ORG_MostPrescrAd 5/10/07 10:05 Page 18
®
Patients should read and follow all instructions in the Follistim Pen
®
Instructions for Use Manual/Treatment Diary prior to
administration of Follistim
®
AQ Cartridge.
Prior to treatment with Follistim
®
AQ Cartridge, patients should be informed of the duration of treatment and monitoring pro-
cedures that will be required. The risks of Ovarian Hyperstimulation Syndrome and multiple births (see WARNINGS), and other
possible adverse reactions (see ADVERSE REACTIONS) should be discussed.
Laboratory Tests
In most instances, treatment with Follistim
®
AQ Cartridge (follitropin beta injection) will result only in follicular growth and
maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following
the administration of Follistim
®
AQ Cartridge or when clinical assessment of the patient indicates that sufficient follicular matu-
ration has occurred. This may be directly estimated by sonographic visualization of the ovaries and endometrial lining and/or
FOR SUBCUTANEOUS USE ONLY
measuring serum estradiol levels. The combination of both ultrasonography and measurement of estradiol levels is useful for
monitoring the growth and development of follicles, timing hCG administration, as well as minimizing the risk of OHSS and
multiple gestations.
The clinical evaluation of estrogenic activity (changes in vaginal cytology, changes in appearance and volume of cervical
BRIEF SUMMARY mucus, spinnbarkeit, and ferning of the cervical mucus) provides an indirect estimate of the estrogenic effect upon the target
Please see package insert for full prescribing information. organs, and therefore, it should only be used adjunctively with more direct estimates of follicular development (e.g., ultra-
INDICATIONS AND USAGE
sonography and serum estradiol determinations).
Follistim
®
AQ Cartridge (follitropin beta injection) is indicated for the development of multiple follicles in ovulatory patients The clinical confirmation of ovulation is obtained by direct and indirect indices of progesterone production. The indices most
participating in an Assisted Reproductive Technology (ART) program. Follistim
®
AQ Cartridge is also indicated for the induc- generally used are as follows:
tion of ovulation and pregnancy in anovulatory infertile patients in whom the cause of infertility is functional and not due to a) A rise in basal body temperature
primary ovarian failure. b) Increase in serum progesterone
Selection of Patients
c) Menstruation following the shift in basal body temperature
Before treatment with Follistim
®
AQ Cartridge (follitropin beta injection) is initiated: When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in deter-
1) A thorough gynecologic and endocrinologic evaluation of the patient must be performed. The evaluation should include mining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of reviewing a) Fluid in the cul-de-sac
a patient’s history, performing a physical examination, determining serum hormonal levels as indicated, and optionally per- b) Follicle showing marked decrease in size
forming an endometrial biopsy. Patients with tubal pathology should receive Follistim
®
AQ Cartridge only if enrolled in an c) Collapsed follicle
ART program.
2) Primary ovarian failure should be excluded by the determination of circulating gonadotropin levels.
Drug Interactions
3) Careful examination should be made to rule out early pregnancy.
No drug-drug interaction studies have been performed.
4) Evaluation of the partner’s fertility potential should be included in the workup procedure.
Carcinogenesis and Mutagenesis, Impairment of Fertility
CONTRAINDICATIONS
Long-term toxicity studies in animals have not been performed with Follistim
®
AQ Cartridge (follitropin beta injection) to evalu-
Follistim
®
AQ Cartridge (follitropin beta injection) is contraindicated in women who exhibit:
ate the carcinogenic potential of the drug. Follistim
®
(follitropin beta for injection) was not mutagenic in the Ames test using
1) Prior hypersensitivity to recombinant hFSH products
S. typhimurium and E. coli tester strains and did not produce chromosomal aberrations in an in vitro assay using human
2) A high circulating FSH level indicating primary ovarian failure
lymphocytes.
3) Uncontrolled thyroid or adrenal dysfunction
Pregnancy
4) Tumor of the ovary, breast, uterus, hypothalamus, or pituitary gland
Pregnancy Category X: (See CONTRAINDICATIONS).
5) Pregnancy Nursing Mothers
6) Heavy or irregular vaginal bleeding of undetermined origin It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of
7) Ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOS) the potential for serious adverse reactions in the nursing infant from Follistim
®
AQ Cartridge (follitropin beta injection), a deci-
8) Hypersensitivity reactions to streptomycin or neomycin. Follistim
®
AQ Cartridge may contain traces of these anti- sion should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
biotics and may cause hypersensitivity reactions in susceptible persons. drug to the mother.
WARNINGS Pediatric Use
Follistim
®
AQ Cartridge (follitropin beta injection) should be used only by physicians who are experienced in infertility Safety and effectiveness in pediatric patients have not been established.
treatment. Changes in brand (manufacturer), type (recombinant, urinary, etc.), and/or method of administration
(Follistim Pen
®
, conventional syringe, etc.) may result in the need to adjust the dose. Follistim
®
AQ Cartridge admin-
Geriatric Use
istered with the Follistim Pen
®
contains a potent gonadotropic substance and delivers on average an 18% higher amount
Clinical studies did not include subjects aged 65 and over.
of follitropin beta as compared to lyophilized preparations administered by conventional syringe. Accordingly, a lower
ADVERSE REACTIONS
starting dose for gonadotropin stimulation and dose adjustments during gonadotropin stimulation should be considered
Assisted Reproductive Technologies (ART)
for each woman treated with Follistim
®
AQ Cartridge (see DOSAGE AND ADMINISTRATION in the full prescribing
Rates of adverse events from an open-label, non-controlled, multicenter study in 60 women undergoing COH for IVF or ICSI
information).
with Follistim
®
AQ Cartridge (follitropin beta injection) administered with the Follistim Pen
®
are summarized in Table 4.
Overstimulation of the Ovary During Treatment With Follistim
®
AQ Cartridge (follitropin beta injection)
TABLE 4: Incidence of Adverse Clinical Experiences (≥5%)
In order to minimize the hazards associated with the occasional abnormal ovarian enlargement that may occur with
Adverse Event Follistim
®
AQ Adverse Event Follistim
®
AQ
Follistim
®
AQ Cartridge therapy, the lowest effective dose should be used (see DOSAGE AND ADMINISTRATION in the full
Cartridge Cartridge
prescribing information). Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels
n=60 n=60
can further minimize the risk of overstimulation.
Abdominal pain 28% Abdomen enlarged 8%
If the ovaries are abnormally enlarged on the last day of treatment with Follistim
®
AQ Cartridge, hCG should not be adminis-
tered in this course of treatment, to reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS).
Flatulence 27% Back pain 7%
Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from uncomplicated ovarian enlargement and
Abdominal pain, gynecological 25% Constipation 5%
may progress rapidly to become a serious medical event. OHSS is characterized by a dramatic increase in vascular permeabil-
Nausea 17% Headache 5%
ity, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early Breast pain, female 15% Ovarian pain 5%
warning signs of OHSS developing are severe pelvic pain, nausea, vomiting, and weight gain. The following symptoms have
Injection site reaction 10%
been reported in cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting
and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria. Clinical evaluation may reveal hypovolemia, Ovulation Induction
hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary dis- Rates of adverse events from an open-label, non-controlled, multicenter study in 43 clomiphene-resistant women with chronic
tress, and thromboembolic events (see WARNINGS-Pulmonary and Vascular Complications). Transient liver function test anovulation (WHO group II) undergoing Ovulation Induction with Follistim
®
AQ Cartridge (follitropin beta injection) adminis-
abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have tered with the Follistim Pen
®
are summarized in Table 5.
been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).
TABLE 5: Incidence of Adverse Clinical Experiences (≥5%)
During clinical trials with Follistim
®
and Follistim
®
AQ Cartridge therapy, OHSS occurred in 60 (5.3%) of the 1132 women
treated and of these 33 (2.9%) were hospitalized. Cases of OHSS are more common, more severe, and more protracted if
Adverse Event Follistim
®
AQ Adverse Event Follistim
®
AQ
pregnancy occurs; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS
Cartridge Cartridge
occurs after treatment has been discontinued and it can develop rapidly, reaching its maximum about seven to ten days follow-
n=43 n=43
ing treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be devel-
Ovarian hyperstimulation syndrome 9% Sinusitis 5%
oping prior to hCG administration (see PRECAUTIONS-Laboratory Tests), the hCG must be withheld. Abdominal pain 5% Upper respiratory tract infection 5%
If serious OHSS occurs, treatment should be stopped and the patient should be hospitalized. Treatment is primarily sympto- Injection site reaction 5%
matic and should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Hemoconcentration asso-
ciated with fluid loss into the peritoneal cavity, pleural cavity, and the pericardial cavity may occur and should be thoroughly The following adverse events have been reported in women treated with gonadotropins: pulmonary and vascular complications
assessed in the following manner: 1) fluid intake and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; (see WARNINGS), hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement), dizziness, tachycardia,
5) urine specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin ratio; 8) coagulation studies; 9) electro- dyspnea, tachypnea, febrile reactions, flu-like symptoms including fever, chills, musculoskeletal aches, joint pains, nausea,
cardiogram to monitor for hyperkalemia and 10) abdominal girth. These determinations should be performed daily or more headache and malaise, breast tenderness, and dermatological symptoms (dry skin, erythema, body rash, hair loss and hives).
often based on clinical need.
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple
OHSS increases the risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless there drug regimens for ovulation induction; however, a causal relationship has not been established.
is the necessity to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture
Congenital Anomalies
of an ovarian cyst, which may result in hemoperitoneum, and should, therefore, be avoided. If bleeding occurs and requires
The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after
surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible.
spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g.,
Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the danger of
maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications
hemoperitoneum resulting from ruptured ovarian cysts.
that the use of gonadotropins during ART is associated with an increased risk of congenital malformations.
The management of OHSS may be divided into three phases: an acute, a chronic, and a resolution phase. Because the use of
Storage
diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolu-
Store refrigerated, 2–8°C (36–46°F) until dispensed. Upon dispensing, the product may be stored by the patient at 2–8°C
tion as described below.
(36–46°F) until the expiration date, or at 25°C (77°F) for 3 months or until expiration date, whichever occurs first. Once the
Acute Phase: Management during the acute phase should be directed at preventing hemoconcentration due to loss of intra- rubber inlay of the Follistim
®
AQ Cartridge has been pierced by a needle, the product can only be stored for a maximum of
vascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Treatment is 28 days at 2–25°C (36–77°F). Protect from light. Do not freeze.
intended to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction
For more information, call 1-866-836-5633
of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation.
Management includes administration of limited intravenous fluids, electrolytes, human serum albumin, and strict monitoring of
fluid intake and output. Monitoring for the development of hyperkalemia is recommended.
Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be
Follistim
®
and Follistim Pen
®
are registered trademarks of N.V. Organon
limited by instituting severe potassium, sodium, and fluid restriction.
Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the
return of the third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys
c5287only
are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase, if
necessary, to combat pulmonary edema.
Pulmonary and Vascular Complications
Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated
with gonadotropins. In addition, thromboembolic events both in association with, and separate from, the Ovarian Hyperstimu-
lation Syndrome have been reported following gonadotropin therapy. Intravascular thrombosis, which may originate in venous
or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included
venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlu-
sion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death.
Multiple Births
Multiple births have been reported for all FSH treatments including Follistim
®
(follitropin beta for injection) treatment. The
Manufactured for Organon USA Inc.
patient and her partner should be advised of the potential risk of multiple births before starting treatment.
Roseland, NJ 07068
PRECAUTIONS
by Vetter Pharma-Fertigung GmbH & Co. KG
General
Ravensburg, Germany
Careful attention should be given to the diagnosis of infertility and in the selection of candidates for treatment with
Follistim
®
AQ Cartridge (follitropin beta injection) (see INDICATIONS AND USAGE-Selection of Patients).
and packaged by Organon (Ireland) Ltd., Swords
Co. Dublin, Ireland
Information for Patients
Physicians must instruct patients on the correct usage and dosing of Follistim
®
AQ Cartridge (follitropin beta injection) in con-
junction with the Follistim Pen
®
.
©2005 Organon USA Inc. FOP-8009 5310202-03 3/05 24
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