Puregon: Male and female infertility treatment

2021-06-08 09:21 PM

Puregon is indicated for the treatment of female infertility. Decreased spermatogenesis due to hypogonadism due to decreased gonadotropins Puregon therapy should be initiated under the supervision of a physician experienced in the treatment of infertility.

Producer

Organon.

Ingredient

Per cartridge: Follitropin beta (FSH) 300 IU or 600 IU.

Each 0.5mL vial: Follitropin beta (FSH) 50 IU or 100 IU.

Describe

Clear and colorless solution.

Dosing tube (cartridge)

The pH can be adjusted with sodium hydroxide and/or hydrochloric acid.

The cartridges are designed for use with injection pens.

Each metered dose tube (cartridge) contains a total net dose of 300 IU or 600 IU of active Follicle-stimulating hormone (FSH) in 0.36 or 0.72 mL of solution.

The solution for injection containing the active ingredient follitropin beta is produced by genetic engineering of the Chinese Hamster Ovary (CHO cell line) at a concentration of 833 IU/mL of solution. This concentration corresponds to 83.3 micrograms of protein/mL (specific in vivo bioactivity is equivalent to about 10,000 IU FSH/mg protein).

Vial form

Each vial contains 50, 100 IU of active recombinant follicle-stimulating hormone (FSH) in a 0.5 mL solution. The respective concentrations are 100 or 200 IU/mL. Each vial contains 5.1 micrograms of protein (specific in vivo bioactivity equivalent to approximately 10,000 IU FSH/mg protein).

The solution for injection contains the active ingredient follitropin beta produced by genetic engineering of the Chinese Hamster Ovary (CHO) cell line.

Pharmacodynamic properties

Pharmacotherapeutic group: Gonadotropins

ATC code: G03G A06

Puregon contains recombinant FSH. The drug is produced by recombinant DNA technology using a Chinese hamster ovary cell line that has been transfected with human FSH genetic units. The base amino acid sequence of recombinant FSH is identical to the parent amino acid sequence of natural human FSH. There are slight differences in the carbohydrate chain structure.

FSH is an indispensable hormone for follicular growth and maturation as well as gonadal steroid production. In females, FSH levels are important for follicular initiation and timing and thus determine the timing and number of mature follicles. Therefore, Puregon can be used to stimulate follicular growth and stimulate steroid production in certain cases of gonadal dysfunction. Furthermore, Puregon can be used to promote multi follicular development in assisted reproductive regimens [e.g. in vitro fertilization/embryo transfer (IVF/ET), gamete transfer into the fallopian tube (GIFT), and intracytoplasmic sperm injection (ICSI)]. After treatment with Puregon, hCG is usually used to stimulate the final maturation of the follicle, mitosis, and induce ovulation.

Pharmacokinetic properties

Following Puregon intramuscular or subcutaneous administration, maximum concentrations of FSH are reached in about 12 hours. After intramuscular injection of Puregon, maximal FSH concentrations were reached in men and earlier than in women. FSH levels continue to increase for 24-48 hours due to gradual release from the injection site and because of a half-life of approximately 40 hours (range 12 to 70 hours). Due to the relatively long half-life, repeated administration of a similar dose results in an approximately 1.5-2.5-fold increase in plasma FSH concentrations compared with a single dose. This makes it easier for FSH to reach therapeutic concentrations.

There were no significant differences in the pharmacokinetics of Puregon between intramuscular and subcutaneous administration. Both routes of administration have an absolute bioavailability of about 77%. Biochemically, recombinant FSH is very similar to human urinary FSH and is distributed, metabolized, and excreted by the same pathways.

Preclinical safety data

A single dose of Puregon administered to rats produced no significant toxicity. In repeated dosing studies in rats (two weeks) and in dogs (13 weeks) at doses up to 100 times the maximum human dose, Puregon also produced no significant toxicity. Puregon has no mutagenic potential in the Ames test and the in vitro assay for chromosomal aberrations in human lymphocytes.

Indications and uses

For women

Puregon is indicated for the treatment of female infertility in the following cases:

Anovulation (including polycystic ovarian syndrome, PCOS) in women who have not responded to treatment with clomifene citrate.
 
Controlled ovarian hyperstimulation to stimulate the growth of multiple follicles in assisted reproductive regimens [such as in-vitro fertilization/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT), and intracytoplasmic sperm injection (ICSI)].

For men

Decreased spermatogenesis due to hypogonadism due to decreased gonadotropin (hypogonadotrophic hypogonadism).

Dosage and Administration

Treatment with Puregon should be initiated under the supervision of a physician experienced in the treatment of infertility.

The first injection of Puregon should be done under the direct supervision of medical personnel.

Dosage

When using an injection pen, it should be recognized that the pen is an accurate dosing device that will dispense the correct dose as set. It was found that on average the injector pen delivered 18% more FSH than a conventional syringe. This is especially important when switching between a pen and a regular syringe during a treatment cycle. Especially when switching from the syringe to pen, it is necessary to reduce the dose to prevent over-injection.

Dosage for women

There is great variation in the ovarian response to exogenous gonadotropins between individuals and between individuals. The same dose regimen cannot be applied. Therefore, it is necessary to adjust the dose in each patient according to the ovarian response. This requires evaluation of follicular growth by ultrasound. Simultaneous measurement of serum estradiol levels may also be useful.

Results of clinical trials comparing Puregon with urinary FSH showed that Puregon was more effective than urinary FSH in terms of a lower total dose and shorter duration of treatment to achieve preovulatory conditions. Therefore, it must be calculated appropriately to administer a lower dose of Puregon than the usual urinary FSH dose, which not only optimizes follicular development but also reduces the risk of unintended ovarian hyperstimulation.

Clinical experience with Puregon is based on three cycles of treatment for both indications. The general experience with IVF shows that the overall treatment success rate remains stable during the first 4 attempts and declines thereafter.

Not ovulating

It is recommended to use a sequential treatment regimen with an initial dose of 50 IU Puregon/day. Maintain this starting dose for at least 7 days. If there is no ovarian response, gradually increase the daily dose until follicle growth and/or plasma estradiol concentrations indicate an adequate pharmacodynamic response. A 40-100% increase in daily estradiol levels is considered optimal. Then maintain this dose until preovulatory conditions are achieved. Pre-ovulatory conditions are achieved when ultrasonography shows a dominant follicle with a minimum diameter of 18 mm and/or a plasma estradiol concentration of 300-900 picogram/mL (1000-3000 pmol/L). Usually, 7 to 14 days of treatment is enough to achieve this effect. Then stop taking Puregon and ovulation can be stimulated by administering human chorionic gonadotropin (hCG).

If the number of responding follicles is too high or the estradiol concentration increases too rapidly, i.e. the daily estradiol concentration more than doubles for 2 or 3 consecutive days, the daily dose should be reduced.

Since cysts over 14mm in diameter are fertile, there is a risk of multiple pregnancy if there are more than 14mm in the preovulatory period. In that case, hCG should be discontinued and pregnancy should be avoided to prevent multiple pregnancy.

The maximum individualized daily dose of Puregon is 250 IU.

Controlled ovarian hyperstimulation in medical assisted reproduction methods

Apply different stimulation regimens. A starting dose of 100-225 IU is recommended for at least the first four days. The dose can then be adjusted based on the individual patient's ovarian response. Clinical studies have shown that a maintenance dose of 75-375 IU for 6 to 12 days is sufficient, with longer treatment if needed.

Puregon can be used alone or in combination with a GnRH agonist or antagonist to prevent premature lutealization. When GnRH agonists are used, higher doses of Puregon may be required to achieve an adequate follicular response.

Ovarian response was monitored and assessed by ultrasound. Simultaneous measurement of serum estradiol levels may also be useful. On ultrasound, there are at least 3 follicles 16-20 mm in size, and a good estradiol response (serum estradiol concentration is about 300-400 picograms/mL (1000-1300 pmol/L) for each sugary follicle. diameter over 18mm), hCG is used to stimulate the final maturation of these follicles. Proceed to collect eggs after 34-35 hours.

The maximum individualized daily dose of Puregon is 500 IU.

Dosage for men

Puregon is injected at a dose of 450 IU weekly, or 225 IU twice weekly or 150 IU three times weekly, taken in combination with hCG. Treatment with Puregon and hCG should be continued continuously for at least 3 to 4 months before improvement in spermatogenesis can be seen. Semen testing should be performed 4 to 6 months after initiation of treatment to assess response. If the patient has no response after this time, the combination therapy as above can be continued; Current clinical experience suggests that treatment for up to 18 months or longer may be required to achieve spermatogenesis. There are no indications for the use of Puregon in children.

How to use

Puregon Injection Solution

In cartridge: designed for use with the Puregon pen and should be injected subcutaneously.

In vials: should be administered subcutaneously or intramuscularly slowly to avoid pain during injection and to minimize leakage from the injection site.

It is necessary to change the subcutaneous injection site to prevent fat tissue atrophy. The best place to inject is the abdomen just below the navel or the upper thigh. The doctor can show the patient other places where the patient can inject Puregon. Change the injection site slightly after each injection to reduce the risk of skin side effects. Any excess solution should be discarded.

Patients can ask a relative or their spouse or can use the Puregon injection pen to inject Puregon if fully instructed by the doctor. Puregon self-injection should only be performed by women who wish to do it themselves, with adequate guidance and expert advice.

Instructions for use and removal

Do not use if the solution for injection contains particles or is not clear.

The Puregon injection solution in the cartridge is designed to be suitable for use with the Puregon injection pen. The instructions for use of the injection pen must be followed carefully.

All air bubbles must be removed from the cartridge before injecting.

Do not reuse empty cartridges.

Puregon cartridges are not designed to mix any other medication into the cartridge.

Used needles must be discarded immediately after injection.

Dispose of unused medication or waste material in accordance with local regulations.

Warning

Puregon may contain trace/very small amounts of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible individuals.

Before starting treatment, the cause of the couple's infertility should be evaluated. In particular, the patient must be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia, pituitary or hypothalamic tumor and evaluated for suitability for this specific treatment. .

In female

Ovarian hyperstimulation syndrome (OHSS) is a medical event different from uncomplicated ovarian enlargement. Clinical signs and symptoms of mild to moderate ovarian hyperstimulation syndrome include abdominal pain, nausea, diarrhea, and mild to moderate ovarian enlargement, and ovarian cysts. Severe ovarian hyperstimulation syndrome can be life-threatening. The clinical signs and symptoms of severe ovarian hyperstimulation syndrome are large ovarian cysts, acute abdominal pain, ascites, pleural effusion, thoracic effusion, dyspnea, oliguria, and abnormalities of the bladder. hematology and weight gain. In rare cases, venous or arterial thromboembolism may occur with ovarian hyperstimulation syndrome. There have been reports of transient liver function test abnormalities suggestive of liver dysfunction, with or without liver biopsy morphological changes associated with ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome can be caused by the use of human placental gonadotropin (hCG) and pregnancy (endogenous hCG). Premature ovarian hyperstimulation syndrome usually occurs within 10 days of hCG injection and may be accompanied by an excessive ovarian response to gonadotropin stimulation. Late ovarian hyperstimulation syndrome occurs more than 10 days after hCG injection, as a result of hormonal changes during pregnancy. Because of the risk of developing ovarian hyperstimulation syndrome, patients should be monitored for at least 2 weeks after hCG injection.

Women who are known to be at high risk for a high ovarian response may be particularly susceptible to ovarian hyperstimulation syndrome during or after treatment with Puregon. For women with the first cycle of ovarian stimulation for which the risk factors are only partially known, close monitoring is recommended for early signs and symptoms of ovarian hyperstimulation syndrome.

To reduce the risk of ovarian hyperstimulation syndrome, ultrasound evaluation of follicular growth should be performed prior to treatment and periodically during treatment. Simultaneous measurement of serum estradiol levels may also be useful. In assisted reproductive technology (ART), the risk of ovarian hyperstimulation syndrome is increased when 18 or more follicles are 11mm or larger in diameter. The hCG injection should be discontinued when a total of 30 or more follicles are found.

Depending on the ovarian response, the following measures may be considered to reduce the risk of ovarian hyperstimulation syndrome:

Discontinue further stimulation with gonadotropins for up to 3 days (coasting)

Stop hCG and cancel the treatment cycle

Inject a lower dose of 10,000 IU of urine hCG to induce final follicular maturation, eg 5,000 IU of urine hCG or 250 micrograms of recombinant hCG (recombinant hCG, rec-hCG) (equivalent to approximately 6,500 Urine hCG)

Cancellation of fresh embryo transfer and embryo cryopreservation

Avoid hCG injections to support the luteal phase.

If Ovarian Hyperstimulation Syndrome develops, the appropriate and standard treatment for OHSS should be instituted and followed.

If severe ovarian hyperstimulation syndrome (OHSS) occurs, gonadotropins including hCG should be discontinued, and whether the patient should be hospitalized. Treatment is mainly symptomatic and overall includes rest, fluid and electrolyte balance, and analgesics (if needed). The use of diuretics may aggravate intravascular volume depletion, therefore diuretics should be avoided except during the convalescent period described below. Management of ovarian hyperstimulation syndrome can be divided into 3 stages as follows:

Acute stage

Management should directly prevent hemoconcentration due to reduced intravascular volume into the third compartment and minimize the risk of thromboembolism and renal injury. Careful assessment should be performed daily or more frequently based on clinical requirements for fluid intake and output, weight, hematocrit, serum and urine electrolytes, urine specific gravity, blood urea nitrogen (BUN), and urine output. creatinine, total protein, and albumin/globulin ratio, coagulation tests, electrocardiogram to monitor hyperkalemia and size of ascites. Treatment, including limited fluids, electrolytes, and serum albumin, balances electrolytes while reducing the intravascular volume to some extent. Adequate correction of intravascular volume deficits may lead to an unacceptable increase in third compartment fluid accumulation.

Chronic phase

After the acute phase has been successfully managed as above, excessive accumulation of fluid in the third compartment should be limited by strict restriction of potassium, sodium, and fluids.

Recovery phase

Because the third compartment fluid returns to the endovascular space, there will be a decrease in hematocrit and an increase in urine output without any increase in fluid intake. Peripheral and/or pulmonary edema may occur if the kidneys are unable to clear the third chamber as quickly as it is mobilized. Diuretics may be prescribed during the recovery period, if necessary, to combat pulmonary edema.

Ovarian torsion has been reported following treatment with gonadotropins, including Puregon. Ovarian torsion may be associated with other risk factors such as ovarian hyperstimulation syndrome, pregnancy, previous abdominal surgery, history of ovarian torsion, previous or current ovarian or ovarian cysts. polycystic eggs. Ovarian damage due to reduced blood supply can be limited with early diagnosis and prompt detorsion.

Thromboembolic events, both related and unrelated to ovarian hyperstimulation syndrome, have been reported following treatment with gonadotropins, including Puregon. Intravascular thrombosis, which can originate in a vein or an artery, can lead to decreased blood flow to vital organs or extremities. In women with known risk factors for thromboembolic events, such as personal or family history, severe obesity or thrombophilia, treatment with gonadotropins, including Puregon, may increase the above risk. In these women, the benefits should be weighed against the risks of using gonadotropins, including Puregon. However, it should be noted that pregnancy itself also increases the risk of blood clots.

Multiple pregnancies and multiple births in one pregnancy have been reported with all gonadotropin treatments, including Puregon. Multiple pregnancies, especially multiple pregnancies, increase the risk of adverse maternal outcomes (pregnancy and delivery complications) and perinatal (low birth weight). For anovulatory women receiving ovulatory therapy, monitoring of follicular growth with transvaginal ultrasound is important to minimize the risk of multiple pregnancies. Simultaneous measurement of serum estradiol levels may also be useful. Patients should be made aware of the risk of multiple pregnancies before starting treatment.

In women undergoing Assisted Reproductive Technologies (ART), the risk of multiple pregnancies is primarily related to the number of embryos transferred. When used for the anovulatory cycle, the dose of FSH should be adjusted accordingly to avoid the development of multiple follicles. In infertile women undergoing assisted reproductive technology, there is an increased incidence of ectopic pregnancy. Therefore, it is very important to conduct an early ultrasound to identify the fetus in the uterus.

The rate of birth defects after applying assisted reproductive techniques may be slightly increased compared to natural conception. This slightly increased rate is thought to be related to different parental characteristics (eg, maternal age, sperm characteristics) and higher rates of multiple pregnancies after ART. There is no indication that the use of gonadotropins during ART increases the risk of birth defects.

Ovarian tumors/cancers and other tumors of the reproductive system, both benign and malignant, have been reported in women who have undergone multiple infertility treatment regimens. It has not been established whether treatment with gonadotropins increases the risk of tumors in infertile women.

Medical conditions contraindicating pregnancy should be evaluated prior to initiating treatment with Puregon.

In men

Increased levels of endogenous FSH in men are indicative of primary testicular failure. These patients did not respond to Puregon/hCG therapy.

Effects on ability to drive and use machinery

No effect on the ability to drive and use machines has been observed.

Overdose

There are no data on the acute toxicity of Puregon in humans, but animal studies have shown that the acute toxicity of Puregon and its gonadotropinuria preparations is very low. Too high a dose of FSH can cause ovarian hyperstimulation.

Contraindications

For men and women

Hypersensitivity/hypersensitivity to the active substance or to any of the excipients of the drug.

Tumors in the ovary, breast, uterus, testicles, pituitary gland, or hypothalamus.

Primary hypogonadism.

Other contraindications for women

Pregnant.

Undiagnosed/unknown vaginal bleeding.

Ovarian cyst or ovary that is abnormally large/increased in size but not related to polycystic ovary syndrome (PCOS).

Malformation of the reproductive organs not suitable for pregnancy.

Uterine fibroids are not suitable for pregnancy.

Use in pregnant and lactating women

Pregnancy

Puregon is contraindicated during pregnancy.

In case of accidental use during pregnancy, there are insufficient clinical data to exclude the possibility of teratogenicity with recombinant FSH.

Breastfeeding

There are no data on the excretion of follitropin beta into human milk in clinical trials and in animal studies. Follitropin beta does not tend to be excreted in human milk due to its high molecular weight. If follitropin beta is secreted into breast milk, it is degraded in the infant's gastrointestinal tract. Follitropin beta may affect lactation.

Interactive

Concomitant administration of Puregon with clomifene citrate may increase follicular response. After pituitary desensitization with a GnRH agonist, higher doses of Puregon may be required to achieve an adequate follicular response.

Incompatibility

Due to the lack of incompatibility studies, Puregon should not be mixed with other medicinal products.

Side effects

Clinical use of Puregon by subcutaneous or intramuscular injection may result in injection site reactions (3% of all treated patients). Most of these local reactions are mild and transient. Systemic hypersensitivity reactions are uncommon (approximately 0.2% of Puregon-treated patients).

Treatment for women

In clinical trials, approximately 4% of women treated with Puregon reported signs and symptoms associated with ovarian hyperstimulation syndrome. Adverse effects associated with this syndrome include pelvic pain and/or congestion, abdominal pain and/or tenderness, breast discomfort, and increased ovarian size.

List adverse events with Puregon reported in clinical trials in women by system organ class and frequency; common/common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100).

In addition, ectopic/ectopic pregnancy, miscarriage, and multiple pregnancies have been reported. These conditions are thought to be related to assisted reproductive technology or to pregnancy through the technique.

In rare cases, thromboembolism has been observed during treatment with Puregon/hCG as well as with other gonadotropins.

Treatment for men

List adverse events with Puregon reported in male clinical trials (30 patients treated) by system organ class and frequency; common/common (≥1/100 to <1/10).

Preservation

Preserved by the pharmacist:

Store in the refrigerator (2oC-8oC). Do not freeze.

Preservation by the patient: there are 2 ways

Store in the refrigerator (2oC-8oC). Do not freeze.

Store at no more than 25°C for a single period not exceeding 3 months.

Keep the cartridge in the carton box.

Presentation and packaging

Injection solution.

The box contains 1 Puregon cartridge and 6 needles (300 IU and 600 IU cartridges) for use with the Puregon injection pen.

The cartridge is made of colorless hydrolyzed (type 1) glass, with a rubber piston and an aluminum cap over the rubber cap. The 300 IU cartridge contains a minimum of 400 IU in 0.480mL. 600 IU cartridge contains a minimum of 700 IU in 0.840mL.

Box of 1, 5, or 10 vials (3mL, colorless, grade 1 hydrolysis resistant glass vial with chlorobutyl rubber stopper).