Tulana

TULANA — norethindrone tablet
RPK Pharmaceuticals, Inc.

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually trans mitted diseases (STDs ) such as Chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DESCRIPTION

Each light yellow to yellow Tulana^TM tablet provides a continuous oral contraceptive regimen of 0.35 mg norethindrone USP daily, and the inactive ingredients include corn starch, D&C Yellow No. 10 aluminum lake, FD&C Yellow # 6 aluminum lake, lactose monohydrate, magnesium stearate, povidone and talc.
The chemical name for norethindrone is 17-Hydroxy-19-Nor-17α-pregn-4-en-20-yn-3-one. The structural formula follows:

CLINICAL PHARMACOLOGY

1. Mode of Action

Tulana progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the mid-cycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium.

2. Pharmacokinetics

Absorption

Norethindrone is rapidly absorbed with maximum plasma concentrations occurring within 1 to 2 hours after Tulana administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first pass metabolism resulting in an absolute bioavailability of approximately 65%.
Figure 1: Mean ± SD Norethindrone Plasma Concentrations Following Tulana Administration

Peak plasma concentrations occur approximately 1 hour after administration (mean T_max 1.2 hours). The mean (SD) C_max was 4816.8 (1532.6) pg/mL and generally occurred within 1 hour (mean) of tablet administration, ranging from 0.5 to 2 hours. The mean (SD) C_avg was 885 (250) pg/mL, however, the mean concentration at 24 hrs was 130 (47) pg/mL. Table 1 provides summary statistics of the pharmacokinetic parameters associated with single dose Tulana administration.

Table 1: Mean ± SD Pharmacokinetic Parameters Following Single Dose Administration of Tulana in 12 Healthy Female Subjects Under Fasting Conditions

Pharmacokinetic Parameter	Norethindrone 0.35 mg
Tmax (hr) Cmax (pg/mL) AUC(0 — 48) (pg·h/mL) t½ (h)	1.2 ± 0.54817 ± 153321233 ± 60027.7 ± 0.5

The food effect on the rate and extent of norethindrone absorption after Tulana administration has not been evaluated.
Distribution

Following oral administration, norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is approximately 4 L/kg.
Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20 to 40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfate, with glucuronides accounting for most of the urinary metabolites.
Excretion
Plasma clearance rate for norethindrone has been estimated to be approximately 600 L/day. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following single dose administration of Tulana is approximately 8 hours.

INDICATIONS AND USAGE

1. Indications

Progestin– only oral contraceptives are indicated for the prevention of pregnancy.

2. Efficacy
If used perfectly, the first-year failure rate for progestin– only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. The following table lists the pregnancy rates for users of all major methods of contraception.

Table 2: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.

	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year3
Method (1)	Typical Use1 (2)	Perfect Use2 (3)	(4)
Chance4	85	85
Spermicides5	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermal6		2
Post-Ovulation		1
Cap7
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm7	20	6	56
Withdrawal	19	4
Condom8
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin only		0.5
Combined		0.1
IUDs
Progesterone T	2	1.5	81
Copper T380A	0.8	0.6	78
LNg20	0.1	0.1	81
Depo-Provera®	0.3	0.3	70
Levonorgestrel Implants (Norplant®)	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.1	100

Emergency Contraceptive Pills
Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.⁹

Lactational Amenorrhea Method

LAM is a highly effective, temporary method of contraception.¹⁰
Source: Trussell, J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.

1. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason.
2. Among couples who initiate use of a method (not necessarily for the first time), and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4. The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5. Foams, creams, gels, vaginal suppositories, and vaginal film.
6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7. With spermicidal cream or jelly.
8. Without spermicides.
9. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral^® (1 dose is 2 white pills), Alesse^® (1 dose is 5 pink pills), Nordette^® or Levlen^® (1 dose is 4 yellow pills).
10. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.