Triptorelin - Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview:

Puberty is a natural and transformative phase in a child's life. However, it arrives too early for some, causing physical and emotional challenges. Triptorelin is used in the treatment of central precocious puberty. By slowing down early puberty, Triptorelin gives children more time to grow, ensuring a healthier and happier path to adolescence. Since March 10, 2010, the Food and Drug Administration (FDA) has granted approval to Triptorelin as an efficacious treatment for central precocious puberty. With its proven ability to slow down early puberty, Triptorelin offers children a chance to experience a healthier and happier adolescence. Discover how this remarkable medication reshapes the journey to adulthood and empowers children to embrace their childhood fully.

Drug Group:

Triptorelin belongs to the drug group known as gonadotropin-releasing hormone (GnRH) agonists.

Available Doses and Dosage Forms:

Triptorelin is available as an extended-release injectable suspension in a single-dose vial. The vial contains 22.5 mg (milligram) of Triptorelin, which appears as a lyophilized powder cake with a white to slightly yellow coloration. To prepare the medication for injection, it is reconstituted using the co-packaged two mL (milliliter) of diluent (sterile water) injection.

For Patients:

What Is Central Precocious Puberty?

Central precocious puberty (CPP) is a condition characterized when children experience the onset of puberty at an abnormally early age. Puberty begins around eight to 13 years in girls and in boys around nine to 14 years. The process starts significantly earlier than these typical age ranges in central precocious puberty. The condition is called "central" because it is triggered by the premature activation of the hypothalamic-pituitary-gonadal axis in the brain, which controls the release of hormones responsible for puberty. This early activation leads to the premature release of sex hormones (estrogen in girls and testosterone in boys) from the ovaries or testes.

Signs and symptoms of central precocious puberty may include:

• Early Development of Secondary Sexual Characteristics: Girls may experience breast development and pubic hair growth, while boys may develop facial and pubic hair.

• Rapid Growth: Children may experience a sudden growth spurt and may surpass their peers in height.

• Bone Maturation: Bones may age faster than usual, leading to early closure of growth plates, potentially resulting in a shorter adult height.

• Emotional and Behavioral Changes: Children may face emotional and psychological challenges due to the physical changes occurring earlier than expected.

The causes of central precocious puberty can vary and may include specific brain abnormalities, tumors, or genetic factors. Medical advice is necessary if signs of early puberty are observed in a child. A pediatric endocrinologist, a doctor specializing in hormone-related disorders, can conduct the necessary tests to determine the exact diagnosis and recommend appropriate treatment options, which may include medications like Triptorelin to slow down the progression of puberty and allow for more normal growth and development.

How Does Triptorelin Work?

Triptorelin targets the hypothalamic-pituitary-gonadal (HPG) axis, a critical system that regulates the production and release of sex hormones in the body. Here is how Triptorelin works:

• Hypothalamus Sensing: The hypothalamus, a brain region, produces and releases gonadotropin-releasing hormone (GnRH). GnRH acts as a signal to the pituitary gland.

• Pituitary Response: In response to GnRH, the pituitary gland releases two hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones stimulate the production of sex hormones (estrogen and testosterone) by the ovaries in females and the testes in males.

• Triptorelin Intervention: Triptorelin is a synthetic analog of GnRH. When administered, it binds to the GnRH receptors on the pituitary gland. However, unlike natural GnRH, which initially stimulates LH and FSH release, continuous administration of Triptorelin leads to the downregulation of these receptors.

• Hormone Suppression: The pituitary gland's response to GnRH is diminished with fewer active receptors. Consequently, the release of LH and FSH is suppressed, leading to decreased production of sex hormones.

• Puberty Suppression: In conditions like central precocious puberty, where early puberty is triggered by premature activation of the HPG axis, the suppression of LH and FSH helps slow the production of estrogen and testosterone. This, in turn, delays the progression of puberty and provides more time for the child's body to grow before reaching the typical age of puberty onset.

• Other Uses: Triptorelin is also used to treat certain hormone-dependent cancers (e.g., prostate cancer, breast cancer) and conditions like endometriosis, a condition characterized by the presence of tissue similar to the lining of the uterus (endometrium) growing outside the uterus and infertility. In these cases, its action in suppressing sex hormones is utilized to manage or treat specific medical conditions.

What Is the Dosage of Triptorelin?

The dosing schedule may vary, but here are some common dosages for Triptorelin in the treatment of CPP are:

1. Monthly Formulation: A common dosage is 11.25 mg per injection for the monthly formulation.

2. Three-Month Formulation: The three-month formulation of Triptorelin may have dosages ranging from 11.25 mg to 22.5 mg per injection, depending on the child's body weight and the healthcare provider's recommendation.

3. Six-Month Formulation: The six-month formulation typically contains higher doses, ranging from 22.5 mg to 45 mg per injection.

How Effective Is Triptorelin?

Triptorelin has shown an efficacy rate of around 90 percent in suppressing puberty in children with central precocious puberty. It has been successful in delaying the onset of puberty for several years in many cases, allowing affected children to have more time to grow before reaching the typical age of puberty onset.

What Are the Things to Inform the Doctor Before Taking the Drug?

Here are some essential things to inform the doctor before starting Triptorelin treatment:

1. Medical History: Provide a comprehensive medical history, including past or present medical conditions, surgeries, allergies, and previous treatments.

2. Current Medications: Inform the doctor about all the medications, including prescription drugs, over-the-counter medicines, vitamins, supplements, and herbal products. Some medications may interact with Triptorelin, affecting its effectiveness or causing adverse effects.

3. Allergies: Let the doctor know if the patient has any known allergies to medications or other substances. This includes allergies to GnRH agonists or any other related drugs.

4. Pregnancy and Breastfeeding: If the patient is pregnant, planning pregnancy, or breastfeeding, the doctors should be made aware of it. The medication may not be suitable during pregnancy or breastfeeding.

5. Hormonal Disorders: Inform about any known hormonal disorders or conditions related to the reproductive system, as these may influence the decision to use Triptorelin.

6. Bone Health: Any bone-related conditions should be discussed with the doctor.

7. Liver or Kidney Problems: Inform about any liver or kidney disease, as Triptorelin may be metabolized or eliminated differently in these conditions.

8. Cardiovascular Health: Inform the doctor about any history of cardiovascular diseases or risk factors. Triptorelin may cause changes in heart function and blood vessels.

9. Diabetes: A history of diabetes should be informed as Triptorelin may affect blood sugar levels.

10. Mental Health: Discuss any history of mental health conditions, such as depression or anxiety, as Triptorelin may have psychological effects.

11. Bone Density Scans: If the patient has undergone bone density scans, provide this information to the doctor.

12. Other Treatments: Inform about any other treatments or therapies, such as radiation or chemotherapy.

How Is Triptorelin Administered?

Follow the appropriate aseptic technique for the preparation and administration of Triptorelin as follows:

1. Twist the plunger rod securely onto the barrel end of the prefilled sterile water diluent syringe to ensure a firm fastening.

2. Take off the cap from the syringe barrel.

3. Using a strong push and turning it clockwise, firmly affix a 21-gauge sterile safety needle to the prefilled sterile water diluent syringe. Please note that this needle is intended for reconstitution purposes only.

4. Gently pull the safety cover back towards the syringe, away from the 21-gauge needle, and then proceed to remove the clear needle shield.

5. Carefully insert the 21-gauge needle into the vial to administer the sterile water diluent. Gently swirl the vial to ensure the diluent rinses the sides. The reconstituted solution should appear as a milky suspension.

6. After the mixture is ready, promptly move on to the next steps and administer without any delay.

7. Invert the vial and position the end of the 21-gauge needle near the level of the stopper, ensuring the needle lumen is still inside the vial.

8. Slowly pull back the plunger rod to withdraw the reconstituted product into the syringe.

9. Slide the safety cover in the direction of the needle and continue until it securely locks in place. Remove and discard the first 21-gauge needle. It will no longer be used.

10. Firmly attach the second sterile needle to the syringe and pull back the safety cover towards the syringe. This needle will be used for administration.

11. Prime the 21-gauge needle to remove air from the syringe and visually inspect the suspension for abnormalities. If the suspension appears milky and homogenous without visible aggregates or precipitates, administer it immediately.

12. Inject the patient using the entire syringe contents, preferably in the buttock or thigh.

13. Administer the injection relatively rapidly and steadily to avoid potential needle blockage.

14. Once the injection is administered, promptly engage the safety cover by pushing it forward to cover the needle until it locks securely.

15. Use the one-handed technique to activate the mechanism away from themselves and others.

16. Dispose of the syringe assembly promptly and appropriately by discarding it into a suitable sharps container.

What Are the Side Effects of Triptorelin?

Common side effects of Triptorelin may include:

1. Injection Site Reactions: Redness, swelling, or pain at the injection site.

2. Menstrual (Vaginal) Bleeding: Changes in menstrual bleeding patterns, which may include irregular bleeding or spotting.

3. Hot Flushes: A sudden feeling of warmth and redness in the face and upper body, often accompanied by sweating.

4. Headache: Mild to moderate headache.

5. Cough: A persistent or recurrent cough.

6. Infections: Various types of infections, such as bronchitis (an inflammation of the bronchial tubes), gastroenteritis (an infection or inflammation of the digestive tract), influenza (a highly contagious viral respiratory infection), nasopharyngitis (an inflammation of the nasal passages and throat), otitis externa (an infection or inflammation of the ear canal), pharyngitis (inflammation of the pharynx), sinusitis (inflammation of the sinuses), and upper respiratory tract infection (sneezing, runny nose, nasal congestion, cough, and sore throat).

Dietary Considerations:

None.

Missed Dose:

In case of a missed dose of Triptorelin or any medication:

1. Check the instructions for the recommended dosing schedule.

2. Take the missed dose when remembered; if close to the next scheduled dose, it is better to skip the dose.

3. Do not try to double dose to compensate for a missed one.

4. Contact the healthcare provider for guidance if unsure or multiple doses are missed.

5. Set reminders to avoid future missed doses.

6. Consistency in taking medication is vital for effectiveness.

Overdose:

Over-dosage has not been reported in clinical trials. In toxicity studies, Triptorelin's subcutaneous LD50 in mice and rats was 400 mg/kg (milligrams per kilogram) in mice and 250 mg/kg in rats, which is higher than the estimated monthly human dose based on body surface area (around 500 to 600 times higher). If over-dosage happens, discontinue therapy immediately and provide appropriate supportive and symptomatic treatment.

Storage:

Store Triptorelin at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit). Triptorelin is supplied in a single-dose delivery system, comprising a vial with a flip-off seal containing sterile lyophilized Triptorelin pamoate micro granules integrated into a biodegradable copolymer made of lactic and glycolic acids. The system also includes a MIXJECT vial adapter and a pre-filled syringe containing sterile water for injection, a unique selling proposition(USP), with a pH range of 6 to 8.5.

For Doctors:

Indication:

Indications of Triptorelin:

• Central Precocious Puberty (CPP): Triptorelin is indicated for treating children with central precocious puberty, which starts earlier than usual due to premature activation of the hypothalamic-pituitary-gonadal axis.

• Advanced Prostate Cancer: Triptorelin is used in the management of advanced prostate cancer in men. It works by suppressing the testosterone hormone, which slows the growth of prostate cancer cells.

• Endometriosis: Triptorelin treats endometriosis, where uterine-like tissue grows outside the uterus. It helps reduce estrogen levels, which can alleviate symptoms and slow the progression of endometriosis.

• Uterine Fibroids: Triptorelin is sometimes used to shrink uterine fibroids before surgical removal. It works by reducing estrogen levels, which can decrease the size of the fibroids.

• Assisted Reproductive Technologies: In some cases, Triptorelin may be used to regulate the menstrual cycle in women who undergo assisted reproductive technologies, such as in vitro fertilization (IVF).

Dose:

1. Central Precocious Puberty (CPP):

• Dosage: The recommended dosage is based on body weight and is usually given as a single subcutaneous injection every 28 days. The dose typically ranges from 50 to 150 mcg/kg (microgram per kilogram).

2. Advanced Prostate Cancer:

• Dosage: For the treatment of advanced prostate cancer, the recommended dose is typically 3.75 mg administered as a single intramuscular injection every 28 days. Alternatively, a higher dose of 11.25 mg may be used every 12 weeks.

3. Endometriosis:

• Dosage: For the management of endometriosis, the usual recommended dose is 3.75 mg given as a single intramuscular injection every 28 days for a period of six months. In some cases, treatment may be extended for up to nine months.

4. Uterine Fibroids (before surgery):

• Dosage: The recommended dose for the management of uterine fibroids before surgery is 3.75 mg, given as a single intramuscular injection every 28 days for a period of two to three months. This helps shrink the fibroids and reduce bleeding prior to surgical removal.

5. Assisted Reproductive Technologies:

• Dosage: In cases where Triptorelin is used to regulate the menstrual cycle in women undergoing assisted reproductive technologies, the dose may vary. Typically, a single injection of 0.1 mg to 0.2 mg is given.

Dosing Considerations:

Various dosing considerations are:

• Triptorelin dosing is individualized based on the patient's condition, age, and response to treatment.

• It can be administered via subcutaneous or intramuscular injections.

• Hormone levels may be monitored during treatment.

• Pregnant and lactating women should use contraception, and its use is not evaluated in children under 18.

• Patients with renal or hepatic impairment may require dosage adjustments.

• Patients should adhere to the prescribed schedule and avoid altering the dosage without medical supervision.

What Are the Pharmacological Aspects of Triptorelin?

1. Pharmacodynamics: After the first administration of Triptorelin, there is a temporary surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. With chronic and continuous administration, typically two to four weeks after starting therapy, there is a sustained decrease in LH and FSH secretion, leading to a significant reduction in testicular steroidogenesis. This results in a decrease in serum testosterone concentration, similar to levels seen in surgically castrated men, leading to the quiescence of tissues and functions dependent on these hormones. These effects are reversible on discontinuation of therapy.

2. Mechanism: Triptorelin is a synthetic drug decapeptide agonist analog of gonadotropin-releasing hormone (GnRH). In comparative in vitro studies, Triptorelin demonstrated 100-fold greater activity than native GnRH in stimulating luteinizing hormone release from dispersed rat pituitary cells in culture and 20-fold greater activity in displacing 125I-GnRH from pituitary receptor sites. In animal studies, Triptorelin pamoate demonstrated a 13-fold increase in luteinizing hormone-releasing activity and a 21-fold increase in follicle-stimulating hormone-releasing activity compared to native GnRH.

3. Pharmacokinetics

• Absorption: After a single intramuscular injection of Triptorelin to patients with prostate cancer, the mean peak serum concentrations were 28.4 ng/mL (nanograms per milliliter), 38.5 ng/mL, and 44.1 ng/mL, occurring one to three hours after administration for the 3.75 mg, 11.25 mg, and 22.5 mg formulations, respectively. Over the course of nine months (for the 3.75 mg and 11.25 mg formulations) or 12 months (for the 22.5 mg formulation) of treatment, Triptorelin did not show any significant accumulation in the body.

• Distribution: After a single intravenous bolus dose of 0.5 mg of Triptorelin peptide, the volume of distribution was estimated to be approximately 30 to 33 liters (L). There is no evidence to suggest that Triptorelin, at clinically relevant concentrations, binds to plasma proteins.

• Metabolism: Although the metabolism of Triptorelin in humans is not completely understood, it is improbable to involve hepatic microsomal enzymes (cytochrome P-450). The impact of Triptorelin on the activity of other drug-metabolizing enzymes is also unknown. So far, no specific metabolites of Triptorelin have been identified. Pharmacokinetic data indicate that C-terminal fragments, resulting from tissue degradation, are either completely degraded within the tissues, rapidly degraded in plasma, or eliminated through the kidneys.

• Excretion: Triptorelin undergoes elimination by both the liver and the kidneys. Following intravenous administration of 0.5 mg of Triptorelin peptide to healthy male volunteers with a creatinine clearance of 149.9 mL/min, approximately 41.7 percent of the dose was excreted in the urine as an intact peptide, resulting in a total Triptorelin clearance of 211.9 mL/min. In patients with liver disease, having a lower creatinine clearance of 89.9 mL/min, this percentage increased to about 62.3 percent. Moreover, in patients with no kidney function (creatinine clearance = 0), the nonrenal clearance of Triptorelin was found to be 76.2 mL/min, indicating that the nonrenal elimination of Triptorelin primarily relies on the liver.

Toxicity:

Triptorelin is generally well-tolerated, but it may cause side effects, including hot flashes, decreased libido, and headache. In case of overdose or hypersensitivity reaction, treatment should be stopped and supportive care given.

Clinical Studies:

1. Triptorelin 3.75 mg: Triptorelin 3.75 mg was studied in a randomized, active control trial involving 277 men with advanced prostate cancer. The study population included 59.9 percent Caucasian, 39.3 percent Black, and 0.8 percent other races. The age range of the patients was 47 to 89 years (mean age = 71 years). During the study, patients were administered either Triptorelin 3.75 mg (N = 140) or an approved GnRH agonist once a month for a duration of nine months. The main effectiveness goals of the study were to assess the achievement of castration by Day 29 and the maintenance of castration levels from Day 57 through Day 253.

2. Triptorelin 11.25 mg: Triptorelin 11.25 mg was studied in a randomized, active control trial involving 346 men with advanced prostate cancer. The study population included 48 percent Caucasian, 38 percent Black, and 15 percent of other races. The age range of the patients was 45 to 96 years (mean age = 71 years). Patients were divided into two groups during the study. The first group received Triptorelin 11.25 mg (N = 174) every 12 weeks for a maximum of three doses (total treatment period of 253 days). The second group received Triptorelin 3.75 mg (N = 172) every 28 days for a maximum of nine doses. The main efficacy endpoints included achieving castration by Day 29 and maintaining castration from Day 57 through Day 253.

3. Triptorelin 22.5 mg: Triptorelin 22.5 mg was studied in a non-comparative trial involving 120 men with advanced prostate cancer. The study population included 64 percent Caucasian, 23 percent Black, and 13 percent of other races, with a mean age of 71.1 years (ranging from 51 to 93). Patients were administered Triptorelin 22.5 mg (N = 120) every 24 weeks for two doses (maximum treatment period of 337 days). The primary efficacy endpoints included the achievement of castration by Day 29 and the maintenance of castration from Day 57 through Day 337.

In all three studies, most patients achieved castration levels of serum testosterone by Day 29, and maintenance of castration was observed in a high percentage of patients from Day 57 through the specified study period.

What Are the Contraindications of Triptorelin?

Triptorelin should not be used in individuals with a known hypersensitivity to Triptorelin or any other product component or to other GnRH agonists or GnR. Hypersensitivity to these substances is a contraindication for the use of Triptorelin.

Warnings and Precautions:

1. Hypersensitivity Reactions: Triptorelin administration may cause hypersensitivity reactions, including anaphylactic shock and angioedema (swelling beneath the skin). If there are any signs of hypersensitivity reaction, immediate discontinuation of Triptorelin therapy is necessary, and appropriate supportive and symptomatic care should be provided.

2. Transient Increase in Serum Testosterone: Triptorelin, like other GnRH agonists, initially causes a temporary rise in serum testosterone levels. Some patients with prostate cancer may experience worsening symptoms, such as bone pain, neuropathy, hematuria, or urinary tract obstruction, during the first weeks of treatment.

3. Metastatic Vertebral Lesions and Urinary Tract Obstruction: Instances of spinal cord compression, which can result in weakness or paralysis, sometimes leading to fatal outcomes, have been reported with GnRH agonists. Patients with metastatic vertebral lesions or urinary tract obstruction should be closely monitored during the initial weeks of therapy.

4. Effect on QT/QTc Interval: The administration of androgen deprivation therapy, including GnRH agonists, may lead to the prolongation of the QT/QTc interval. Healthcare providers must assess the potential risks and benefits of therapy in patients with congenital long QT syndrome, congestive heart failure, electrolyte imbalances, or taking medications known to prolong the QT interval. Correcting electrolyte abnormalities and periodically monitoring electrocardiograms and electrolytes should also be taken into consideration.

5. Hyperglycemia and Diabetes: GnRH agonists have been associated with hyperglycemia (diabetes) in men. Blood glucose and glycosylated hemoglobin (HbA1c) levels should be monitored periodically in patients receiving GnRH agonists, and appropriate management for hyperglycemia or diabetes should be implemented.

6. Cardiovascular Diseases: The use of GnRH agonists in men has been linked to an increased risk of myocardial infarction, sudden cardiac death, and stroke. Healthcare providers should carefully evaluate cardiovascular risk factors when deciding on a treatment for patients with prostate cancer.

7. Laboratory Tests: During Triptorelin treatment, serum testosterone levels should be periodically measured to monitor the response to the medication.

8. Embryo-Fetal Toxicity: Based on animal studies, administering Triptorelin to pregnant women can result in fetal harm. Pregnant patients and females of reproductive potential should be informed of the potential risks.

What Are the Drug Interactions of Triptorelin?

No specific drug-drug interaction studies involving Triptorelin have been conducted. Human pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation of Triptorelin are either completely degraded within tissues or rapidly cleared by the kidneys or further degraded in plasma. Therefore, it is unlikely that hepatic microsomal enzymes are involved in Triptorelin metabolism.

Specific Considerations:

Pregnancy:

Based on animal studies, Triptorelin can cause fetal harm when administered to pregnant women. Hormonal changes induced by Triptorelin treatment increase the risk of pregnancy loss. In animal studies, daily administration of Triptorelin to pregnant rats during organogenesis resulted in maternal and fetal toxicity, including pregnancy loss, at low doses. Pregnant patients and females of reproductive potential should be informed about the risks to the fetus.

Lactation:

The safety and efficacy of Triptorelin have not been established in lactating females. There is no data on the presence of Triptorelin in human milk.

Females and Males of Reproductive Potential:

Infertility in males may occur due to the mechanism of action of Triptorelin.

Pediatric Use:

The safety and effectiveness of Triptorelin have not been established in pediatric patients.

Geriatric Use:

Clinical studies with Triptorelin have been primarily conducted in patients aged 65 years and older, considering prostate cancer primarily affects an older population.

Renal Impairment:

Individuals with renal impairment may have higher exposure to Triptorelin than young, healthy males.

Hepatic Impairment:

Individuals with hepatic impairment may have higher exposure to Triptorelin than young, healthy males.