Ovidrel - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Ovidrel - Scientific Information

Manufacture: EMD Serono, Inc
Country: Canada
Condition: Female Infertility, Hypogonadism, Male, Ovulation Induction, Prepubertal Cryptorchidism
Class: Gonadotropins
Form: Liquid solution, Subcutaneous (SC)
Ingredients: choriogonadotropin alfa, mannitol, phosphoric acid, methionine, poloxamer 188, sodium hydroxide, water.

Pharmaceutical Information

Proper or Common Name: Choriogonadotropin alpha for injection
Chemical Name: Not applicable
Structural Formula: The full amino acid sequence is as follows:
The α-subunit:
Ala-Pro-Asp-Val-Gln-Asp-Cys-Pro-Glu-Cys-Thr-Leu-Gln-Glu-Asn- Pro
Phe-Phe-Ser-Gln-Pro-Gly-Ala-Pro-Ile-Leu-Gln-Cys-Met-Gly-Cys-Cys
Phe-Ser-Arg-Ala-Tyr-Pro-Thr-Pro-Leu-Arg-Ser-Lys-Lys-Thr-Met-Leu
Val-Gln-Lys-Asn-Val-Thr-Ser-Glu-Ser-Thr-Cys-Cys- Val-Ala-Lys-Ser
Tyr-Asn-Arg-Val-Thr-Val-Met-Gly-Gly-Phe-Lys-Val-Glu-Asn-His-Thr
Ala-Cys-His-Cys-Ser-Thr-Cys-Tyr-Tyr-His-Lys-Ser
The β-subunit:
Ser-Lys-Glu-Pro-Leu-Arg-Pro-Arg-Cys-Arg-Pro-Ile-Asn-Ala-Thr-Leu
Ala-Val-Glu-Lys-Glu-Gly-Cys-Pro-Val-Cys-Ile-Thr-Val-Asn-Thr-Thr-Ile
Cys-Ala-Gly-Tyr-Cys-Pro-Thr-Met-Thr-Arg-Val-Leu-Gln-Gly-Val-Leu
Pro-Ala-Leu-Pro-Gln-Val-Val-Cys-Asn-Tyr-Arg-Asp-Val-Arg-Phe-Glu
Ser-Ile-Arg-Leu-Pro-Gly-Cys-Pro-Arg-Gly-Val-Asn-Pro-Val-Val-Ser-Tyr
Ala-Val-Ala-Leu-Ser-Cys-Gln-Cys-Ala-Leu-Cys-Arg-Arg-Ser-Thr-Thr
Asp-Cys-Gly-Gly-Pro-Lys-Asp-His-Pro-Leu-Thr-Cys-Asp-Asp-Pro-Arg
Phe-Gln-Asp-Ser-Ser-Ser-Ser-Lys-Ala-Pro-Pro-Pro-Ser-Leu-Pro-Ser-Pro
Ser-Arg-Leu-Pro-Gly-Pro-Ser-Asp-Thr-Pro-Ile-Leu-Pro-Gln
Molecular Weight: 70 kDa
pH: pH 6.5-7.5
Bioactivity: A dose of 250 µg is equivalent to approximately 6,500 IU.

Composition

Solution for Injection in a pre-filled syringe

Ovidrel (choriogonadotropin alpha injection) is a sterile liquid intended for subcutaneous (s.c.) injection. Each pre-filled syringe of Ovidrel contains 250 µg of choriogonadotropin alpha, 27.3 mg of mannitol, 0.49 mg of phosphoric acid, 0.1mg of L-methionine, 0.05mg of Poloxamer 188, sodium hydroxide (for pH adjustment) and water for injection to 0.5ml.

Solution for Injection in a pre-filled pen

Ovidrel (choriogonadotropin alpha injection) is a sterile liquid intended for subcutaneous (s.c.) injection. Each pre-filled pen of Ovidrel contains 250 µg of choriogonadotropin alpha, 27.3 mg of mannitol, phosphoric acid (qs to pH 7.0± 0.2), 0.1 mg of L-methionine, 0.05 mg of Poloxamer 188, sodium hydroxide (qs to pH 7.0± 0.2), 0.56 mg of disodium hydrogen phosphate dihydrate, 0.23 mg of sodium dihydrogen phosphate monohydrate and water for injection to 0.5 ml.

Stability and Storage Recommendations

Refer to the date indicated on the labels for the expiry date. Do not use after expiry date. Do not freeze. Store in the original package. Protect from light.

Ovidrel in pre-filled syringes is to be stored at 2-8°C (in a refrigerator). The patient may store the pre-filled syringe at 25°C (room temperature) for up to 30 days, however after this time the pre-filled syringe should be discarded.

Ovidrel in pre-filled pens is to be stored at 2-8°C (in a refrigerator).

Reconstituted Solutions

Solution for Injection: The solution in the pre-filled syringe or pre-filled pen is ready for use. Single use only.

Parenteral Products

The pre- filled syringe solution or pre-filled pen solution should not be administered if it contains particles or is not clear. Administration by the subcutaneous route.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Availability of Dosage Form

Ovidrel (choriogonadotropin alpha) is supplied in three formats:

  • Sterile solution in a ready-to-use pre-filled syringe containing 250 µg of r-hCG.
  • Sterile solution in a ready-to-use pre-filled pen containing 250 µg of r-hCG.
  • Sterile, lyophilised single dose vial containing 285 µg of r-hCG to deliver 250 µg of r-hCG, after reconstitution with the diluent.

The following package combinations are available:

  • 1 pre-filled syringe of 250 µg Ovidrel solution for Injection
  • 1 pre-filled pen of 250 µg Ovidrel solution for Injection and 1 needle to be used with the pen for administration
  • 1 vial of 250 µg Ovidrel and 1 vial or ampoule of 1 mL Sterile Water for Injection, USP/Ph.Eur.
  • 10 vials of 250 µg Ovidrel and 10 vials or ampoules of 1 mL Sterile Water for Injection, USP/Ph.Eur.

The product is to be administered subcutaneously.

Pharmacology

Animal

Pharmacodynamics

The in vivo and in vitro experiments have shown that r-hCG has the same binding affinity to the LH/hCG receptor on MA 10 cells as u-hCG, it stimulates progesterone production by those cells with the same potency as u-hCG and several national and international reference standards, it had the same potency as several reference standards and u-hCG in Ph. Eur. and USP bioassays in the rat, and, in a detailed test in the primed adult female rhesus monkey, r- and u-hCG stimulated the production of oocytes of the same maturity, and exerted the same hormonal activities on luteinisation of ovarian follicles. The time course of the actions of r-hCG and u-hCG were identical in the in vivo studies.

Taken together, these results show the quantitative, functional identity of r-hCG and u-hCG by a number of independent means. The experiment in the rhesus monkey has also demonstrated that r-hCG has the intended pharmacodynamic action as it was a close model of its clinical use to induce ovulation and to produce oocytes of sufficient maturity to be capable of being fertilized.

With regards to the general pharmacology, r-hCG had no particular effect on the functioning of the cardiovascular and respiratory systems.

These findings were also supported by the acute toxicity tests which did not indicate any action on the CNS or PNS, and the lack of clinical signs in those experiments and the repeat dose toxicity tests is a reasonable indication that r-hCG does not affect smooth muscle or the gastrointestinal tract.

All these findings together permit a reasonable assessment of the general pharmacological actions of r-hCG. It does not exhibit actions of this type that suggest a risk to humans.

Pharmacokinetics

Formal pharmacokinetic studies and the results of toxicokinetic investigations have shown that the kinetics of r-hCG in the Cynomolgus monkey is relatively straightforward. r-hCG is rapidly distributed through the central compartment and slowly cleared by metabolism and renal excretion of molecular fragments. The kinetics was linear with dose. Bioavailability after s.c. and i.m. injection was very high at 85 and 100%, respectively. As expected from an elimination half-life of about 23h in that species, there was a slight increase in plasma concentration on repeat daily dosing, steady state being reached after 3 days.

AUC, corrected for dose, was higher in man than in monkeys after single i.v. administration. A similar difference was found after single s.c. doses but it was blunted after repeat injections. Recombinant hCG and u-hCG had similar kinetics in the monkeys after i.v. injection. No formal metabolism study has been done, but reports from the literature about humans indicate that proteolysis to presumed inactive fragments which are largely excreted in the urine occurs quite rapidly.

Even after a few single doses by various routes, and more often after repeat doses, antibodies to r-hCG developed in the monkey, which sometimes sharply accelerated clearance from the circulation.

Although metabolism of r-hCG in animals has not been examined, there is evidence from man, and from the investigation of the related 125I-r-hLH in the rat, to suggest that the fate of the molecule is similar in animals and man.

The limited information about metabolism, and the absence of data on protein binding, should be considered in relation to the pattern of human treatment, which will involve only a single administration, and the demonstration of the intended pharmacodynamic activity in vivo.

Human

Pharmacokinetics

The pharmacokinetics of Ovidrel was studied in healthy male and female volunteers both after intravenous administration at a dose of 270 µg (GF7012) and after single subcutaneous administration at a dose of 132 µg (GF7013) or 250 µg (IMP23286).

Pharmacokinetic parameter estimates following single SC administration of Ovidrel to males and females are presented in Table 1.

Table 1: Pharmacokinetic Parameters (mean ± SD) of r-hCG after Single Dose (132 or 250 µg) Subcutaneous Administration of Ovidrel in Healthy Male and Female Volunteers (GF7013 and IMP23286)
Pharmacokinetic Parameter Single dose @ 132 µg
Freeze-dried
(GF7013)
Single dose @ 250 µg
Freeze-dried
(IMP23286)
Single dose @ 250 µg
Liquid
(IMP23286)
Male Female Male Female Male Female
Cmax (µg/L) 4.10 ± 1.40 4.26 ± 0.21 5.78 ± 1.59 8.10 ± 3.35 5.62 ± 1.54 7.10 ± 2.99
Tmax (h)* 18 (12-24) 18 (12-24) 24 (12-48) 24 (9-48) 16 (9-48) 22 (12-48)
AUC (h*µg/L) 250 ± 61 290 ± 30 523 ± 108 609 ± 214 498 ± 129 560 ± 148
T1/2 (h) 27 ± 6 28 ± 7 39 ± 4 37 ± 3 40 ± 4 37 ± 6
F 0.37 ± 0.11 0.40 ± 0.10 # # # #

Cmax: peak concentration (above baseline), tmax: time of Cmax, AUC: total area under the curve, t½: apparent elimination half-life, F: bioavailability, * median (range), # not evaluated in IMP23286

The absorption, distribution and metabolism/excretion in healthy females only are described hereafter.

Absorption

Following a single subcutaneous administration of Ovidrel 250 µg to healthy female

volunteers (IMP23286), the maximum serum concentration (7.10 ± 2.99 µg/L) is reached after approximately 12 to 48 hours. The mean absolute bioavailability of Ovidrel following a single subcutaneous injection to healthy female volunteers at the dose of 132 µg (GF7013) is about 40%.

Distribution

Following a single intravenous administration of Ovidrel at the dose of 270 µg to healthy female volunteers (GF7012), the serum profile of hCG is described by a two-compartment model with a distribution half-life of 4.5 ± 0.5 hours. The steady state volume of distribution is 5.8 ± 1.0 L.

Following repeated subcutaneous administration of Ovidrel 132 µg to healthy female volunteers (one administration every 48 hours, GF7013), the accumulation ratio is 1.61 ± 0.40.

Metabolism/Excretion

After a single intravenous administration of Ovidrel 270 µg to healthy female volunteers (GF7012), the mean terminal half-life is 27 ± 3 hours and the total body clearance is 0.29 ± 0.04 L/h. The exposure is linear in the range 25 – 1000 µg. One-tenth of the dose is excreted in the urine. After single subcutaneous administration of Ovidrel 250 µg to healthy female volunteers

(IMP23286), the apparent terminal half-life is 37 ± 6 hours.

Bioequivalence of Formulations

Ovidrel liquid has been determined to be bioequivalent to Ovidrel freeze-dried formulation based on the statistical evaluation of AUCT (AUC up the last measurable sampling time) and Cmax (IMP23286). A summary of the Ovidrel freeze-dried and liquid ratios (test/reference) and 90% confidence intervals calculated from the ANOVA (on AUCT and Cmax after log transformation) and corrected for the measured content is presented in Table 2.

Table 2: Ovidrel Liquid vs. Freeze-dried Estimates Based on Correction for Measured Content
Liquid r-hCG Freeze dried r-hCG
Lot Number VGS101 BZ008A
Expiry date 30 April 2002 30 November 2002
Label claim 250 µg / 0.5 mL 250 µg / vial
Measured content 256.4 µg / 0.5 mL 270 µg / mL
Measured content as % of label claim 102.56% 108.0%

Based on the measured content the following factor is obtained:

Ln (108/102.56) = 0.05168

AUC ratio = 103.3%

  • Lower Limit = 95.5%
  • Upper Limit = 111.8%

Cmax ratio = 103.4%

  • Lower Limit = 89.8%
  • Upper Limit = 119.0%

Clinical Studies

The safety and efficacy of Ovidrel (choriogonadotropin alpha) have been examined in four well-controlled studies in women; three studies for assisted reproductive technologies and one study for ovulation induction (OI).

The safety and efficacy of Ovidrel 250 µg administered subcutaneously versus 5,000 IU of an approved urinary-derived hCG product administered subcutaneously were assessed in a double-blind, randomized, multicenter study in anovulatory infertile women (Study 8209) which was conducted in 19 centers in Australia, Canada, Europe, Switzerland and Israel. The primary efficacy parameter in this single-cycle study was the patient ovulation rate. 242 patients entered the study, of whom 99 received Ovidrel 250 µg. The efficacy of Ovidrel 250 µg was found to be clinically and statistically equivalent to that of the approved urinary-derived hCG product. The results of those patients who received Ovidrel 250 µg are summarized in Table 4.

Table 3: Efficacy Outcomes of r-hCG in OI (Study 8209)
Parameter OVIDREL250 µg (n = 99)
Ovulation Rate 91 (91.9%)
Clinical Pregnancy Rate 22 (22%)

Clinical pregnancy, defined as a pregnancy during which a fetal sac (with or without heartbeat activity) was detected by ultrasound on day 35-42 after hCG administration.

For the 22 patients who had a clinical pregnancy with Ovidrel 250 µg, the outcome of the pregnancy is presented in Table 5.

Table 4: Pregnancy Outcomes of r-hCG in OI (Study 8209)
Parameter OVIDREL 250 µg (n = 22)
Clinical pregnancies not reaching term 7 (31.8%)
Live births 15 (68.2%)
  Singleton 13 (86.7%)
  Multiple birth 2 (13.3%)

The trials demonstrated that the 250 µg dose of Ovidrel was associated with a lower risk of OHSS, while the 500 µg dose of Ovidrel was significantly more stimulatory to the ovary than the lower dose. However, there was no demonstrable benefit in terms of pregnancy or pregnancy outcome.

Toxicology

Recombinant hCG had almost no effect in the single dose studies apart from the predictable pharmacological action on the gonads in the sexually mature rat. The occurrence of antibodies in animals is of no concern as the protein is of human type and will therefore be treated as a foreign antigen.

The subacute tests in the monkey and rat have shown only the anticipated endocrine effects of high doses of this potent gonadotrophin, including some of the known oestrogenic actions in the rat. Antibodies were formed after a few weeks both in the rat and monkey, which greatly accelerated clearance of the injected r-hCG but did not completely reverse the endocrine actions during continued dosing. The effects all disappeared completely or almost so during the 4-week recovery period. There was almost no reaction at the injection sites.

Administration of r-hCG at up to 5,000 U (250 µg)/kg/d, s.c. for up to 26 weeks, to sexually mature male Cynomolgus monkeys, of u-hCG 500 U/kg/d s.c. again for 26 weeks and of up to 20,000 U (1,000 µg)/kg/d s.c. to the rat for up to 4 weeks, has not revealed any specific toxic actions.

There have been extensive pharmacodynamic actions, due both to the direct effect of the hCGs and, in the longer term experiments, to the secondary actions of the stimulated production of testosterone in males and oestrogens in females (rats only), always in a dose–related manner. They have comprised effects on body growth in the monkey, on the male and female gonads in both species, and on the pituitary and certain secondary sex organs in both sexes. When assessed after the 4-week studies, the actions have been largely reversed.

The injection sites showed only slight inflammatory cell infiltration. In the 26-week test, the production, morphology and functionality of sperm were normal. In the monkey, serum antibodies to r- and u-hCG appeared in a dose related manner, more often after s.c. than i.v. dosing, usually becoming detectable after about 2 weeks, and being present in most or all animals after 4-12 weeks. Despite their presence, the effects of the hCGs were maintained and serum levels could still be measured even after 26 weeks.

Given that a heterologous protein has been tested, albeit in responsive species, it is apparent that r-hCG has the same biological actions as u-hCG in these experiments, that it lacks any conventional target organ toxicity, and that antibody formation has not led either to neutralisation of its actions or to immune complex disease.

The overall pattern of toxicity findings, therefore, is that of high dose pharmacodynamic actions under circumstances remote from human experience, and with the same actions occurring after the new r-hCG and the identical u-hCG, which is already well-studied and has been extensively used by patients for many years.

The extent of our knowledge of the effects of u-hCG in humans is a good reason why the lack of a formal chronic toxicity test in the rodent does not represent a serious weakness in the studies of r-hCG. Further the present application is only for a single-dose administration per fertility treatment, and women undergo only a limited number of fertility treatments.