Gonal-F

follitropin alfa

Dosage Form: injection
Gonal-F® (follitropin alfa for injection)

For subcutaneous injection

DESCRIPTION

Gonal-F® (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the α- and β-subunits. The α- and β-subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone.  Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors.  Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity.  The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats.  The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for Recombinant Human Follicle Stimulation Hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization.  Gonal-F® contains no luteinizing hormone (LH) activity.  Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable.

Gonal-F® is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.

Each Gonal-F® Multi-Dose vial is filled with 600 IU (44 μg) or 1200 IU (87 μg) follitropin alfa to deliver 450 IU (33 μg) or 1050 IU (77 μg) follitropin alfa, respectively, and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate and 0.45 mg monobasic sodium phosphate monohydrate.  O-phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment.  Multiple Dose vials are reconstituted with Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP.

Under current storage conditions, Gonal-F® may contain up to 10% of oxidized follitropin alfa.

Therapeutic Class: Infertility

CLINICAL PHARMACOLOGY

Gonal-F® (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure.  FSH, the active component of Gonal-F® is the primary hormone responsible for follicular recruitment and development.  In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Gonal-F® when monitoring of the patient indicates that sufficient follicular development has occurred.  There is interpatient variability in response to FSH administration.  The physico-chemical, immunological, and biological activities of recombinant FSH (r-hFSH) are comparable to those of pituitary and human menopausal urine-derived FSH. Gonal-F® (follitropin alfa for injection), when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism.  FSH, the active component of Gonal-F®, is the primary hormone responsible for spermatogenesis.

Pharmacokinetics

Single dose pharmacokinetics of follitropin alfa were determined following intravenous, subcutaneous and intramuscular administration of 150 IU Gonal-F® to 12 healthy, down-regulated female volunteers.  Steady-state pharmacokinetics were also determined in 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days.  These pharmacokinetics were confirmed in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET), treated with FSH doses of up to 450 IU per day.   Additionally, single dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 225 IU Gonal-F® to 12 healthy adult male volunteers in a cross-over design. Steady state pharmacokinetics were also determined in 6 healthy adult male volunteers who were administered a single daily dose of 225 IU Gonal-F® for 7 days.  No significant difference in pharmacokinetics is expected in males versus females when administered Gonal-F® subcutaneously. The pharmacokinetic parameters from these studies are included in Table 1.

Table 1: Pharmacokinetic parameters (mean ± SD) of FSH following administration of Gonal-F®

Population	Female				Male
	Healthy Female Volunteers			IVF/ET Patients	Healthy Male Volunteers
Dose (IU)	Single Dose IM	Single Dose SC	Multiple Dose SC	Multiple Dose SC	Single Dose SC	Multiple Dose SC
	(150 IU)	(150 IU)	(7 x 150 IU)	(5 x 225 IU)*	(225 IU)	(7 x 225 IU)
Abbreviations are: IVF/ET: in vitro fertilization/embryo transfer;
Cmax: peak concentration (above baseline);
tmax : time of Cmax;
CL/F: apparent clearance;
V/F: apparent volume of distribution; calculated using a one-compartment model.
t½: absorption half-life;
F: bioavailability compared to IV
# Steady-state AUC144-168 (After the 7th daily SC dose)
* First five days of fixed regimen followed by adjustment of the dose depending on response
** increases with body mass index
AUC  (IU-hr/L)	206 ± 66	176 ± 87	187 ± 61#	---	220 ± 109	186 ± 23#
Cmax (IU/L)	3 ± 1	3 ± 1	9 ± 3	---	2.5 ± 0.8	8.3 ± 0.9
tmax (hr)	25 ± 10	16 ± 10	8 ± 6	---	20 ± 14	10.7 ± 6.7
t½ terminal (hr)	50 ± 27	24 ± 11	24 ± 8	32**	41 ± 14	32 ± 4
CL/F (L/hr)	---	---	---	0.7 ± 0.2	0.86 ± 0.48	0.90 ± 0.12
V/F (L)	---	---	---	10 ± 3	---	---
F (%)	76 ± 30	66 ± 39	---	---	---	---

Absorption

The absorption rate of Gonal-F® following subcutaneous or intramuscular administration was found to be slower than the elimination rate.  Hence the pharmacokinetics of Gonal-F® are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-F®.

After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours.  Steady-state serum levels were reached after 4 to 5 days of daily administration.

Metabolism/Excretion

FSH metabolism following administration of Gonal-F® has not been studied in humans. Total clearance after IV administration in healthy females was 0.6 L/hr; mean residence time was 17-20 hours.  FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.

Pharmacodynamics

Following daily subcutaneous administration of 150 IU of Gonal-F® for 7 days in healthy female volunteers, serum inhibin and estradiol, and total follicular volume responded as a function of time, with pronounced inter-individual variability.  Pharmacodynamic effect lagged behind FSH serum concentration.  Of the three pharmacodynamic parameters, serum inhibin levels responded with the least delay and declined rapidly after discontinuation of Gonal-F®. Follicular growth was most delayed and continued even after discontinuation of Gonal-F® administration, and after serum FSH levels had declined.  Maximum follicular volume was better correlated with either inhibin or estradiol peak levels than with FSH concentration.  Inhibin rise was an early index of follicular development.  In healthy male volunteers, despite high interindividual variation and the absence of down-regulation, daily administration of 225 IU Gonal-F® was shown to increase the levels of inhibin to reach a plateau during the whole administration period and then return to baseline.

Population pharmacokinetics and pharmacodynamics

To establish the pharmacokinetics and pharmacodynamics of FSH in a target population, measurements performed during a clinical study of in vitro fertilization/embryo transfer were used in conjunction with pharmacokinetic data from studies in healthy female volunteers. The apparent clearance was comparable to that in healthy volunteers.  The absorption rate was found to be influenced by the body mass index (BMI), suggesting that the higher the BMI, the lower the rate of absorption.  However, FSH serum levels following fixed (during the first five days) and then adjusted doses of Gonal-F® were found to be poor predictors of follicular growth rate.  High pre-treatment serum FSH levels may predict lower follicular growth rates.

Special populations:  Safety, efficacy, and pharmacokinetics of Gonal-F® in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions:  No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies:

Women:

The safety and efficacy of Gonal-F® have been examined in four clinical studies, two studies for ovulation induction and two studies for assisted reproductive technologies (ART).  In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.

1. Ovulation Induction:

The safety and efficacy of Gonal-F® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy (Study 5642).

The primary efficacy parameter was the ovulation rate.  Two hundred and  twenty-two patients entered into the first cycle of treatment, of whom 110 received Gonal-F® and 112 received urofollitropin.  Ovulation rates were similar between Gonal-F® and urofollitropin treatment groups.  The study results for the 222 patients who received treatment in at least one cycle are summarized in Table 2.

Table 2: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5642			Gonal-F® (n=110)	Urofollitropin (n=112)
* A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Cumulative Ovulation Rate
		Cycle 1	64%	59%
		Cycle 2	78%	82%
		Cycle 3	84%	91%
Cumulative Clinical Pregnancy*  Rate
	Cycle 1		21%	21%
	Cycle 2		28%	38%
	Cycle 3		35%	46%

For the 90 patients who had a clinical pregnancy (39 in Gonal-F® group; 51 in urofollitropin group), the outcome of the pregnancy was:

Table 3: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5642	Gonal-F® (n=39)	Urofollitropin  (n=51)
Pregnancies not reaching term	20.5%	13.7%
Single births	74.4%	74.5%
Multiple births	5.1%	11.8%

A second  randomized, comparative, open-label, multicenter study was conducted in 23 U.S. centers (Study 5727).  The primary efficacy parameter was ovulation rate.  Ovulation rates were similar between Gonal-F® and urofollitropin treatment groups.  Two hundred and thirty-two patients with oligo-anovulatory infertility received treatment with up to three cycles of Gonal-F® administered subcutaneously (118 patients) or urofollitropin administered intramuscularly (114 patients).

The cumulative patient ovulation rate and clinical pregnancy rates by cycle are presented for the 232 patients who received treatment in at least one cycle.

Table 4: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5727			Gonal-F® (n=118)	Urofollitropin (n=114)
* A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Cumulative Ovulation Rate
		Cycle 1	58%	68%
		Cycle 2	72%	86%
		Cycle 3	81%	93%
Cumulative Clinical Pregnancy* Rate
	Cycle 1		13%	14%
	Cycle 2		25%	25%
	Cycle 3		37%	36%

For the 85 patients who had a clinical pregnancy (44 in Gonal-F® group; 41 in urofollitropin group), the outcome of the pregnancy is shown in Table 5.

Table 5: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5727	Gonal-F® (n=44)	Urofollitropin (n=41)
Pregnancies not reaching term	22.7%	22.0%
Single births	63.6%	65.9%
Multiple births	13.7%	12.2%

2. Assisted Reproductive Technologies (ART):

The safety and efficacy of Gonal-F® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist (Study 5503).  The purpose of the study was to demonstrate that Gonal-F®, administered subcutaneously, was clinically not different in terms of safety and efficacy from urofollitropin, administered intramuscularly.  The initial and maximal doses of Gonal-F® were 225 and 450 IU, respectively.  The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration.  One hundred and twenty-three patients were randomized and received either Gonal-F® (60 patients) or urofollitropin (63 patients).

The results summarized in Table 6 are mean data with Gonal-F® and urofollitropin administered to ovulatory infertile women undergoing multiple follicular development for IVF/ET.

Table 6: Treatment Outcomes by Treatment Group in ART

Study 5503	Gonal-F® (n=60)	Urofollitropin (n=63)
*  A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Mean number of follicles ≥ 14mm diameter on day of hCG	7.8	9.2
Mean number of oocytes recovered per patient	9.3	10.7
Mean Serum E2 (pg/mL) on day of hCG	1576	2193
Mean treatment duration in days (range)	9.9 (5-20)	9.4 (5-14)
Clinical pregnancy* rate per attempt	20%	16%
Clinical pregnancy* rate per embryo transfer	24%	19%

For the 22 patients who had a clinical pregnancy (12 in Gonal-F® group; 10 in urofollitropin group), the outcome of the pregnancy is shown in Table 7.

Table 7: Pregnancy Outcome by Treatment Group in ART

Study 5503	Gonal-F® (n=12)	Urofollitropin (n=10)
Pregnancies not reaching term	25.0%	20.0%
Single births	41.7%	50.0%
Multiple births	33.3%	30.0%

A second randomized, comparative, open-label, multicenter study was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen patients with ovulatory infertility undergoing IVF/ET were randomized and received either Gonal-F® by subcutaneous administration (56 patients) or urofollitropin by intramuscular administration (58 patients) following pituitary down-regulation with a GnRH agonist.  The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration.  Results are summarized in Table 8.

Table 8: Treatment Outcomes by Treatment Group in ART

Study 5533	Gonal-F® (n=56)	urofollitropin (n=58)
*  A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Mean number of follicles ≥ 14mm diameter on day of hCG	7.2	8.3
Mean number of oocytes recovered per patient	9.3	12.3
Mean Serum E2 (pg/mL) on day of hCG	1236	1513
Mean treatment duration in days (range)	10.1(5-15)	9.0 (5-12)
Clinical pregnancy* rate per attempt	21%	22%
Clinical pregnancy* rate per embryo transfer	26%	25%

For the 25 patients who had a clinical pregnancy (12 in Gonal-F® group; 13 in urofollitropin group), the outcome of the pregnancy is shown in Table 9.

Table 9:  Pregnancy Outcome by Treatment Group in ART

Study 5533	Gonal-F® (n=12)	Urofollitropin (n=13)
Pregnancies not reaching term	33.3%	30.8%
Single births	41.7%	38.5%
Multiple births	25.0%	30.8%

Men:

The safety and efficacy of Gonal-F® administered concomitantly with hCG have been examined in three open-label clinical studies for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism.

The three multicenter studies involved three to six months of pretreatment with chorionic gonadotropin for injection (Profasi®) to normalize serum testosterone levels, followed by 18 months of treatment with Gonal-F® and hCG.  The objective of each study was induction of spermatogenesis (a sperm density of ≥ 1.5 x 106/mL).

Study 5844 enrolled 32 patients in six centers in the United Kingdom, France and Germany.  The second trial, Study 6410, was conducted in Australia and enrolled 10 patients in two centers.  Study 6793, conducted in 7 centers in the United States, was planned to enroll 32 patients.  The interim data for the US study includes 30 of the planned 32 patients. For all 3 studies, a total of 72 patients were enrolled and received hCG and 56 of those patients entered the Gonal-F® treatment phase of the trials.

The populations enrolled in the three studies were similar: Study 5844 studied a naïve population who had had no prior treatment with gonadotropins; mean age was 25.9 (range 16 to 48) years, mean (± SD) testis volume was 2.0 ± 1.2 mL, and 12 of the 32 patients (37.5%) were anosmic.  Thirty-one of the patients were Caucasian and one was Asian.  In Study 6410, mean age was 36 (range 26 to 48) years, 6 and 1 of the 10 patients had previously been treated with gonadotropins and GnRH, respectively; mean testis volume was 4.5 ± 2.9 mL; and 2 of the 10 patients (20%) were anosmic.  Seven patients were Caucasian and three were Asian.  In the 30 patients reported in the interim analysis of Study 6793, the mean age was 30.1 (range 22 to 44) years; 4 and 3 of the 30 patients had been treated with gonadotropins and GnRH, respectively, in the past; mean testis volume was 4.4 ± 1.3 mL; and 10 of  the 30 patients (33.3%) were anosmic. Twenty five of the patients were Caucasian, three were Asian, and one each of Moroccan and Indian ancestry.

The primary efficacy endpoint of all three studies was the achievement of a sperm density ≥ 1.5 x 106/mL.  The study results for the patients treated with Gonal-F® and hCG are summarized in Table 10.

Table 10: Number of Men Receiving Gonal-F® Who Achieved a Sperm Density ≥1.5 x 106/mL

			Study 5844 (n=26)	Study 6410 (n=8)	Study 6793 (n=22) *
* Interim data
Sperm Concentration ≥ 1.5 x 106/mL
		Yes	12 (46.2%)	5 (62.5%)	14 (63.6%)
		No	14 (53.8%)	3 (37.5%)	8 (36.4%)
	95% Confidence Interval		(26.6% - 66.6%)	(24.5% - 91.5%)	(40.7% - 82.8%)

The time to achievement of the primary efficacy endpoint is summarized in Table 11.

Table 11: Time to Achievement of Sperm Density ≥1.5 x 106/mL in Men Receiving Gonal-F®

		Study 5844 (n=26)	Study 6410 (n=8)	Study 6793 (n=22) *
* Interim data
Number of Men Achieving Sperm Concentration
	n	12	5	14
	Time (Months) to Sperm
	Concentration ≥ 1.5 x 106/mL
	Median	12.4	9.1	6.8
	Range	(2.7 – 18.1)	(8.8 – 11.7)	(2.8 – 15.7)

Table 12: Pregnancy Outcome in Partners of Men Desiring Fertility

	Study 5844 (n=7)	Study 6410 (n=10)	Study 6793 (n=20) *
* Interim data
Pregnancy	6 (86%)	3 (30%)	3 (15%)
Pregnancy not reaching term	1 (14%)	1 (10%)	2 (10%)
Single births	5 (71%)	2 (20%)	1 (5%)

Of the 56 patients who received Gonal-F® in Studies 5844, 6410, and 6793, 12 pregnancies were achieved in 10 partners of the 37 patients who were seeking pregnancy and who currently had a partner during the studies.  Thus, pregnancy (clinical and chemical)  was documented to have been achieved by 27% of the patients’ partners seeking pregnancy during the exposure period to Gonal-F® in the 3 trials.  Eight pregnancies continued to term, and 8 healthy babies were born to 7 couples as a result of those studies.

INDICATIONS AND USAGE

Women:  Gonal-F® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure.  Gonal-F® is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.

Selection of Patients:

1. Before treatment with Gonal-F® is instituted, a thorough gynecologic and endocrinologic evaluation must be performed.  This should include an assessment of pelvic anatomy.  Patients with tubal obstruction should receive Gonal-F® only if enrolled in an in vitro fertilization program.


2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.


3. Appropriate evaluation should be performed to exclude pregnancy.


4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders.  A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-F® therapy.


5. Evaluation of the partner’s fertility potential should be included in the initial evaluation.

Men:

Gonal-F® (follitropin alfa for injection) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism  in whom the cause of infertility is not due to primary testicular failure.

Selection of Patients:

1. Before treatment with Gonal-F® is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed.


2. Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels.


3. Prior to Gonal-F® therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.

CONTRAINDICATIONS

Gonal-F® (follitropin alfa for injection) is contraindicated in women and men who exhibit:

1. Prior hypersensitivity to recombinant FSH preparations or one of their excipients.


2. High levels of FSH indicating primary gonadal failure.


3. Uncontrolled thyroid or adrenal dysfunction.


4. Sex hormone dependent tumors of the reproductive tract and accessory organs.


5. An organic intracranial lesion such as a pituitary tumor.
   

   And in women who exhibit:

   
   


6. Abnormal uterine bleeding of undetermined origin (see "Selection of Patients").


7. Ovarian cyst or enlargement of undetermined origin (see "Selection of Patients").


8. Pregnancy.

WARNINGS

Gonal-F® (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonal-F® is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications.  Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see "Precautions / Laboratory Tests").  Safe and effective use of Gonal-F® in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis.  The lowest effective dose should be used.

Overstimulation of the Ovary During FSH Therapy:

Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks.  Careful monitoring of ovarian response can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Gonal-F® therapy, hCG should not be administered in this course of therapy.  This will reduce the chances of development of  Ovarian Hyperstimulation Syndrome.

Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement.  Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event.  It is characterized by an apparent 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 development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain.  The following symptomatology has been seen with 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 "Pulmonary and Vascular Complications").  Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).

OHSS occurred in 9 of 228 (3.9%) Gonal-F® treated women during ovulation induction clinical trials and of this number, 1 of 228 (0.4%) was classified as severe.  In ART clinical studies, OHSS occurred in 0 of 116 (0.0%) Gonal-F® treated women.  OHSS may be more severe and more protracted if pregnancy occurs.  OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration.  Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at 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 severe OHSS occurs, treatment must be stopped and the patient should be hospitalized.

A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.

Pulmonary and Vascular Complications:

Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported.  In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported.  Intravascular thrombosis and embolism can result in reduced blood flow to critical 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.

Multiple Births:

Reports of multiple births have been associated with  Gonal-F® treatment.  In ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving Gonal-F® and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving Gonal-F® and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred.  The patient should be advised of the potential risk of multiple births before starting treatment.

PRECAUTIONS

General:

Careful attention should be given to the diagnosis of infertility in candidates for Gonal-F® (follitropin alfa for injection) therapy (see "Indications and Usage / Selection of Patients").

Infor

Tyzeka

Dosage Form: tablet, film coated, oral solution
FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS & SEVERE ACUTE EXACERBATIONS OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals [see Warnings and Precautions (5.1)].

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].

 INDICATIONS AND USAGE

Chronic Hepatitis B

Tyzeka is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

The following points should be considered when initiating therapy with Tyzeka:

●       This indication is based on virologic, serologic, biochemical and histologic responses in nucleoside treatment naïve adult patients with HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease [see Clinical Studies (14)].

 ●       For HBeAg-positive patients, Tyzeka should only be initiated in patients with HBV DNA less than 9 log10 copies/mL and ALT greater than or equal to 2x Upper Limit of Normal (ULN) prior to treatment.

 ●       For HBeAg-negative patients, Tyzeka should only be initiated in patients with HBV DNA less than 7 log10 copies/mL prior to treatment.

 ●       On-treatment response should guide continued therapy [see Dosage and Administration (2.1) and Microbiology (12.4)].

●       Tyzeka has not been evaluated in patients co-infected with HIV, HCV or HDV.

●       Tyzeka has not been evaluated in liver transplant recipients or in patients with decompensated liver disease.

●       Tyzeka has not been studied in well-controlled trials for the treatment of patients with established nucleoside analog reverse transcriptase inhibitor-resistant hepatitis B virus infection, but is expected to be cross-resistant to lamivudine [see Microbiology (12.4)].

●       The safety and efficacy of Tyzeka have not been evaluated in Black/African American or Hispanic patients [see Use in Specific Populations (8.9)].

 DOSAGE AND ADMINISTRATION

Adults and Adolescents (16 years of age and older)

 Due to higher rates of resistance that may develop with longer term treatment among patients with incomplete viral suppression, treatment should only be initiated, if pre-treatment HBV DNA and ALT measurements are known, in the following patient populations:

 For HBeAg-positive patients, HBV DNA should be less than 9 log10 copies/mL and ALT should be greater than or equal to 2x ULN prior to treatment with Tyzeka.

 For HBeAg-negative patients, HBV DNA should be less than 7 log10 copies/mL prior to treatment with Tyzeka.

HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies/mL). Alternate therapy should be initiated for patients who have detectable HBV DNA after 24 weeks of treatment. Optimal therapy should be guided by further resistance testing.

The recommended dose of Tyzeka for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food.

Tyzeka oral solution (30 mL) may be considered for patients who have difficulty with swallowing tablets. 

Renal Impairment

 Tyzeka may be used for the treatment of chronic hepatitis B in patients with impaired renal function. No adjustment to the recommended dose of Tyzeka is necessary in patients whose creatinine clearance is greater than or equal to 50 mL/min. Adjustment of the total daily dose of Tyzeka oral solution or of the interval for administration of Tyzeka tablets is required in patients with creatinine clearance less than 50 mL/min including those with ESRD on hemodialysis (Table 1).

Table 1 Dose Adjustment of Tyzeka in Patients with Renal Impairment

Creatinine Clearance (mL/min)	Tyzeka Oral Solution Dose (5 mL = 100 mg)	Tyzeka Tablet Dose (1 tablet = 600 mg)
greater than or equal to 50	30 mL once daily	1 tablet every 24 hrs
30-49	20 mL once daily	1 tablet every 48 hrs
less than 30 (not requiring dialysis)	10 mL once daily	1 tablet every 72 hrs
ESRD	6 mL once daily	1 tablet every 96 hrs1
1When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.

Hepatic Impairment

No adjustment to the recommended dose of Tyzeka is necessary in patients with hepatic impairment.

Duration of Therapy 

 For patients with incomplete viral suppression (HBV DNA greater than or equal to 300 copies/mL) after 24 weeks of treatment, alternate therapy should be instituted. HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, alternate treatment should be instituted. Optimal therapy should be guided by resistance testing.

The optimal duration of therapy with Tyzeka for patients with chronic hepatitis B is unknown.

 DOSAGE FORMS AND STRENGTHS

Tablets

Tyzeka (telbivudine) 600 mg tablets are white to slightly yellowish film-coated, ovaloid-shaped tablets, imprinted with “LDT” on one side.

Oral Solution

Tyzeka (telbivudine) oral solution is a clear, colorless to pale yellow, passion fruit flavored liquid. Tyzeka oral solution contains 100 mg of telbivudine per 5 milliliters. Therefore, 30 mL of the oral solution provides a 600 mg dose of telbivudine.  

 CONTRAINDICATIONS

Combination of Tyzeka with pegylated interferon alfa-2a is contraindicated because of increased risk of peripheral neuropathy [see Warnings and Precautions (5.4) and Drug Interactions (7)].

 WARNINGS AND PRECAUTIONS

Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Female gender, obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering HBV nucleoside analogue reverse transcriptase inhibitors to patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Tyzeka should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Exacerbations of Hepatitis B after Discontinuation of Treatment

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted [see Adverse Reactions (6.1)].

Myopathy

Cases of myopathy/myositis have been reported with Tyzeka use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Rhabdomyolysis has been reported during postmarketing use of Tyzeka [see Adverse Reactions (6.2)].

Uncomplicated myalgia has been reported in Tyzeka-treated patients [see Adverse Reactions (6.1)]. Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness in conjunction with increases in creatine kinase (CK) values, should be considered in any patient with diffuse myalgias, muscle tenderness or muscle weakness. Among patients with Tyzeka-associated myopathy, no pattern with regard to the degree or timing of CK elevations has been observed. In addition, the predisposing factors for the development of myopathy among Tyzeka recipients are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness or weakness. Tyzeka therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is confirmed. It is unknown whether the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy, including but not limited to: corticosteroids, chloroquine, hydroxychloroquine, certain HMGCoA reductase inhibitors, fibric acid derivatives, penicillamine, zidovudine, cyclosporine, erythromycin, niacin, and certain azole antifungals. Physicians initiating concomitant treatment with any drug associated with myopathy should monitor patients closely for any signs or symptoms of unexplained muscle pain, tenderness, or weakness.

Peripheral Neuropathy

Peripheral neuropathy has been reported with Tyzeka alone or in combination with pegylated interferon alfa-2a and other interferons. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of Tyzeka 600mg daily and pegylated interferon alfa-2a 180 micrograms once weekly compared to Tyzeka or pegylated interferon alfa-2a alone [see Contraindications (4) and Drug Interactions (7)]. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a, or other alfa interferons (pegylated or standard). The safety and efficacy of Tyzeka in combination with pegylated interferons or other interferons for the treatment of chronic hepatitis B has not been demonstrated. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Tyzeka therapy should be interrupted if peripheral neuropathy is suspected, and discontinued if peripheral neuropathy is confirmed [see Adverse Reactions (6.1)].

 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)]
  


• Severe acute exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning, Warnings and Precautions (5.2)]
  


• Myopathy [see Warnings and Precautions (5.3)]
  


• Peripheral Neuropathy [see Warnings and Precautions (5.4)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Assessment of adverse reactions is primarily based on two studies (007 GLOBE and NV-02B-015) in which 1,699 subjects with chronic hepatitis B received double-blind treatment with Tyzeka 600 mg/day (n=847 subjects) or lamivudine (n=852 subjects) for 104 weeks. The median duration of therapy was 104 weeks for both treatment groups.

In the 104 week clinical studies, most adverse experiences reported with Tyzeka were classified as mild or moderate in severity and were not attributed to Tyzeka. Selected adverse events of any severity which were reported in greater than or equal to 3% of Tyzeka and lamivudine recipients are shown in Table 2. With the exception of increased creatine kinase (CK), which was reported more frequently among Tyzeka recipients, the adverse event profile was similar for the two drugs.

Table 2 Selected Common Adverse Eventsa in Pooled Studies 007 GLOBE and NV-02B-015

Adverse Event (Preferred Term)	Tyzeka N=847 n (%)b	Lamivudine  N=852 n (%)b
Fatigue	106 (13)	95 (11)
CK increased	90 (11)	52 (6)
Headache	83 (10)	95 (11)
Cough	52 (6)	45 (5)
Diarrhea	50 (6)	46 (5)
Abdominal pain, upper	49 (6)	52 (6)
Nausea	45 (5)	40 (5)
Pharyngolaryngeal pain	38 (5)	31 (4)
Arthralgia	37 (4)	38 (5)
Pyrexia	34 (4)	27 (3)
Rash	33 (4)	21 (3)
Back pain	33 (4)	32 (4)
Dizziness	32 (4)	43 (5)
Abdominal pain	29 (3)	31 (4)
Myalgia	27 (3)	17 (2)
ALT increased	27 (3)	31 (4)
Dyspepsia	24 (3)	39 (5)
Insomnia	24 (3)	22 (3)
Abdominal distension	22 (3)	19 (2)
Pruritus	18 (2)	23 (3)
Hepatitis B exacerbation	17 (2)	36 (4)
a Adverse events reported in greater than or equal to 3% subjects in either treatment group b n (%) = the number and proportion of subjects in whom adverse event was reported

Moderate to severe (Grade 2-4) adverse events were reported in 239/847 (28%) of Tyzeka recipients and 229/852 (27%) of lamivudine recipients. The profile of adverse events of moderate to severe intensity was similar in both treatment groups and no individual adverse event was reported in greater than 2% of subjects in either treatment group.

Discontinuations due to adverse events were reported in 4% of Tyzeka recipients and 4% of lamivudine recipients. The most common adverse events resulting in Tyzeka discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy.

Peripheral neuropathy was reported as an adverse event in less than 1% (2/847) of subjects receiving Tyzeka monotherapy [see Warnings and Precautions (5.4)]. Of Tyzeka-treated subjects less than 1% (5/847) were diagnosed with myopathy/myositis (presenting with muscular weakness) [see Warnings and Precautions (5.3)].

Laboratory Abnormalities

Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE and NV-02B-015 studies are listed in Table 3.

Table 3 Selected Treatment-Emergent Grade 3-4 Laboratory Abnormalitiesa in Patients with Chronic Hepatitis B in the 104-Week Pooled 007 GLOBE and NV-02B-015 Studies

Test	Tyzeka 600 mg (n=847)	Lamivudine 100 mg (n=852)
Creatine Kinase (CK) greater than 7.0 x ULN	13%	4%
ALT greater than 10.0 x ULN and 2.0 x baselineb	5%	8%
ALT greater than 3 x baseline	7%	13%
AST (SGOT) greater than 3.0 x baseline	6%	10%
Lipase greater than 2.5 x ULN	2%	4%
Amylase greater than 3.0 x ULN	less than 1%	less than 1%
Total Bilirubin greater than 5.0 x ULN	less than 1%	less than 1%
Neutropenia (ANC less than or equal to 749/mm3)	2%	2%
Thrombocytopenia (Platelets less than or equal to 49,999/mm3)	less than 1%	less than 1%
a On-treatment value worsened from baseline to Grade 3 or Grade 4 during therapy
b American Association for the Study of Liver Diseases (AASLD) definition of acute hepatitis flare

Creatine Kinase (CK) Elevations

Creatine kinase (CK) elevations were more frequent among subjects on Tyzeka treatment. By 104 weeks of treatment, Grade 1-4 CK elevations occurred in 79% of Tyzeka-treated subjects and 47% of lamivudine-treated subjects. Grade 3 or 4 CK elevations occurred in 13% of Tyzeka-treated subjects and 4% of lamivudine-treated subjects. Most CK elevations were asymptomatic, but the mean recovery time was longer for subjects on Tyzeka than subjects on lamivudine.

Among Tyzeka-treated subjects with Grade 1-4 CK elevations, 10% developed a musculoskeletal adverse event compared to 5% of lamivudine-treated subjects. A total of 2% (13/847) Tyzeka-treated subjects interrupted or discontinued study drug due to CK elevation or musculoskeletal adverse events1.

______________________

1 Includes the Preferred Terms: back pain, chest wall pain, non-cardiac chest pain, chest discomfort, flank pain, muscle cramp, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, myofascial pain syndrome, myopathy, myositis, neck pain, and pain in extremity.

______________________

ALT Flares during Treatment

The incidence of ALT flares, defined as ALT greater than 10 x ULN and greater than 2 x baseline, was similar in the two treatment arms (3%) in the first six months. After week 24, ALT flares were reported less frequently in the Tyzeka arm (2%) compared to the lamivudine arm (5%). Periodic monitoring of hepatic function is recommended during chronic hepatitis B treatment.

Exacerbations of Hepatitis after Discontinuation of Treatment

In the subset of subjects who discontinued treatment prematurely for reasons other than efficacy, or who elected not to continue Tyzeka in another clinical trial, 9/154 (6%) Tyzeka-treated and 10/180 (6%) lamivudine-treated subjects experienced an exacerbation of hepatitis (ALT elevation greater than 2 x baseline and greater than 10 x ULN) in the 4-month post-treatment period.

Postmarketing Experience 

The following adverse reactions have been reported during postmarketing use of Tyzeka. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to Tyzeka exposure.

Musculoskeletal and Connective Tissue Disorders

Rhabdomyolysis

Nervous System Disorders

Paraesthesia, hypoaesthesia

Metabolism and Nutrition Disorders

Lactic acidosis 

 DRUG INTERACTIONS

Tyzeka is excreted mainly by passive diffusion so the potential for interactions between Tyzeka and other drugs eliminated by renal excretion is low. However, because Tyzeka is eliminated primarily by renal excretion, coadministration of Tyzeka with drugs that alter renal function may alter plasma concentrations of Tyzeka [see Clinical Pharmacology (12.3)].

A clinical trial investigating the combination of Tyzeka, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of peripheral neuropathy occurrence and severity, in comparison to Tyzeka or pegylated interferon alfa-2a alone [see Contraindications (4) and Warnings and Precautions (5.4)].

 USE IN SPECIFIC POPULATIONS

Pregnancy

Category B: Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg/kg/day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg/day dose in humans.

There are no adequate and well-controlled studies of Tyzeka in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, Tyzeka should be used during pregnancy only if potential benefits outweigh the risks.

Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tyzeka, healthcare providers are encouraged to register such patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.

Labor and Delivery

There are no studies in pregnant women and no data on the effect of Tyzeka on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.

Nursing Mothers

Telbivudine is excreted in the milk of rats. It is not known whether Tyzeka is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Tyzeka.

Pediatric Use

Safety and effectiveness of Tyzeka in pediatric patients have not been established.

Geriatric Use

Clinical studies of Tyzeka did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing Tyzeka to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)].

Renal Impairment

Tyzeka is eliminated primarily by renal excretion, therefore dose regimen adjustment is recommended in patients with creatinine clearance less than 50 mL/min, including patients with ESRD requiring hemodialysis [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 

Liver Transplant Recipients

The safety and efficacy of Tyzeka in liver transplant recipients has not been evaluated. The steady-state pharmacokinetics of Tyzeka was not altered following multiple dose administration in combination with cyclosporine. If Tyzeka treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with Tyzeka [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)].

 Co-Infected Patients

Tyzeka has not been investigated in co-infected hepatitis B patients (e.g., patients co-infected with HIV, HCV or HDV).

Racial/Ethnic Minorities

The safety and efficacy of Tyzeka have not been evaluated in Black/African American or Hispanic patients. It is not known if safety and efficacy can be extrapolated from studied populations.

 DRUG ABUSE AND DEPENDENCE

Tyzeka is not a controlled substance and no potential for dependence has been observed.

OVERDOSAGE

There is no information on intentional overdose of Tyzeka, but one subject experienced an unintentional and asymptomatic overdose. Healthy subjects who received Tyzeka doses up to 1800 mg/day for 4 days had no increase in or unexpected adverse events. A maximum tolerated dose for Tyzeka has not been determined. In the event of an overdose, Tyzeka should be discontinued, the patient must be monitored for evidence of toxicity, and appropriate general supportive treatment applied as necessary.

In case of overdosage, hemodialysis may be considered. Within 2 hours, following a single 200 mg dose of telbivudine, a 4-hour hemodialysis session removed approximately 23% of the telbivudine dose.

 DESCRIPTION

Tyzeka is the trade name for telbivudine, a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV). The chemical name for telbivudine is 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-y1)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-β-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified β-L enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is C10H14N2O5, which corresponds to a molecular weight of 242.23. Telbivudine has the following structural formula:

Telbivudine is a white to slightly yellowish powder. Telbivudine is sparingly soluble in water (greater than 20 mg/mL), and very slightly soluble in absolute ethanol (0.7 mg/mL) and n-octanol (0.1 mg/mL).

Tyzeka film-coated tablets are available for oral administration in 600 mg strength. Tyzeka 600 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet coating contains titanium dioxide, polyethylene glycol, talc and hypromellose.

Tyzeka oral solution is available for oral administration in 100 mg/5 mL strength. Tyzeka oral solution contains the following inactive ingredients: citric acid anhydrous, benzoic acid, passion fruit flavor, sodium saccharin, sodium hydroxide, and purified water. A 600 mg dose (30 mL) of Tyzeka oral solution contains approximately 47 mg of sodium.

 CLINICAL PHARMACOLOGY

Mechanism of Action

Tyzeka is an antiviral drug [see Microbiology (12.4)]. 

Pharmacodynamics

In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover study, 53 healthy subjects were administered Tyzeka 600 mg, a supratherapeutic Tyzeka 1800 mg dose, placebo, and moxifloxacin 400 mg. After 7 days of dosing, Tyzeka did not prolong the QT interval. The maximum placebo-adjusted mean (upper 1-side 95% CI) change from baseline in QTcF on day 7 were 3.4 msec (5.9 msec) for the 600 mg and 4.4 msec (6.9 msec) for the 1800 mg dosing regimens.

Pharmacokinetics in Adults

The single- and multiple-dose pharmacokinetics of Tyzeka were evaluated in healthy subjects and in patients with chronic hepatitis B. Tyzeka pharmacokinetics are similar between both populations.

Absorption and Bioavailability

Following oral administration of Tyzeka 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (Cmax) was 3.69 ± 1.25 μg/mL (mean ± SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1 ± 7.2 μg h/mL (mean ± SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 μg/mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.

Effects of Food on Oral Absorption

Tyzeka absorption and exposure were unaffected when a single 600 mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. Tyzeka may be taken with or without food.

Distribution

In-vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.

Metabolism and Elimination

No metabolites of telbivudine were detected following administration of [14C]-telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system.

After reaching the peak concentration, plasma concentrations of Tyzeka declined in a biexponential manner with a terminal elimination half-life (T1/2) of 40-49 hours. Tyzeka is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of Tyzeka approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of Tyzeka. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose regimen adjustment [see Dosage and Administration (2.2)].

Special Populations

Gender: There are no significant gender-related differences in Tyzeka pharmacokinetics.

Race: There are no significant race-related differences in Tyzeka pharmacokinetics.

Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects.

Renal Impairment: Single-dose pharmacokinetics of Tyzeka have been evaluated in subjects (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 4, adjustment of the dose regimen for Tyzeka is recommended in patients with creatinine clearance of less than 50 mL/min [see Dosage and Administration (2.2)].

Table 4 Pharmacokinetic Parameters (mean ± SD) of Tyzeka in Subjects with Various Degrees of Renal Function

	Renal Function (Creatinine Clearance in mL/min)
	Normal (greater than 80) (n=8) 600 mg	Mild (50-80) (n=8) 600 mg	Moderate (30-49) (n=8) 400 mg	Severe (less than 30) (n=6) 200 mg	ESRD/Hemodialysis (n=6) 200 mg
Cmax (μg/mL)	3.4±0.9	3.2±0.9	2.8±1.3	1.6±0.8	2.1±0.9
AUC0-INF (μg•hr/mL)	28.5±9.6	32.5±10.1	36.0±13.2	32.5±13.2	67.4±36.9
CLRENAL (L/h)	7.6±2.9	5.0±1.2	2.6±1.2	0.7±0.4

Renally Impaired Subjects on Hemodialysis: Hemodialysis (up to 4 hours) reduces systemic Tyzeka exposure by approximately 23%. Following dose regimen adjustment for creatinine clearance [see Dosage and Administration (2.2)], no additional dose modification is necessary during routine hemodialysis. When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.

Hepatic Impairment: The pharmacokinetics of Tyzeka following a single 600 mg dose have been studied in subjects (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in Tyzeka pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.

Drug Interactions

Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine, pegylated interferon alfa-2a and tenofovir disoproxil fumarate do not alter Tyzeka pharmacokinetics. In addition, Tyzeka does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, cyclosporine, or tenofovir disoproxil fumarate. No definitive conclusion could be drawn regarding the effects of Tyzeka on the pharmacokinetics of pegylated interferon alfa-2a due to the high inter-individual variability of pegylated interferon alfa-2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in-vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.

Microbiology

Mechanism of Action

Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine 5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine 5'-triphosphate into viral DNA causes DNA chain termination. Telbivudine is an inhibitor of both HBV first strand (EC50 value = 1.3 ± 1.6 µM) and second strand synthesis (EC50 value = 0.2 ± 0.2 µM). Telbivudine 5'-triphosphate at concentrations up to 100 μM did not inhibit human cellular DNA polymerases α, β, or γ. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 μM.

Antiviral Activity in Cell Culture

The antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15, as well as in primary duck hepatocytes infected with duck hepatitis B virus. The concentration of telbivudine that effectively inhibited 50% of viral DNA synthesis (EC50) in both systems was approximately 0.2 μM. The anti-HBV activity of telbivudine was additive with adefovir in cell culture, and was not antagonized by the HIV NRTIs didanosine and stavudine. Telbivudine is not active against HIV-1 (EC50 value greater than 100 µM) and was not antagonistic to the anti-HIV activity of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.

Resistance

In an as-treated analysis of the Phase III global registration trial (NV-02B-007 GLOBE study), 59% (252/430) of treatment-naïve HBeAg-positive and 89% (202/227) of treatment-naïve HBeAg-negative subjects receiving Tyzeka 600 mg once daily achieved non-detectable serum HBV DNA levels (less than 300 copies/mL) by Week 52. Of those who continued treatment beyond Week 52, 58% (243/418) and 85% (190/224) of HBeAg-positive and HBeAg-negative Tyzeka recipients, respectively, had undetectable HBV DNA at Week 104 (or at the end of dosing in treatment Year 2). 

The cumulative frequency of genotypic resistance (emergence of the rtM204I/V substitution) to Tyzeka based on an as-treated analysis of HBeAg-positive and HBeAg-negative subjects at Weeks 52 and 104 was 7% and 22%, respectively. Genotypic analysis of paired baseline and Tyzeka-treatment failure isolates from 182 evaluable subjects with amplifiable HBV DNA and greater than or equal to 16 weeks of treatment showed that the rtM204I/V substitution was associated with virologic failure (HBV DNA greater than or equal to 1,000 copies/mL) and virologic rebound (greater than or equal to 1 log10 increase above nadir). The rtM204I substitution was the most frequent substitution, detectable in isolates from 143/182 (79%) of evaluable subjects, and was frequently found with substitutions rtL80I/V and rtL180M. The rtM204I substitution was found infrequently with rtV27A, rtL82M, rtV173L, rtT184I/S, rtA200V, rtL229F/V/W, and rtR289K substitutions. The HBV of 16 subjects developed rtA181S/T amino acid substitutions while receiving Tyzeka. Eight of these 16 subjects had outgrowth of HBV expressing an rtM204I/V substitution without the rtA181 substitution and 1 subject’s HBV had both the rtM204I and rtA181T substitutions.

Subjects with higher baseline viral load had higher rates of genotypic resistance to Tyzeka, while subjects who achieved HBV DNA levels less than 300 copies/mL at Week 24 had lower rates of genotypic resistance to Tyzeka. By Week 104, 32% (95/293) of HBeAg-positive subjects with baseline viral DNA levels greater than or equal to 9 log10 copies/mL developed genotypic resistance to Tyzeka, compared to 15% (20/136) of the subjects with viral DNA levels less than 9 log10 copies/mL. In HBeAg-negative subjects, 17% (22/132) of the subjects with baseline viral DNA levels greater than or equal to 7 log10 copies/mL developed genotypic resistance to Tyzeka, compared to 5% (5/95) of the subjects with viral DNA levels less than 7 log10 copies/mL. By Week 104, 41% (97/239) of HBeAg-positive subjects who failed to achieve viral DNA levels less than 300 copies/mL at Week 24 developed genotypic resistance to Tyzeka, compared to 9% (18/190) of the subjects with non-detectable serum HBV DNA levels (less than 300 copies/mL) at Week 24. In HBeAg-negative subjects, 35% (15/43) of the subjects who failed to achieve viral DNA levels less than 300 copies/mL at Week 24 developed genotypic resistance to Tyzeka, compared to 7% (12/184) of the subjects with non-detectable serum HBV DNA levels (less than 300 copies/mL) at Week 24.

Cross-Resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, lamivudine-resistant HBV strains expressing either the rtM204I substitution or the rtL180M/rtM204V double substitution had greater than or equal to 1,000-fold reduced susceptibility to telbivudine. Telbivudine retained wild-type phenotypic activity (1.2-fold reduction) against the lamivudine resistance-associated substitution rtM204V alone. The efficacy of telbivudine against HBV harboring the rtM204V substitution has not been established in clinical trials.

HBV encoding the adefovir resistance-associated substitution rtA181V showed 3- to 5-fold reduced susceptibility to telbivudine in cell culture. The rtA181S and rtA181T substitutions conferred 2.7- and 3.5-fold reductions in susceptibility to telbivudine, respectively. The rtA181T substitution is associated with decreased clinical response in patients with HBV treated with adefovir and entecavir. HBV encoding the adefovir resistance-associated substitution rtN236T remained susceptible to telbivudine.

 NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg/day.

There was no evidence of genotoxicity based on in-vitro or in-vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in-vivo micronucleus study in mice.

Effects on fertility were studied in rats administered telbivudine as juveniles or adults. Juvenile rats were treated with telbivudine at doses of 0, 250, 1000, and 2000 mg/kg/day from post natal days 14 to 70. These rats were mated following a 5 week drug-free recovery period. Up to 50% reduction of fertility was associated with doses 1000 mg/kg/day and higher, which was equivalent to a systemic exposure approximately 7.5 times that achieved in humans at the therapeutic dose. The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters was 250 mg/kg/day, which was equivalent to systemic exposure levels 2.5 to 2.8 times that achieved in humans at the therapeutic dose. In contrast, such reduction of fertility was absent in adult rats treated with telbivudine at doses up to 2000 mg/kg/day, equivalent to a systemic exposure approximately 14 times that achieved in humans at the therapeutic dose.

 CLINICAL STUDIES

Clinical Experience in Nucleoside-Naïve Adults

The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical study (NV-02B-007 GLOBE Study) that included 1,367 subjects with chronic hepatitis B and a smaller supportive study (NV-02B-015) that included 332 subjects. Subjects were 16 years of age or older, with chronic hepatitis B, evidence of HBV infection with viral replication (HBsAg-positive, HBeAg-positive or HBeAg-negative, HBV DNA detectable by a PCR assay), and elevated ALT levels greater than or equal to 1.3 x  ULN, no evidence of hepatic decompensation, and chronic inflammation on liver biopsy compatible with chronic viral hepatitis.

NV-02B-007 GLOBE Study

The Week 52 and Week 104 results of the 007 GLOBE study are summarized below.

The 007 GLOBE study was a Phase III, randomized, double-blind, multinational study of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 1,367 (n= 680 Tyzeka; n=687 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The primary data analysis was conducted after all subjects had reached Week 52.

HBeAg-positive Subjects: (n= 458 Tyzeka; n= 463 lamivudine) The mean age of subjects was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.52 log10 copies/mL; and mean serum ALT was 153 IU/L. Pre- and post-liver biopsy samples were adequate for 86% of subjects.

HBeAg-negative Subjects: (n=222 Tyzeka; n= 224 lamivudine)The mean age of subjects was 43 years, 77% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 7.54 log10 copies/mL; and mean serum ALT was 140 IU/L. Pre- and post-liver biopsy samples were adequate for 92% of subjects.

Clinical Results 

Clinical and virologic efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative subject populations. 

The primary endpoint of Therapeutic Response at Week 52 was a composite endpoint requiring suppression of HBV DNA to less than 5 log10 copies/mL in conjunction with either loss of serum HBeAg or ALT normalization. Key secondary endpoints included histologic response, ALT normalization, and measures of virologic response.

At Week 52, in HBeAg-positive patients, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative patients 75% of Tyzeka subjects and 77% of lamivudine subjects had a Therapeutic Response.

Analysis of the histological response at Week 52 is shown in Table 5.

Table 5 Histological Improvement and Change in Ishak Fibrosis Score at Week 52 (007 GLOBE Study)

	HBeAg-positive (n=797)		HBeAg-negative (n=417)
	Tyzeka  600 mg (n=399)1	Lamivudine 100 mg (n=398)1	Tyzeka  600 mg (n=205)1	Lamivudine 100 mg (n=212)1
Histologic Response2
Improvement	69%	60%	69%	68%
No Improvement	19%	26%	23%	25%
Missing Week 52 Biopsy	12%	15%	8%	7%
Ishak Fibrosis Score3
Improvement	41%	46%	48%	44%
No Change	39%	32%	34%	43%
Worsening	9%	7%	10%	5%
Missing Week 52 Biopsy	12%	15%	8%	7%
1 Patients with greater than or equal to one dose of study drug with evaluable baseline liver biopsies and baseline Knodell Necroinflammatory Score greater than or equal to 2
2 Histologic Response defined as greater than or equal to 2 point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score
3 For Ishak Fibrosis Score, improvement defined as greater than or equal to a 1-point reduction in Ishak Fibrosis Score from baseline to Week 52

Subjects were eligible to continue blinded treatment to Week 104. In the ITT population, 624/680 (92%) Tyzeka recipients and 599/687 (87%) lamivudine recipients completed study treatment to Week 104. At Week 104, in HBeAg-positive patients, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative patients 78% of Tyzeka subjects and 66% of lamivudine subjects had a Therapeutic Response.

Selected virologic, biochemical, and serologic outcome measures at Weeks 52 and 104 are shown in Table 6.

Table 6 Virological, Biochemical and Serologic Endpoints at Weeks 52 and 104 (007 GLOBE Study)

Response Parameter	HBeAg-positive (n=921)				HBeAg-negative (n=446)
	Tyzeka  600 mg (n=458)		Lamivudine 100 mg (n=463)		Tyzeka  600 mg (n=222)		Lamivudine 100 mg (n=224)
	Week 52	Week 104	Week 52	Week 104	Week 52	Week 104	Week 52	Week 104
Mean HBV DNA Reduction from Baseline (log10 copies/mL) ± SEM1	-6.45 (0.11)	-5.74 (0.15)	-5.54 (0.11)	-4.42 (0.15)	-5.23 (0.13)	-5.00 (0.15)	-4.40 (0.13)	-4.17 (0.16)
% Subjects HBV DNA Negative by PCR	60%	56%	40%	39%	88%	82%	71%	57%
ALT Normalization2	77%	70%	75%	62%	74%	78%	79%	70%
HBeAg Seroconversion3	23%	30%	22%	25%	NA	NA	NA	NA
HBeAg Loss3	26%	35%	23%	29%	NA	NA	NA	NA
1 Roche COBAS Amplicor® Assay (LLOQ less than or equal to 300 copies/mL). 2ALT normalization assessed only in subjects with ALT greater than ULN at baseline.
3 HBeAg seroconversion and loss assessed only in subjects with detectable HBeAg at baseline.

Patients who achieved non-detectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achiev

Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets

Pronunciation: pree-NATE-al VYE-ta-mins
Generic Name: Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA
Brand Name: Prenatal + DHA

Accidental overdose of products that contain iron is a leading cause of fatal poisoning in children younger than 6 years old. Keep this and all medicines out of the reach of children. In case of accidental ingestion, call the poison control center or doctor at once.

Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets are used for:

Treating or preventing a lack of vitamins during pregnancy and while breast-feeding. It may also be used for other conditions as determined by your doctor.

Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets are a vitamin and mineral combination. It works by providing vitamins and minerals to the body to help meet nutritional requirements.

Do NOT use Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets if:

• you are allergic to any ingredient in Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets


• you have high blood iron levels, hemochromatosis (an iron metabolism problem), Wilson disease (a copper metabolism problem), or certain bleeding problems (eg, hemophilia)


• you are taking acitretin or an anticoagulant (eg, warfarin)

Contact your doctor or health care provider right away if any of these apply to you.

Before using Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets:

Some medical conditions may interact with Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances (including fish or fish oil)


• if you have stomach or intestinal problems (eg, peptic ulcer, colitis, Crohn disease, diverticulitis), blood problems (eg, pernicious anemia, other types of anemia, porphyria), or a history of kidney stones


• if you have had multiple blood transfusions

Some MEDICINES MAY INTERACT with Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin) because the risk of bleeding may be increased by Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets


• Acitretin, cation exchange resins (eg, sodium polystyrene sulfonate), or fluorouracil because the risk of their side effects may be increased by Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets


• Doxycycline, hydantoins (eg, phenytoin), penicillamine, or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets:

Use Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Check with your doctor or pharmacist to see if you should take Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets with food or on an empty stomach. If stomach upset occurs, take with food to reduce stomach irritation.


• Dissolve contents of the packet in 8 to 12 oz (240 to 360 mL) cold water. Allow the powder to dissolve completely, then drink all of the liquid. Rinse the container with an additional small amount of water and drink the contents to ensure the entire dose is taken.


• Avoid taking Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets with dairy products; they may interfere with the absorption of the iron in Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets.


• If you also take an antacid, bisphosphonate (eg, alendronate), cefdinir, eltrombopag, methyldopa, quinolone antibiotic (eg, ciprofloxacin), or tetracycline antibiotic (eg, minocycline), ask your doctor or pharmacist how to take it with Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets.


• If you miss a dose of Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets.

Important safety information:

• Do not take more than the recommended dose of Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets without checking with your doctor.


• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets may discolor the stools. This is normal and not a cause for concern.


• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets has iron in it. Iron overdose is a leading cause of fatal poisoning in children younger than 6 years of age. In case of an overdose, call a doctor or poison control center right away.


• PREGNANCY and BREAST-FEEDING: Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets are intended for use during pregnancy and breast-feeding. If you are or will be breast-feeding while you use Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets, check with your doctor.

Possible side effects of Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dark or discolored stools; diarrhea; nausea; stomach upset; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood or streaks of blood in the stools; stomach pain or cramping.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include black, tarry stools; chest pain; lack of feeling alert; loss of balance; seizure; severe nausea, vomiting, diarrhea, or stomach pain; shortness of breath; sluggishness; trouble breathing; unusual tiredness or weakness; unusually pale skin; weak pulse.

Proper storage of Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets:

Store Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets out of the reach of children and away from pets.

General information:

• If you have any questions about Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets, please talk with your doctor, pharmacist, or other health care provider.


• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Powder Packets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA resources

• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Use in Pregnancy & Breastfeeding
• Drug Images
• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Drug Interactions
• Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA Support Group
• 21 Reviews for Prenatal Multivitamin with Minerals, Iron, Folic Acid, and DHA - Add your own review/rating

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• Vitamin/Mineral Supplementation during Pregnancy/Lactation

femhrt 1 mg/5 mcg HRT

Generic Name: ethinyl estradiol and norethindrone (HRT) (ETH in ill ess tra DYE ole/ nor ETH in drone)

Brand Names: femhrt, femhrt 1 mg/5 mcg

What are ethinyl estradiol and norethindrone?

Ethinyl estradiol is a form of estrogen. Estrogen is a female sex hormone necessary for many processes in the body.

Norethindrone is a form of progesterone. Progesterone is a female hormone important for the regulation of ovulation and menstruation.

The combination of ethinyl estradiol and norethindrone is used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to prevent osteoporosis.

Estradiol and norethindrone may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about ethinyl estradiol and norethindrone?

This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. Do not use this medication if you have any of the following conditions: a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, abnormal vaginal bleeding, if you have recently had a stroke or heart attack, if you have had your uterus removed (hysterectomy), or if you have ever had an allergic reaction to birth control pills or other hormones.

Before taking ethinyl estradiol and norethindrone, tell your doctor if you have high blood pressure or heart disease, high cholesterol, gallbladder disease, diabetes, asthma, seizures, liver disease, a thyroid disorder, high levels of calcium in your blood, migraine headaches or a history of depression, fibroid tumors in your uterus, or a history of breast cancer or an abnormal mammogram.

Avoid smoking while using this medication. Smoking can increase your risk of blood clots, stroke, or heart attack caused by taking hormones.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using ethinyl estradiol and norethindrone.

What should I discuss with my healthcare provider before taking ethinyl estradiol and norethindrone?

This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. Do not use this medication if you have:

• 
  

  abnormal vaginal bleeding that a doctor has not checked;

  
  


• 
  

  a hormone-related cancer such as breast or uterine cancer;

  
  


• 
  

  a history of blood clot or circulation problems;

  
  


• 
  

  if you have recently had a stroke or heart attack;

  
  


• 
  

  if you have had your uterus removed (hysterectomy); or

  
  


• 
  

  if you have ever had an allergic reaction to birth control pills or other hormones.

  
  

Before using this medication, tell your doctor if you have any of the following conditions.

• 
  

  high blood pressure or heart disease;

  
  


• 
  

  high cholesterol, gallbladder disease, or diabetes;

  
  


• 
  

  asthma;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  liver disease;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  high levels of calcium in your blood;

  
  


• 
  

  migraine headaches or a history of depression;

  
  


• 
  

  fibroid tumors in your uterus; or

  
  


• 
  

  a history of breast cancer or an abnormal mammogram.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely use this medication.

The hormones in this medication can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

How should I take ethinyl estradiol and norethindrone?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor. Follow the instructions on your prescription label.

Try to take your medicine at the same time each day.

If you need to have any type of medical tests or surgery, or if you will be on bed rest, you may need to stop using this medication for a short time. Any doctor or surgeon who treats you should know that you are using hormones.

It is important to use ethinyl estradiol and norethindrone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using ethinyl estradiol and norethindrone.

Store this medication at room temperature away from moisture and heat.

See also: Femhrt 1 mg/5 mcg dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the dose you missed and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

An overdose of ethinyl estradiol and norethindrone is unlikely to threaten life. Call an emergency room or poison control center for advice.

Symptoms of a ethinyl estradiol and norethindrone overdose might include nausea, vomiting, and vaginal bleeding.

What should I avoid while taking my ethinyl estradiol and norethindrone?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using this medication.

Avoid smoking while using this medication. Smoking can increase your risk of blood clots, stroke, or heart attack caused by taking hormones.

My ethinyl estradiol and norethindrone side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden headache, confusion, pain behind the eyes, problems with vision, speech, or balance;

  
  


• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; or

  
  


• 
  

  gallbladder problems (pain in your upper right stomach area with nausea and vomiting);

  
  


• 
  

  jaundice (yellowing of the skin or eyes); or

  
  


• 
  

  a breast lump.

  
  

Less serious side effects may include:

• 
  

  mild nausea, vomiting, stomach pain;

  
  


• 
  

  breast tenderness or swelling;

  
  


• 
  

  freckles or darkening of facial skin;

  
  


• 
  

  increased hair growth, loss of scalp hair;

  
  


• 
  

  changes in weight or appetite;

  
  


• 
  

  problems with contact lenses;

  
  


• 
  

  runny nose;

  
  


• 
  

  vaginal itching or discharge;

  
  


• 
  

  changes in your menstrual periods, decreased sex drive; or

  
  


• 
  

  headache, dizziness, sleep problems.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect ethinyl estradiol and norethindrone?

Before taking ethinyl estradiol and norethindrone, tell your doctor if you are taking any of the following medicines:

• 
  

  acetaminophen (Tylenol);

  
  


• 
  

  cyclosporine (Neoral, Gengraf, Sandimmune);

  
  


• 
  

  prednisolone (Orapred);

  
  


• 
  

  theophylline (Respbid, Theo-Dur);

  
  


• 
  

  St. John's wort;

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., E-Mycin, Ery-Tab, Erythrocin), itraconazole (Sporanox), or ketoconazole (Nizoral);

  
  


• 
  

  seizure medication such as carbamazepine (Carbatrol, Tegretol) or phenobarbital (Solfoton);

  
  


• 
  

  rifampin (Rifadin, Rifamate, Rimactane); or

  
  


• 
  

  HIV or AIDS medication such as ritonavir (Norvir, Kaletra).

  
  

This list is not complete and there may be other drugs that can interact with ethinyl estradiol and norethindrone. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More femhrt 1 mg/5 mcg resources

• Femhrt 1 mg/5 mcg Side Effects (in more detail)
• Femhrt 1 mg/5 mcg Dosage
• Femhrt 1 mg/5 mcg Use in Pregnancy & Breastfeeding
• Drug Images
• Femhrt 1 mg/5 mcg Drug Interactions
• Femhrt 1 mg/5 mcg Support Group
• 5 Reviews for Femhrt mg/5 mcg - Add your own review/rating

Compare femhrt 1 mg/5 mcg with other medications

• Abnormal Uterine Bleeding
• Acne
• Birth Control
• Endometriosis
• Gonadotropin Inhibition
• Menstrual Disorders
• Polycystic Ovary Syndrome
• Postmenopausal Symptoms
• Prevention of Osteoporosis

Where can I get more information?

• Your pharmacist can provide more information about ethinyl estradiol and norethindrone.

See also: femhrt mg/5 mcg side effects (in more detail)