Menopur 75 IU - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Menopur 75 IU - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Female Infertility, Follicle Stimulation, Ovulation Induction
Class: Gonadotropins
Form: Subcutaneous (SC), Powder
Ingredients: menotropins, lactose monohydrate, polysorbate 20, and sodium phosphate, phosphoric buffer (sodium phosphate dibasic, heptahydrate, phosphoric acid)

Pharmaceutical Information

Drug Substance: Menotropins for injection
Chemical Name: Human Menopausal Gonadotropin
Structure: Menotropins contain Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH).
Physiochemical characteristics: Off-white to yellowish powder, soluble in water up to concentrations of approximately 200 mg/mL. Completely insoluble in ethanol, acetone and ether.

Clinical Trials

Study Demographics and Trial Design

Table 1: Summary of patient demographics for clinical trials for in vitro fertilization.

Table 1
Study Demographics and Trial Design
Study # Trial Design Dosage, Route of
Administration and Duration
Number
of
Subjects
Mean
Age
Range
Gender
IVF Study
0399E
Open-label, active
control, parallel-group,
randomized, multi-centre.
Menopur SC 75-450 IU QD
Gonal -F SC 75 -450 IU QD
727 18-38 Female
IVF Study
2000-02
Open-label, active
control, parallel-group,
randomized, multi-centre.
Menopur SC or IM 75-450 IU QD
Repronex SC 75-450 IU QD
190 18-39 Female
PK Study
2000-03
Randomized, open-label,
cross-over, parallel group,
multi-centre.
Two dosing groups (SC and IM)
Three Phases: (I, II, and III) spaced 7 days
apart.

Phase I and II: Single dose Menopur SC
or IM 225 IU.
Phase I and II: Single dose Repronex 225
IU SC and IM.

Phase III: Single dose Menopur SC or IM
225 IU.

225 IU on day 1 followed by 150 IU QD x
6 days
33 18-39 Female
BE Study
2003-02
Multi-centre, open-label,
randomized, single-dose,
two period cross-over
study.
US Menopur SC 400 IU
EU Menopur SC 400 IU Single dose; two 6-day testing periods each
preceded by a 15-28 day pre-treatment
period of Lupron Depot 3.75 mg IM
57 18-39 Female

The first trial (IVF Study 0399E) was designed to compare the safety and efficacy of the European formulation of Menopur, administered SC, to recombinant FSH (Gonal-F) in infertile women undergoing an IVF cycle. The second IVF Study 2000-02 compared the safety and efficacy of Menopur, administered SC or IM, to the earlier generation version of the product, Repronex, administered SC, in infertile women undergoing an IVF cycle.

Study Results

In the IVF study 0399E, Menopur was non-inferior to Gonal-F in terms of percentage of patients with an ongoing pregnancy in the treatment of women undergoing IVF/ICSI. This was true for both the ITT population and the PP population.

Table 2
Primary Efficacy Parameter - Patients with Ongoing Pregnancy - Intent to Treat IVF Study 0399E
Parameter Menopur
n = 373
Gonal-F
n = 354
95% CI1
of difference
p-value2
No. % No. %
Ongoing Pregnancy 87 23.3 73 20.6 -3.3, 8.7 0.42

1 Not adjusted for centre

2 Chi-Square test

Table 3
Primary Efficacy Parameter - Patients with Ongoing Pregnancy - Per Protocol IVF Study 0399E
Parameter Menopur
n = 357
Gonal-F
n = 336
95% CIg1
of difference
p-value2
No. % No. %
Ongoing Pregnancy 85 23.8 71 21.1 -3.5, 7.9 0.41

1 Not adjusted for centre

2 Chi-Square test

In the IVF study 2000-02, Menopur in terms of the primary efficacy parameter - the number of oocytes retrieved per cycle (patient), showed no statistically significant differences to Repronex SC in either the ITT or primary efficacy responder (received hCG) population as shown below.

Table 4
Primary Efficacy Parameter: Number Oocytes Retrieved – Intent to Treat IVF Study 2000-02
Parameter Menopur SC
n = 61
Repronex SC
n = 64
95% CI p-value
Mean SD Mean SD
Number of oocytes retrieved 13.1 ±7.2 14.4 ±7.7 -4.0 0.341
Number of mature oocytes
retrieved
9.9 ±4.8 10.9 ±7.0 0.621
Table 5
Primary Efficacy Parameter: Number Oocytes Retrieved Primary Efficacy Responders (Received hCG) IVF Study 2000-02
Parameter Menopur SC
n = 61
Repronex SC
n = 62
95% CI p-value1
Mean SD Mean SD
Number of oocytes retrieved 13.1 ±7.2 14.9 ±7.4 -4.3 0.188
Number of mature oocytes
retrieved
9.9 ±4.8 11.2 ±6.8 0.209

Study 2003-02 was conducted to assess bioequivalence between the US and EU Menopur formulation after subcutaneous injection in female subjects. The data from this study demonstrated that the pharmacokinetic profile of US Menopur was similar to that of EU Menopur. The mean serum FSH parameters from the 52 subjects (Cmax, AUC0-120 and Tmax) after subcutaneous administration of the US Menopur and EU Menopur are presented in Table 6 below.

Table 6
Mean* (+ SD) Values and Comparisons for Baseline Corrected** Serum FSH Concentrations Study 2003-02
EU Menopur US Menopur Test/Ref 90% CI
Cmax
(mIU/mL)
11.43±2.31 10.59±3.07 92.72% 83.19 - 103.34%
AUC0-120
(mIU·hr/mL)
675.70±162.53 651.65±182.89 96.44% 84.93 - 109.53%
Tmax
(hr)
18.85±6.96 19.32±6.27 102.48% 86.52 - 118.44%

* Reported values are least squared means

** Baseline correction is done by subtracting the mean of pre study baseline concentrations

Detailed Pharmacology

Pharmacodynamics

Assisted Reproductive Technologies (ART)

The efficacy and safety of Menopur have been established in two randomized, controlled clinical studies, 0399E and 2000-02, of women undergoing in vitro fertilization (IVF) or IVF plus intracytoplasmic injection to achieve pregnancy.

Study 0399E was a Phase III, randomized, open-label, multicenter, multinational (in Europe and Israel), comparative clinical trial of ovulatory, infertile females undergoing ovarian stimulation to produce multiple follicles for IVF and embryo transfer (IVF/ET) after pituitary suppression with a GnRH agonist. A total of 727 patients were enrolled. Three hundred seventy three (373) patients were randomized to the Menopur arm and three hundred fifty four (354) were randomized to the Gonal-F arm. Randomization was stratified by insemination technique [conventional in-vitro fertilization (IVF) vs. intra-cytoplasmic sperm injection (ICSI)]. Efficacy was assessed based on the primary efficacy parameter of continuing pregnancy. The initial daily dose of Menopur was 225 IU SC for five days. Thereafter, the dose was individualized according to each patient's response, up to a maximum of 450 lU/day for a total maximum duration of stimulation of 20 days. Treatment outcomes are summarized in Table 7.

Table 7: Efficacy Outcomes for IVF Study 0399E (one cycle of treatment)
Parameter Menopur SC
n=373
Gonal F SC
n=354
Average Number of Days of Stimulation 11.5 11.5
Mean Number of Vials/Ampoules Used 37 37
Mean Peak Serum E2 (pg/mL) 2213 1700
Mean Total Oocytes Retrieved Per Patient 13 14
Oocyte Retrieval (%) 361 (97) 339 (96)
Embryo Transfer (%) 336 (90) 316 (89)
Chemical Pregnancy (%) 119 (32) 101 (29)
Clinical Pregnancy (%) 98 (26) 78 (22)
Continuing Pregnancy (%) 87 (23) 87 (23)

Study 2000-02 was an open label, parallel group, randomized study in women undergoing in vitro fertilization. A total of 190 patients were randomized, of whom 126 received Menopur (Menopur SC n=61 and Menopur IM n=65). All patients received luteal phase GnRH agonist pituitary suppression and underwent controlled ovarian stimulation at an initial daily dose of 225 IU for five days. Thereafter, the dose was individualized according to each patient’s response, up to a maximum of 450 IU/day for a total maximum duration of stimulation of 12 days. When transvaginal ultrasound showed ≥3 follicles of diameter ≥16 mm with a clinically appropriate serum E2 level, hCG was administered (10,000 IU) and oocytes were retrieved approximately 36 hours later. One to four embryos were transferred.

The primary efficacy outcome was the total number of oocytes retrieved following the administration of hCG. Treatment outcomes are summarized in Table 8.

Table 8: Efficacy Outcome for IVF Study 2000-02 (one cycle of treatment)
Parameter Menopur SC
n = 61
Average Number of Days of Stimulation 9.6
Mean Number of Vials/Ampoules Used 35
Mean Peak Serum E2 (pg/mL) 2007
Mean Total Oocytes Retrieved Per Patient 13
Mean Mature Oocytes Retrieved Per Patient 10
Oocyte Retrieval (%) 61 (100)
Embryo Transfer (%) 57 (93)
Chemical Pregnancy (%) 24 (39)
Clinical Pregnancy (%) 18 (30)
Continuing Pregnancy (%) 18 (30)
Patients with Live Births (%) 12 (20)

Calculated from mean total dose/75 IU (Menopur SC=2625/75 IU)

A comparison in terms of the numbers of oocytes retrieved in the IVF studies 0399E and 2000-02 between Menopur SC and Repronex SC is shown in Table 9.

Table 9
Mean Number of Oocytes Retrieved
Intent To Treat
Controlled Study Menopur SC
n=61
Repronex SC
n=64
p-value
IVF Study 2000-02 13.1 14.4 0.341
n=373 Gonal-F SC
n=354
IVF Study 0399E 12.4 13.4 0.1261

1 From t-test

Comparisons in terms of the percentage of patients (cycles) with chemical, clinical and continuing pregnancies in the IVF studies 0399E and 2000-02, between Menopur SC and Repronex SC are shown in Tables 10, 11, and 12.

Table 10
Patients with Chemical1 Pregnancy Intent To Treat
Controlled Study n Menopur SC Repronex SC p-value2
No. % No. %
IVF Study
2000-02
190 24 39.3 32 50 0.231
Gonal-F SC
IVF Study 0399E 727 119 31.9 101 28.5 0.320

1 Positive serum βhCG

2 From between groups ANOVA for studies 2000-01 and -02, and from Chi-Square test for MKF/IVF/0399E

Table 11
Patients with Clinical1 Pregnancy Intent To Treat
Controlled Study n Menopur SC Repronex SC p-value2
No. % No. %
IVF Study
2000-02
190 18 29.5 26 40.6 0.193
Gonal-F SC
IVF Study 0399E 727 98 26.3 78 22.0 0.190

1 Ultrasound showing intrauterine sac

2 From between groups ANOVA for studies 2000-01 and -02, and from Chi-Square test for MKF/IVF/0399E

Table 12
Patients with Continuing1 Pregnancy Intent To Treat
Controlled Study n Menopur SC Repronex SC p-value2
No. % No. %
IVF Study
2000-02
190 18 29.5 24 37.5 0.344
Gonal-F SC
IVF Study 0399E 727 87 23.3 73 20.6 0.42

1 Ultrasound showing intrauterine sac and fetal heart motion

2 From between groups ANOVA for studies 2000-01 and -02, and from Chi-Square test for MKF/IVF/0399E

A comparison between Menopur, Repronex and Gonal-F with respect to the major secondary endpoint of serum estradiol level, is illustrated in Table 13.

Table 13
Mean Peak Serum E2 Levels pg/mL (Intent To Treat Population)
Controlled Study n Menopur SC Repronex SC p-value1
Mean SD Mean SD
FPI Purified Repronex
2000-02
190 2007.1 1008.3 2462.8 1483.1 0.053
Gonal-F SC
MFK/IVF/0399E 6792 2213.03 1614.5 1700.0 1203.8 0.001

1 For the US study, from one-way ANOVA. For the multinational study, from Wilcoxon Rank Sum Test

2 Forty-eight patients from the ITT population did not have estradiol data available on the day of hCG administration; therefore the n was reduced to 679

3 A conversion factor of 3.671 was used to convert pmol/mL to pg/mL

The number of days of stimulation required to reach hCG criteria and total dose of gonadotropin administered in the IVF studies 0399E and 2000-02 between Menopur SC and Repronex SC are presented in Tables 14 and 15.

Table 14
Number of Days to Meet hCG Criteria
Controlled Study n Menopur SC Repronex SC p-value1
Mean SD Mean SD
FPI Purified Repronex
2000-02
190 9.60 1.40 9.4 1.40 0.356
Gonal-F SC
MFK/IVF/0399E 727 11.54 1.91 11.52 2.00 0.860

1 From one-way ANOVA

Table 15
Average Total Dose of Gonadotropin
Controlled Study n Menopur SC Repronex SC p-value1
Mean SD Mean SD
FPI Purified Repronex
2000-02
190 2625.0 847.7 2463.3 831.3 0.297
Gonal-F SC
MFK/IVF/0399E 727 2767.52 --- 2775.03 --- 0.850

1 For the US studies, from one-way ANOVA. For the multinational study, from Wilcoxon Rank Sum Test

2 Calculated from mean number of vials/ampoules used - 36.0 x 75 IU/vial

3 Calculated from mean number of vials/ampoules used - 37.0 x 75 IU/vial