Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1198
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Follistim (Kit)
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Assisted Reproductive
Technologies (ART): A starting dose of 150 to
225 IU of Follistim' (follitropin beta for injection) is recommended for at least
the first four days of treatment. After this, the dose may be adjusted for the
individual patient based upon their ovarian response. In clinical studies with
patients who are responding, it was shown that daily maintenance dosages ranging
from 75 to 300IU for six to twelve days are sufficient, although longer treatment
may be necessary. However, in patients that were low or poor responders,
maintenance doses of 375 to 600 IU were administered according to individual
response. This later category comprised approximately 10% of the women evaluated
during clinical studies. The maximum, individualized, daily dose of Follistim'
that has been used in clinical studies is 600 IU. When a sufficient number of
follicles of adequate size are present, the final maturation of the follicles is
induced by administering hCG at a dose of 5,000 IU to 10,000 IU. Oocyte (egg)
retrieval is performed 34 to 36 hours later. The administration of hCG must be
withheld in cases where the ovaries are abnormally enlarged on the last day of
Follistim' therapy; this will reduce the chance of developing OHSS.<br/>Ovulation Induction: There are a variety of
treatment protocols available for ovulation induction. In studies using
Follistim', a stepwise gradually increasing dosing scheme was used. The starting
dose was 75 IU of Follistim' for up to 14 days. The dose was then increased by
37.5 IU of Follistim' at weekly intervals until follicular growth and/or serum
estradiol levels indicated an adequate response. The maximum, individualized,
daily dose of Follistim' that has been safely used for ovulation induction
patients during clinical trials is 300 IU. The patient should be treated until
ultrasonic visualizations and/or serum estradiol determinations indicate
pre-ovulatory conditions equivalent to or greater than those of the normal
individual followed by hCG, 5,000 IU to 10,000 IU. If the ovaries are abnormally
enlarged on the last dayof Follistim' therapy, hCG must be withheld during this
course of treatment; this will reduce the chances of developing OHSS. During treatment with
Follistim' and during a two week post-treatment period, patients should be
examined at least every other day for signs of excessive ovarian stimulation. It
is recommended that Follistim' administration be stopped if the ovaries become
abnormally enlarged or abdominal pain occurs. Most OHSS occurs after treatment has
been discontinued and reaches its maximum at about seven to ten days
post-ovulation. For ovulation induction,
the couple should be encouraged to have intercourse daily, beginning on the day
prior to the administration of hCG and until ovulation becomes apparent from the
indices employed for the determination of progestational activity (see PRECAUTIONS-Laboratory
Tests). Care should be taken to insure insemination. In the light of
the foregoing indices and parameters mentioned, it should become obvious that,
unless a physician is willing to devote considerable time to these patients and be
familiar with and conduct these necessary laboratory studies, he/she should not
use Follistim'.<br/>Directions for using Follistim':
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Follistim' (follitropin beta
for injection) contains human follicle-stimulating hormone (hFSH), a glycoprotein
hormone which is manufactured by recombinant DNA (rDNA) technology. Follitropin beta
has a dimeric structure containing two glycoprotein subunits (alpha and beta). Both
the 92 amino acid alpha-chain and the 111 amino acid beta-chain have complex
heterogeneous structures arising from two N-linked oligosaccharide chains. Follitropin
beta is synthesized in a Chinese hamster ovary (CHO) cell line that has been
transfected with a plasmid containing the two subunit DNA sequences encoding for hFSH.
The purification process results in a highly purified preparation with a consistent
hFSH isoform profile and high specific activity. The biological
activity is determined by measuring the increase in ovary weight in female rats. The
intrinsic luteinizing hormone (LH) activity in follitropin beta is less than 1 IU per
40,000 IU FSH. The compound is considered to contain no LH activity. The amino acid sequence and
tertiary structure of the product are indistinguishable from that of human
follicle-stimulating hormone (hFSH) of urinary source. Also, based on available data
derived from physio-chemical tests and bioassay, follitropin beta and follitropin
alfa, another recombinant follicle-stimulating hormone product, are indistinguishable. Follistim' is presented as a
sterile, freeze-dried cake, intended for SUBCUTANEOUS or INTRAMUSCULAR administration
after reconstitution with Sterile Water for Injection, USP. Each vial of Follistim'
contains 75 IU of FSH activity plus 25.0 mg sucrose, NF; 7.35 mg sodium citrate
dihydrate, USP; 0.10 mg polysorbate 20, NF, and hydrochloric acid, NF and/or sodium
hydroxide, NF to adjust the pH in a sterile, lyophilized form. The pH of the
reconstituted preparation is approximately 7.0. The recombinant protein in Follistim'
has been standardized for FSH in vivo
bioactivity in terms of the First International Reference Preparation for human
menopausal gonadotropins (code 70/45), issued by the World Health Organization Expert
Committee on Biological Standardization (1982). Under current storage conditions,
Follistim' may contain up to 20% of oxidized follitropin beta. In clinical trials with
Follistim', serum antibodies to FSH or anti-CHO cell derived proteins were not
detected in any of the treated patients after exposure to Follistim' for up to three
cycles. Therapeutic Class: Infertility.
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Follistim' (follitropin beta
for injection) stimulates ovarian follicular growth in women who do not have primary
ovarian failure. FSH, the active component of Follistim', is required for normal
follicular growth, maturation, and gonadal steroid production. In the female, the
level of FSH is critical for the onset and duration of follicular development, and
consequently for the timing and number of follicles reaching maturity. In order to
effect the final phase of follicle maturation, resumption of meiosis and rupture of
the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Follistim' when patient monitoring
indicates that appropriate follicular development parameters have been
reached.<br/>Pharmacokinetics:<br/>Absorption: The bioavailability of
Follistim' following subcutaneous and intramuscular administration was
investigated in healthy, pituitary-suppressed, female subjects given a single
300 IU dose. After subcutaneous or intramuscular injection the apparent dose
absorbed was 77.8% and 76.4%, respectively. The subcutaneous (455.6��141.4 IU*h/L) and intramuscular (445.7��135.7 IU*h/L) routes of
administration were equivalent with respect to area under the curve (AUC) in
healthy, pituitary-suppressed, female subjects given a single 300 IU dose.
However, equivalence could not be established for Cbetween the
subcutaneous (5.41��0.72 IU/L) and intramuscular (6.86��2.90 IU/L) routes of
administration. The pharmacokinetics
and pharmacodynamics of a single, intramuscular dose (300 IU) of Follistim'
were also investigated in a group of gonadotropin-deficient, but otherwise
healthy women. Peak (C) serum FSH levels in these women were 4.3��1.7 IU/L (mean��SD) and it occurred approximately 27 hours after
intramuscular administration. A multiple, dose
proportionality, pharmacokinetic study of Follistim' was completed in healthy,
pituitary-suppressed, female subjects given intramuscular doses of 75 IU, 150
IU or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached
with all doses after 4 days of treatment based on the minimum concentrations
of FSH just prior to dosing (C). Peak blood concentrations with
the 75 IU, 150 IU, and 225 IU dose were 4.65��1.49 IU/L, 9.46��2.57 IU/L and
11.30��1.77 IU/L, respectively. A multiple, dose
proportionality, pharmacokinetic study of Follistim' was completed in healthy,
pituitary-suppressed, female subjects given subcutaneous doses of 75 IU, 150
IU, or 225 IU for 7 days. Steady-state blood concentrations of FSH were
reached with all doses after 5 days of treatment based on the minimum
concentrations of FSH just prior to dosing (C min). Peak blood concentrations
with the 75 IU, 150 IU, and 225 IU dose were 4.30��0.60 IU/L, 8.51��1.16
IU/L and 13.92��1.81 IU/L, respectively.<br/>Distribution: The volume of
distribution of Follistim' in healthy, pituitary-suppressed, female subjects
following intravenous administration of a 300 IU dose was approximately 8
L.<br/>Metabolism: The recombinant FSH in
Follistim' is biochemically very similar to urinary FSH and it is therefore
anticipated that it is metabolized in the same manner.<br/>Elimination: The elimination
half-life following a single intramuscular dose (300 IU) of Follistim' in
female subjects was 43.9��14.1 hours (mean��SD). The elimination half-life
following a 7-day intramuscular treatment with 75 IU, 150 IU or 225 IU was
26.9��7.8 hours (mean��SD), 30.1��6.2 and 28.9��6.5,
respectively.<br/>Special Populations: The effect of body weight
on the pharmacokinetics of Follistim' was evaluated in a group of European and
Japanese women who were significantly different in terms of body weight. The
European subjects had a body weight of (mean��SD) 67.4��13.5 kg and the Japanese
subjects were 46.8��11.6 kg. Following a single intramuscular dose of 300 IU of
Follistim', the AUC (IU*h/L) was significantly smaller in European subjects (339��105) than in Japanese subjects (544��201). However, clearance per kg of body
weight was essentially the same for the respective groups (0.014 and 0.013
1*hkg).<br/>Clinical Studies: The efficacy of Follistim'
was established in four controlled, clinical studies [three studies for Assisted
Reproductive Technologies (ART) and one study for Ovulation Induction], three of
which are described below. In these comparative studies, there were no clinically
significant differences between treatment groups in study outcomes.<br/>Assisted Reproductive Technologies
(ART): Results from a
randomized, assessor-blind, group comparative, multicenter safety and efficacy
study of Follistim' (Protocol 37608) in 981 infertile women treated for one
cycle with in vitro fertilization with
Follistim' or Metrodin' after pituitary suppression with a GnRH agonist are
summarized in Table I. Metrodin' is a
registered trademark of Serono Laboratories, Inc., Randolph, MA 02368. The outcomes of the 286
clinical pregnancies (179 in Follistim' and 107 in Metrodin') are shown in
Table II: Results from a
randomized, assessor-blind, group comparative, single center safety and
efficacy study of Follistim' (Protocol 37604) in 89 infertile women treated
with in vitro fertilization with
Follistim' or Humegon' without pituitary suppression with a GnRH agonist are
summarized in Table III. The outcomes of the 22
clinical pregnancies (14 in Follistim' and 8 in Humegon' ) are shown in Table
IV:<br/>Ovulation Induction: Results from a
randomized, assessor-blind, group comparative, multicenter safety and efficacy
study of Follistim' (Protocol 37609) in 172 chronic anovulatory women who
failed to ovulate and/or conceive during clomiphene citrate treatment are
summarized in Tables V, VI, and VII. The outcomes of the 56
clinical pregnancies (35 in Follistim' and 21 in Metrodin') are shown in Table
VII:
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Follistim' (follitropin beta
for injection) is contraindicated in women who exhibit:
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Follistim' (follitropin beta
for injection) is supplied in a sterile, freeze-dried form, as a white to off-white
cake or powder in vials containing 75 IU of FSH activity. The following package
combinations are available:<br/>Storage: Lyophilized powder may be
stored refrigerated or at room temperature
(2-25C/36-77F). Protect from
light. Use immediately after reconstitution. Discard unused material. Rx Only Manufactured byOrganon
Inc.West Orange, NJ 07052Diluent manufactured byLuitpold
Pharmaceuticals, Inc.Shirley, NY 11967
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General: Careful attention should be
given to the diagnosis of infertility and in the selection of candidates for
Follistim' (follitropin beta for injection) therapy (see INDICATIONS AND USAGE -
Selection of Patients).<br/>Information for Patients: Prior to therapy with
Follistim', patients should be informed of the duration of treatment and
monitoring procedures that will be required. The risks of Ovarian Hyperstimulation
Syndrome and multiple births , and other
possible adverse reactions
should be discussed.<br/>Laboratory Tests: In most instances,
treatment with Follistim' 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' or when
clinical assessment of the patient indicates that sufficient follicular maturationhas occurred. This may be directly estimated by sonographic visualization of the
ovaries and endometrial lining and/or 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 mucus, spinnbarkeit, and ferning of the cervical mucus) provides an
indirect estimate of the estrogenic effect upon the target organs, and therefore
it should only be used adjunctively with more direct estimates of follicular
development (e.g., ultrasonography and serum estradiol determinations). The clinical confirmation
of ovulation is obtained by direct and indirect indices of progesterone
production. The indices most generally used are as follows: a) A rise in basal body
temperature, b) Increase in serum
progesterone, and c) Menstruation following
the shift in basal body temperature. When used in conjunction
with indices of progesterone production, sonographic visualization of the ovaries
will assist in determining if ovulation has occurred. Sonographic evidence of
ovulation may include the following: a) Fluid in the cul-de-sac, b) Follicle showing marked
decrease in size, and c) Collapsed
follicle.<br/>Drug Interactions: No drug/drug interaction
studies have been performed.<br/>Carcinogenesis and Mutagenesis
and Impairment of Fertility: Long-term toxicity studies
in animals have not been performed with Follistim' to evaluate the carcinogenic
potential of the drug. Follistim' was not mutagenic in the Ames test using
S. typhimurium and E. coli tester strains and did not produce
chromosomal aberrations in an in vitro
assay using human lymphocytes.<br/>Pregnancy: Pregnancy Category X: (See
CONTRAINDICATIONS).<br/>Nursing Mothers: It is not known whether
this drug is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in the nursing infant
from Follistim', a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.<br/>Pediatric Use: Safety and effectiveness in
pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of
Follistim' did not include subjects aged 65 and over.
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Aside from the possibility of
Ovarian Hyperstimulation Syndrome (see WARNINGS-Overstimulation of the
Ovary During Follistim' Therapy) and multiple gestations (see WARNINGS-Multiple
Births), there is no additional information concerning the consequences of
acute overdosage with Follistim' (follitropin beta for injection).
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follitropin beta
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Follistim (Kit)
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Assisted Reproductive
Technologies (ART): Rates of adverse events
from a randomized, assessor-blind, group comparative, multicenter safety and
efficacy study of Follistim' (Protocol 37608) in 989 infertile women treated with
in vitro fertilization with Follistim' or
Metrodin' after pituitary suppression with a GnRH agonist are summarized in Table
VIII.<br/>Ovulation Induction: Rates of adverse events
from a randomized, assessor-blind, group comparative, multicenter safety and
efficacy study of Follistim' (Protocol 37609) in 172 chronic anovulatory women who
failed to ovulate and/or conceive during clomiphene citrate treatment are
summarized in Table IX. The following adverse
events have been reported in women treated with gonadotropins: pulmonary and
vascular complications ,
hemoperitoneum, adnexal torsion (as a complication of ovarian enlargement),
dizziness, tachycardia, dyspnea, tachypnea, febrile reactions, flu-like symptoms
including fever, chills, musculoskeletal aches, joint pains, nausea, headache and
malaise, breast tenderness, and dermatological symptoms (dry skin, body rash, hair
loss and hives). There have been infrequent
reports of ovarian neoplasms, both benign and malignant, in women who have
undergone multiple drug regimens for ovulation induction; however, a causal
relationship has not been established.
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Follistim' (follitropin beta
for injection) should be used only by physicians who are experienced in infertility
treatment. Follistim' is a potent gonadotropic substance capable of causing Ovarian
Hyperstimulation Syndrome (OHSS) (see WARNINGS-Overstimulation of the
Ovary During Follistim' Therapy) with or without pulmonary or vascular
complications (see WARNINGS-Pulmonary and Vascular
Complications) and multiple births (see WARNINGS-Multiple
Births). Gonadotropin therapy requires the availability of appropriate
monitoring facilities .<br/>Overstimulation of the Ovary
During Follistim' Therapy: In order to minimize the
hazards associated with the occasional abnormal ovarian enlargement that may occur
with Follistim' therapy, the lowest effective dose should be used (see DOSAGE AND
ADMINISTRATION). Use of ultrasound monitoring of ovarian response
and/or measurement of serum estradiol levels can further minimize the risk of
overstimulation. If the ovaries are
abnormally enlarged on the last day of Follistim' therapy, hCG should not be
administered in this course of treatment; this will reduce the chances of
developing Ovarian Hyperstimulation Syndrome (OHSS). The Ovarian
Hyperstimulation Syndrome (OHSS): OHSS is a medical entity distinct from
uncomplicated ovarian enlargement and may progress rapidly to become a serious
medical event. OHSS is characterized by a dramatic increase in vascular
permeability, which can result in a rapid accumulation of fluid in the peritoneal
cavity, thorax, and potentially, the pericardium. The early warning signs of OHSS
developing are severe pelvic pain, nausea, vomiting and weight gain. The following
symptoms have 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, hemoconcentration, electrolyte imbalances,
ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress,
and thromboembolic events (see WARNINGS-Pulmonary and Vascular
Complications). During clinical trials with
Follistim' therapy, OHSS occurred in 53 (5.2%) of the 1,029 women treated and of
these 29 (2.8%) were hospitalized. Cases of OHSS are more common, more severe, and
more protracted if pregnancy occurs; therefore, patients should be followed for at
least two weeks after hCG administration. Most often, OHSS occurs after treatment
has been discontinued and it can develop rapidly, reaching its maximum about seven
to ten days following treatment. Usually, OHSS resolves spontaneously with the
onset of menses. If there is evidence that OHSS may be developing prior to hCG
administration (see PRECAUTIONS-Laboratory
Tests), the hCG must be withheld. If serious OHSS occurs,
treatment should be stopped and the patient should be hospitalized. Treatment is
primarily symptomatic and should consist of bed rest, fluid and electrolyte
management, and analgesics (if needed). Hemoconcentration associated with fluid
loss into the peritoneal cavity, pleural cavity, and the pericardial cavity may
occur and should be thoroughly assessed in the following manner: 1) fluid intake
and output; 2) weight; 3) hematocrit; 4) serum and urinary electrolytes; 5) urine
specific gravity; 6) BUN and creatinine; 7) total proteins with albumin: globulin
ratio; 8) coagulation studies; 9) electrocardiogram to monitor for hyperkalemia
and 10) abdominal girth. These determinations should be performed daily or more
often based on clinical need. OHSS increases the risk of
injury to the ovary. The ascitic, pleural, and pericardial fluid should not be
removed unless there is the necessity to relieve symptoms such as pulmonary
distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian
cyst, which may result in hemoperitoneum, and should therefore be avoided. If
bleeding occurs and requiressurgical intervention, the clinical objective should
be to control the bleeding and retain as much ovarian tissue as possible.
Intercourse should be prohibited in patients with significant ovarian enlargement
after ovulation because of the danger of hemoperitoneum resulting from ruptured
ovarian cysts. The management of OHSS may
be divided into three phases: an acute, a chronic, and a resolution phase. Because
the use of diuretics can accentuate the diminished intravascular volume, diuretics
should be avoided except in the late phase of resolution as described below. Acute Phase: Management
during the acute phase should be directed at preventing hemoconcentration due to
loss of intravascular volume to the third space and minimizing the risk of
thromboembolic phenomena and kidney damage. Treatment is intended to normalize
electrolytes while maintaining an acceptable but somewhat reduced intravascular
volume. Full correction 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 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 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.<br/>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 Hyperstimulation 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 occlusion resulting in loss of limb. In
rare cases, pulmonary complications and/or thromboembolic events have resulted in
death.<br/>Multiple Births: Reports of multiple births
have been associated with Follistim' treatment. The patient and her partner should
be advised of the potential risk of multiple births before starting treatment. In
clinical trials with Follistim' and Metrodin', multiple gestation rates in ART
patients were 31% and 38%, respectively, and in ovulation induction patients, the
rates were 8% in both groups.
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Follistim' (follitropin beta
for injection) is indicated for the development of multiple follicles in ovulatory
patients participating in an Assisted Reproductive Technology (ART) program.
Follistim' is also indicated for the induction of ovulation and pregnancy in
anovulatory infertile patients in whom the cause of infertility is functional and not
due to primary ovarian failure.<br/>Selection of Patients: Before treatment with
Follistim' is instituted:
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Follistim
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