The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may occur.
The effects of an overdose of Gonal Fin alfa are unknown, nevertheless, there is a possibility that OHSS may occur.
The effects of an overdose of follitropin alfa are unknown, nevertheless, there is a possibility that OHSS may occur.
Aside from possible ovarian hyperstimulation and multiple gestations , little is known concerning the consequences of acute overdosage with BRAVELLE®.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.
The safety of BRAVELLE® was examined in four clinical studies that enrolled a total of 222 women who received BRAVELLE®.
Ovulation InductionIn a randomized, multi-center, active controlled study, a total of 72 women received BRAVELLE® (35 in a subcutaneous administration arm and 37 in an intramuscular administration arm) for induction of ovulation. Adverse reactions occurring at an incidence of ≥ 2% incidence in women receiving BRAVELLE® are shown in Table 1.
Table 1: Ovulation Induction Safety Profile
| Adverse Events (%) | All Patients with Adverse Events ≥ 2% | |
| BRAVELLE® subcutaneous N=35 | BRAVELLE® intramuscular N=37 | |
| Genitourinary/Reproductive | ||
| OHSS | 4 (11.4) | 2 (5.4) |
| Vaginal Hemorrhage | 3 (8.6) | 0 (0.0) |
| Ovarian Disorder (Pain, Cyst) | 1 (2.9) | 3 (8.1) |
| Urinary tract infection | 0 | 1 (2.7) |
| Cervix disorder | 1 (2.9) | 0 |
| Gastrointestinal | ||
| Nausea | 2 (5.7) | 0 (0.0) |
| Enlarged Abdomen | 1 (2.9) | 1 (2.7) |
| Abdominal Pain | 1 (2.9) | 2 (5.4) |
| Vomiting | 0 | 1 (2.7) |
| Constipation | 0 | 1 (2.7) |
| Diarrhea | 0 | 1 (2.7) |
| Metabolic/Nutritional | ||
| Dehydration | 0 | 1 (2.7) |
| Weight gain | 1 (2.9) | 0 |
| Skin/Appendages | ||
| Acne | 1 (2.9) | 0 |
| Exfoliative dermatitis | 0 | 1 (2.7) |
| Other Body Systems | ||
| Headache | 4 (11.4) | 3 (8.1) |
| Pain | 2 (5.7) | 0 (0.0) |
| Neck pain | 0 | 1 (2.7) |
| Respiratory Disorder | 2 (5.7) | 0 (0.0) |
| Hot Flashes | 2 (5.7) | 0 (0.0) |
| Fever | 0 | 1 (2.7) |
| Hypertension | 0 | 1 (2.7) |
| Emotional lability | 0 | 1 (2.7) |
| Depression | 0 | 1 (2.7) |
| Accidental injury | 0 | 1 (2.7) |
Three studies examined the safety profile of BRAVELLE® in ART. A total of 150 women received treatment with BRAVELLE® in these studies. Adverse reactions occurring at an incidence of ≥ 2% incidence for this integrative assessment are presented in Table 2.
Table 2: Integrated IVF Safety Profile
| All Patients with Adverse Events ≥ 2% | |
| Adverse Events (%) | BRAVELLE® subcutaneous N=150 |
| Genitourinary/Reproductive | |
| Vaginal hemorrhage | 7 (4.7) |
| Post retrieval pain | 12 (8.0) |
| Pelvic pain/cramps | 10 (6.7) |
| OHSS | 9 (6.0) |
| Uterine spasms | 4 (2.7) |
| Vaginal spotting | 4 (2.7) |
| Urinary tract infection | 5 (3.3) |
| Ovarian disorder | 3 (2.0) |
| Breast tenderness | 3 (2.0) |
| Vaginal Discharge | 4 (2.7) |
| Infection fungal | 3 (2.0) |
| Gastrointestinal | |
| Abdominal cramps | 21 (14.0) |
| Nausea | 13 (8.7) |
| Abdominal pain | 7 (4.7) |
| Abdominal fullness/enlargement | 10 (6.7) |
| Constipation | 3 (2.0) |
| Other Body Systems | |
| Headache | 19 (12.7) |
| Pain | 8 (5.3) |
| Rash | 4 (2.7) |
| Respiratory disorder | 6 (4.0) |
| Sinusitis | 3 (2.0) |
| Injection site reaction | 6 (4.0) |
| Hot flash | 6 (4.0) |
| Emotional lability | 3 (2.0) |
The following adverse reactions have been reported during postmarketing use of gonadotropins. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to BRAVELLE® cannot be reliably determined.
Gastrointestinal disorders: Abdominal pain, Nausea, Vomiting, Abdominal distension, Abdominal discomfort, Diarrhea, Constipation
General disorders and administration site conditions: Pain, Injection site reactions (redness, bruising, swelling and/or pruritus)
Infections and infestations: Urinary tract infection, Nasopharyngitis
Musculoskeletal and connective tissue disorders: Muscle spasm
Nervous system disorders: Headache
Reproductive system disorders: Vaginal hemorrhage, OHSS , Pelvic pain, Breast tenderness, Vaginal discharge. Ovarian enlargement, Multiple pregnancies
Skin and subcutaneous tissue disorders: Rash
Vascular disorders: Hot flushes
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.
In rabbits, the formulation reconstituted with 0.9 % benzyl alcohol and 0.9 % benzyl alcohol alone, both resulted in a slight haemorrhage and subacute inflammation after single subcutaneous injection or mild inflammatory and degenerative changes after single intramuscular injection respectively.
Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.
Given in high doses (> 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being a teratogen, and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since GONAL-f is not indicated in pregnancy, these data are of limited clinical relevance.
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.
Impaired fertility has been reported in rats exposed to pharmacological doses of Gonal Fin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.
Given in high doses (> 5 IU/kg/day) Gonal Fin alfa caused a decrease in the number of viable foetuses without being a teratogen and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since Ovaleap is not indicated in pregnancy, these data are of limited clinical relevance.
Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.
Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (> 40 IU/kg/day) for extended periods, through reduced fecundity.
Given in high doses (> 5 IU/kg/day) follitropin alfa caused a decrease in the number of viable foetuses without being a teratogen and dystocia similar to that observed with urinary Menopausal Gonadotropin (hMG). However, since Ovaleap is not indicated in pregnancy, these data are of limited clinical relevance.
Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.
In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.
Clinical efficacy and safety in women
In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.
In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.
Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of GONAL-f with urinary FSH in assisted reproduction technologies)
| GONAL-f (n = 130) | urinary FSH (n = 116) | |
| Number of oocytes retrieved | 11.0 ± 5.9 | 8.8 ± 4.8 |
| Days of FSH stimulation required | 11.7 ± 1.9 | 14.5 ± 3.3 |
| Total dose of FSH required (number of FSH 75 IU ampoules) | 27.6 ± 10.2 | 40.7 ± 13.6 |
| Need to increase the dose (%) | 56.2 | 85.3 |
Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.
Clinical efficacy and safety in men
In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.
Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.
Ovaleap is a biosimilar medicinal product.Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Pharmacodynamic effects
In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of Gonal Fin alfa therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.
Clinical efficacy and safety in women
In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.
In clinical studies comparing r-hFSH (Gonal Fin alfa) and urinary FSH in ART (see table 3 below) and in ovulation induction, Gonal Fin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
In ART, Gonal Fin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.
| Table 3: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of Gonal Fin alfa with urinary FSH in ART) | ||
| Gonal Fin alfa (n = 130) | urinary FSH (n = 116) | |
| Number of oocytes retrieved | 11.0 ± 5.9 | 8.8 ± 4.8 |
| Days of FSH stimulation required | 11.7 ± 1.9 | 14.5 ± 3.3 |
| Total dose of FSH required (number of FSH 75 IU ampoules) | 27.6 ± 10.2 | 40.7 ± 13.6 |
| Need to increase the dose (%) | 56.2 | 85.3 |
| Differences between the 2 groups were statistically significant (p < 0.05) for all criteria listed. | ||
Clinical efficacy and safety in men
In men deficient in FSH, Gonal Fin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis.
Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.
Ovaleap is a biosimilar medicinal product.Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Pharmacodynamic effects
In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of follitropin alfa therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.
Clinical efficacy and safety in women
In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.
In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table 3 below) and in ovulation induction, follitropin alfa was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.
In ART, follitropin alfa at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.
| Table 3: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of follitropin alfa with urinary FSH in ART) | ||
| follitropin alfa (n = 130) | urinary FSH (n = 116) | |
| Number of oocytes retrieved | 11.0 ± 5.9 | 8.8 ± 4.8 |
| Days of FSH stimulation required | 11.7 ± 1.9 | 14.5 ± 3.3 |
| Total dose of FSH required (number of FSH 75 IU ampoules) | 27.6 ± 10.2 | 40.7 ± 13.6 |
| Need to increase the dose (%) | 56.2 | 85.3 |
| Differences between the 2 groups were statistically significant (p < 0.05) for all criteria listed. | ||
Clinical efficacy and safety in men
In men deficient in FSH, follitropin alfa administered concomitantly with hCG for at least 4 months induces spermatogenesis.
Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.
Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Following intravenous administration, Gonal Fin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the Gonal Fin alfa dose is excreted in the urine.
Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, Gonal Fin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, Gonal Fin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.
Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Single doses of 225 International Units and multiple daily doses (7 days) of 150 International Units of BRAVELLE® were administered to healthy volunteer female subjects while their endogenous FSH was suppressed. Sixteen subjects received BRAVELLE® subcutaneously and 12 received the drug intramuscularly. Serum FSH concentrations were determined. Based on the steady state ratio of FSH C max and AUC, subcutaneous and intramuscular administration of BRAVELLE® were not bioequivalent. Multiple doses of BRAVELLE® intramuscular resulted in C max and AUC of 77.7% and 81.8% compared to multiple doses of BRAVELLE® subcutaneous. The FSH pharmacokinetic parameters for single and multiple dose BRAVELLE®, administered subcutaneously and intramuscularly are in Table 3.
Table 3: FSH Pharmacokinetic Parameters (Mean ± SD) Following BRAVELLE® Administration
| PK Parameters | Single Dose (225 IU) | Multiple Dose X 7 (150 IU) | ||
| Subcutaneous | Intramuscular | Subcutaneous | Intramuscular | |
| Cmax (mIU/mL) | 6.0 (1.7) | 8.8 (4.5) | 14.8 (2.9) | 11.5 (2.9) |
| Tmax (hrs) | 20.5 (7.7) | 17.4 (12.2) | 9.6 (2.1) | 11.3 (8.4) |
| AUC obs (mIU•hr/mL) | 379 (111) | 331 (179) | 234.7 (77.0) | 192.1 (52.3) |
| t½ (hrs) | 31.8 | 37 | 20.6 | 15.2 |
The subcutaneous route of administration trends toward greater bioavailability than the IM route for single and multiple doses of BRAVELLE®.
DistributionHuman tissue or organ distribution of FSH has not been studied for BRAVELLE®.
MetabolismMetabolism of FSH has not been studied for BRAVELLE® in humans.
EliminationThe mean elimination half-lives of FSH for subcutaneous and intramuscular single dosing are 31.8 and 37 hours, respectively. However, following multiple dosing (X 7 days) they are 20.6 and 15.2 hours for SC and IM, respectively.
No special requirements for disposal.
The solution must not be used if it contains particles or if the solution is not clear.
Ovaleap is designed for use in conjunction with the Ovaleap Pen only. The instructions for use of the pen must be followed carefully.
Each cartridge must be used by a single patient only.
Empty cartridges must not be refilled. Ovaleap cartridges are not designed to allow any other medicinal product to be mixed in the cartridges. Discard used needles immediately after injection.
