pregnancies were complicated by pregestational diabetes (type 1 or 2) and that type 2 diabetes accounted for 65% in that year, compared to 26% in 1980.2

Fetal Complications of Type 2 Diabetes during Pregnancy: There is concern that rising rates of type 2 diabetes in pregnancy could lead to increasing numbers of pregnancy complications for mothers and infants, with risks at least similar to, if not greater than, those observed among women with type 1 diabetes.3 Perinatal mortality in infants of women with type 2 diabetes was 32.3 per 1000 births in population-based study of 2359 pregnancies to women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland who delivered between 1 March 2002 and 28 February 2003.4 Although perinatal mortality was comparable in babies of women with type 1 diabetes (31.7 per 1000), the rate was nearly 4-times higher than the general population. The prevalence of major congenital anomaly in infants of mothers with type 2 diabetes was 43 per 1000 births, more than double of that expected in the general population.4 This increase was due to anomalies of the nervous system, notably neural tube defects (4.2-fold), and congenital heart disease (3.4-fold).

Previous, smaller studies have reported similar patterns of perinatal mortality and congenital malformations in infants born to women with type 2 diabetes. One study reported a 3-fold increase in perinatal mortality in women with type 2 diabetes, primarily due to late stillbirths,5 while a UK case series reported a perinatal mortality rate of 25 per 1000 (primarily in infants with congenital heart disease), 2.5-fold greater than regional/national figures, and miscarriage rates of 8.8% (doubling to 15.7% in women with poor glycemic control), with half occurring in the first trimester.6 The UK case series also reported congenital malformations in 9.9% (18/182) singleton pregnancies complicated by type 2 diabetes, the most common malformations being cardiac (53%) and musculoskeletal (27%). The majority of malformations occurred in women with poor glycemic control who did not receive pre-pregnancy care.

Enrollment

Healthcare providers are encouraged to report cases of prenatal exposure as early in pregnancy as possible to facilitate the collection of prospective, unbiased information. Enroll your patient by completing the simple 1-page enrollment form available below. You will be asked to complete a second 1-page Outcome of Pregnancy form at the end of the pregnancy. We provide you with a 1-page patient consent form that explains the Pregnancy Registry to your patient. We encourage you to review it with your patient and have her sign it before the end of her pregnancy. All forms can be faxed (or mailed) to the Pregnancy Registry.

Criteria for enrollment include:

  1. A report of pregnancy from a patient or healthcare provider (US residents only)
  2. Exposure to JANUVIA or JANUMET during pregnancy (anytime after the woman's last menstrual period)
  3. Name of a healthcare provider (to confirm diagnoses and to obtain outcome information)
  4. Name of the patient or, if you wish to keep the report confidential, patient initials and one other patient identifier, such as date of birth or chart number, to allow for follow-up at expected date of delivery

Information from the Registry is used to respond to inquiries from healthcare providers who call to request information on the use of a product during pregnancy. Data may be published or used to update the pregnancy section of the product label, as appropriate. Dissemination of data collected in the Registry is done without compromising individual patient confidentiality. Information from the Registry is shared, as required, with regulatory authorities (eg, the FDA).

Annual Reports

Reports of the aggregate data in the Registry are updated annually and are available to healthcare providers in the United States upon request. (In countries outside the United States, information is available through the local Merck subsidiary). To request a report, call the toll-free number below or download and complete the attached Annual Report Request Form and fax it to the Registry. Please include your fax number. A report will be sent to you within 3 business days.

Pregnancy Registry for JANUVIA and JANUMET
1-800-986-8999

(FAX) 215-993-1220

References

1. Mokdad AH, Ford ES, Bowamn BA et al. Diabetes trends in the US: 1990-1998. Diabetes Care 2000; 23: 1278 – 83.

2. Engelgau MM, Herman Wh, Smith P, et al. The epidemiology of diabetes and pregnancy in the US, 1998. Diabetes Care 1995; 18:1029-33.

3, Feig DS, Palda VA. Type 2 diabetes in pregnancy: a growing concern. The Lancet 2002; 359:1690 – 1692.

4. Macintosh MCM, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population-based study. BMJ 2006; 333:177-180.

5. Cundy T, Gable G, Townsend K. Perinatal mortality in type 2 diabetes. Diabet Med 20000; 17:33-9.



 


Enrollment form for JANUVIA and JANUMET
Patient consent form for JANUVIA and JANUMET
Spanish patient consent form for JANUVIA and JANUMET
Request for the Annual Report form for JANUVIA and JANUMET
Package insert for JANUVIA
Patient package insert for JANUVIA
Package insert for JANUMET
Patient package insert for JANUMET


Or call 1-800-986-8999 to enroll a patient, report an outcome of pregnancy, request an annual report, or request any of the above forms.


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