Label: CETROTIDE- cetrorelix acetate kit

Cetrorelix acetate

(Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-D-Ala10-NH2)

Cetrotide® (cetrorelix acetate for injection) 0.25 mg is a sterile lyophilized powder intended for subcutaneous injection after reconstitution with Sterile Water for Injection, that comes supplied in a 1.0 mL pre-filled syringe. Each vial of Cetrotide® 0.25 mg contains 0.26-0.27 mg cetrorelix acetate, equivalent to 0.25 mg cetrorelix, and 54.80 mg mannitol.

Pharmacokinetics

The pharmacokinetic parameters of single and multiple doses of Cetrotide® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in Table 1.

Drug-Drug Interactions

No formal drug-drug interaction studies have been performed with Cetrotide® (see PRECAUTIONS).

Clinical Studies

Seven hundred thirty two (732) patients were treated with Cetrotide® (cetrorelix acetate for injection) in five (two Phase 2 dose-finding and three Phase 3) clinical trials. The clinical trial population consisted of Caucasians (95.5%) and Black, Asian, Arabian and others (4.5%). Women were between 19 and 40 years of age (mean: 32). The studies excluded subjects with polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve, and subjects with stage III-IV endometriosis.

Two dose regimens were investigated in these clinical trials, either a single dose per treatment cycle or multiple dosing. In the Phase 2 studies, a single dose of 3 mg was established as the minimal effective dose for the inhibition of premature LH surges with a protection period of at least 4 days. When Cetrotide® is administered in a multidose regimen, 0.25 mg was established as the minimal effective dose. The extent and duration of LH-suppression is dose dependent.

In the Phase 3 program, efficacy of the single 3 mg dose regimen of Cetrotide® and the multiple 0.25 mg dose regimen of Cetrotide® was established separately in two adequate and well controlled clinical studies utilizing active comparators. A third non-comparative clinical study evaluated only the multiple 0.25 mg dose regimen of Cetrotide®. The ovarian stimulation treatment with recombinant FSH or human menopausal gonadotropin (hMG) was initiated on day 2 or 3 of a normal menstrual cycle. The dose of gonadotropins was administered according to the individual patient's disposition and response.

In the single dose regimen study, Cetrotide® 3 mg was administered on the day of controlled ovarian stimulation when adequate estradiol levels (400 pg/mL) were obtained, usually on day 7 (range day 5-12). If hCG was not given within 4 days of the 3 mg dose of Cetrotide®, then 0.25 mg of Cetrotide® was administered daily beginning 96 hours after the 3 mg injection until and including the day of hCG administration.

In the two multiple dose regimen studies, Cetrotide® 0.25 mg was started on day 5 or 6 of COS. Both gonadotropins and Cetrotide® were continued daily (multiple dose regimen) until the injection of human chorionic gonadotropin (hCG).

Oocyte pick-up (OPU) followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) as well as embryo transfer (ET) were subsequently performed. The results for Cetrotide® are summarized below in Table 2.

In addition to IVF and ICSI, one pregnancy was obtained after intrauterine insemination. In the five Phase 2 and Phase 3 clinical trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos).

In the 3 mg regimen, 9 patients received an additional dose of 0.25 mg of Cetrotide® and two other patients received two additional doses of 0.25 mg Cetrotide®. The median number of days of Cetrotide® multiple dose treatment was 5 (range 1-15) in both studies.

No drug related allergic reactions were reported from these clinical studies.

General

Cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance (see ADVERSE REACTIONS). A severe anaphylactic reaction associated with cough, rash, and hypotension, was observed in one patient after seven months of treatment with Cetrotide® (10 mg/day) in a study for an indication unrelated to infertility.

Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide® is not advised in women with severe allergic conditions.

Information for Patients

Prior to therapy with Cetrotide® (cetrorelix acetate for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). Cetrotide® should not be prescribed if a patient is pregnant.

If Cetrotide® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet (see below).

Laboratory Tests

After the exclusion of preexisting conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving Cetrotide® during controlled ovarian stimulation. The elevations ranged up to three times the upper limit of normal. The clinical significance of these findings was not determined.

During stimulation with human menopausal gonadotropin, Cetrotide® had no notable effects on hormone levels aside from inhibition of LH surges.

Drug Interactions

No formal drug interaction studies have been performed with Cetrotide®.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic in vitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome aberration test, mouse micronucleus test). Cetrorelix acetate induced polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg cetrorelix acetate for 4 weeks resulted in complete infertility in female rats which was reversed 8 weeks after cessation of treatment.

Pregnancy

(see CONTRAINDICATIONS)

Cetrotide® is contraindicated in pregnant women.

When administered to rats for the first seven days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 μg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 μg/kg (approximately 4 times the human dose) resulted in a resorption rate and a postimplantation loss of 100%. When administered from day 6 to near term to pregnant rats and rabbits, very early resorptions and total implantation losses were seen in rats at doses from 4.6 μg/kg (0.2 times the human dose) and in rabbits at doses from 6.8 μg/kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.

The fetal resorption observed in animals is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of Cetrotide®, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.

Nursing Mothers

It is not known whether Cetrotide® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Cetrotide® on lactation and/or the breast-fed child have not been determined, Cetrotide® should not be used by nursing mothers.

Geriatric Use

Cetrotide® is not intended to be used in subjects aged 65 and over.

Congenital Anomalies

Clinical follow-up studies of 316 newborns of women administered Cetrotide® were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after four days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal defect and another child with bilateral congenital glaucoma.

Four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In three of these four cases, intracytoplasmic sperm injection (ICSI) was the fertilization method employed; in the fourth case, in vitro fertilization (IVF) was the method employed.

The minor congenital anomalies reported include: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome.

The causal relationship between the reported anomalies and Cetrotide® is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.

Administration

Cetrotide® 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor.

Directions for using Cetrotide® 0.25 mg with the enclosed needles and pre-filled syringe:

1. Wash hands thoroughly with soap and water.
2. Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab.
3. Twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe.
4. Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial.
5. Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles.
6. Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents of the vial.
7. Replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge).
8. Invert the syringe and push the plunger until all air bubbles have been expelled.
9. Choose an injection site in the lower abdominal area, preferably around, but staying at least one inch away from the navel. Choose a different injection site each day to minimize local irritation. Use a second alcohol swab to clean the skin at the injection site and allow alcohol to dry. Gently pinch up the skin surrounding the site of injection.
10. Inject the prescribed dose as directed by your doctor, nurse or pharmacist.
11. Use the syringe and needles only once. Dispose of the syringe and needles properly after use. If available, use a medical waste container for disposal.

Storage

Store Cetrotide® 0.25 mg refrigerated, 2-8ºC (36-46ºF). Store the packaged tray in the outer carton in order to protect from light.