Triptorelin

Triptorelin is a synthetic hormone belonging to the pharmacological class of natural gonadotropin-releasing hormone (GnRH) agonists.

The FDA has approved Triptorelin for treating prostate cancer, central precocious puberty, and endometriosis.

Following intramuscular injection, Triptorelin actively absorbs, distributes with a volume of 30–33 L, and undergoes metabolism unlikely to involve hepatic enzymes. It actively eliminates, primarily via urine (42% intact peptides), with a half-life of 2.8 ± 1.2 hours.

The most common side effects of Triptorelin are hot flashes, weakness, increased sweating, fatigue, back pain, and erectile dysfunction.

Triptorelin is available in the form of an injectable suspension.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Japan and Spain.

Triptorelin is a synthetic hormone belonging to the pharmacological class of natural gonadotropin-releasing hormone (GnRH) agonists.

Triptorelin stimulates the pituitary to release more LH and FSH, which initially raises the concentration of estrogen in women's serum and testosterone in men's serum. Triptorelin inhibits pituitary LH and FSH release after long-term dosing, which lowers testicular and ovarian steroidogenesis and brings serum testosterone and estradiol concentrations down to within the castrate or postmenopausal ranges, respectively. In animal experiments, triptorelin was found to have a 21-fold higher releasing activity for follicle-stimulating hormone and a 13-fold higher releasing activity for luteinizing hormone when compared to native GnRH.

Triptorelin is available in the form of an injectable suspension.

Injectable suspension: To be administered parenterally, as applicable.

As the physician recommends, injections are typically given in the gluteal region or deltoid muscle, following established guidelines for aseptic technique to optimize therapeutic delivery.

• Prostate cancer
• Endometriosis
• Precocious puberty (premature puberty)

• In Prostate Cancer: Inhibiting cancer cell growth by reducing testosterone levels, Triptorelin benefits prostate cancer patients, alleviating symptoms like difficulty urinating and facilitating easier urination. Its demonstrated effectiveness in managing prostate cancer contributes to positive treatment outcomes for this condition.
• In Endometriosis: Abnormal tissue growth in endometriosis causes pain, menstrual issues, and fertility challenges. Triptorelin inhibits the rapid growth of womb lining and endometriosis tissue, relieving symptoms like lower stomach or back pain and menstrual discomfort and improving well-being for those affected by endometriosis.
• In Precocious Puberty: By delaying the early onset of adulthood, Triptorelin benefits individuals experiencing precocious puberty. It regulates puberty, typically before age 8 in girls and 9 in boys. Doctors administer it, ensuring effective management and limiting the premature development of a child's body.

• Triptorelin is indicated for hormone-sensitive metastatic and locally advanced prostate cancer, as well as in palliative treatment.
• Triptorelin is indicated for central precocious puberty in patients aged ≥2 yr.
• Triptorelin is indicated for endometriosis treatment, managing symptoms like pelvic pain.

Parenterally: Triptorelin suspension is administered parenterally, typically through subcutaneous or intramuscular injection, ensuring proper reconstitution of lyophilized powder with the accompanying diluent before the injection. They carefully mix the suspension to achieve a homogeneous solution and commonly target the gluteal region or deltoid muscle as the injection site. This method facilitates Triptorelin's controlled and sustained release, optimizing therapeutic effectiveness. The dosage and frequency depend on the specific medical condition; patients receive injections at scheduled intervals. Healthcare providers must follow established guidelines for aseptic techniques to minimize infection risk and ensure the effective therapeutic delivery of Triptorelin.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Suspension for injection: 3.75 mg, 11.25 mg, 22.5 mg.

Triptorelin is available in the form of Injectable suspensions.

Dose Adjustment in Adult Patients:

Prostate Cancer

Hormone-sensitive metastatic prostate cancer: 3.75 mg OD q4 weeks given via deep IM or SC in. An alternative treatment regimen may initially use 0.1 mg OD daily (triptorelin acetate 0.1 mg immediate-release preparation) provided via SC for 7 days, followed by 3.75 mg on day 8 (triptorelin acetate 3.75 mg prolonged-release depot preparation) given via IM, repeated every 4 weeks.

Hormone-sensitive locally advanced prostate cancer: 3.75 mg OD q4 weeks given via deep IM or SC. An alternative treatment regimen may initially use 0.1 mg once daily (triptorelin acetate 0.1 mg immediate-release preparation) provided via SC for 7 days, followed by 3.75 mg on day 8 (triptorelin acetate 3.75 mg prolonged-release depot preparation) given via IM, repeated every 4 weeks.

Palliative treatment of advanced prostate cancer: 3.75 mg every 4 weeks via IM into the buttock.

Endometriosis

3.75 mg is given once every 4 weeks via deep IM or SC. Initiate treatment during the 1st five days of the menstrual cycle. Maximum treatment duration: 6 months (for endometriosis); 3 or 6 months (for uterine fibroids).

Follow dietary recommendations and safety guidelines for optimal well-being while taking Triptorelin. Maintain a fibre-rich diet with healthy carbohydrates from fruits, vegetables, and whole grains. To potentially reduce prostate cancer risk, include fish, soy, tomatoes, Brussels sprouts, kale, broccoli, and oils containing omega-3 fatty acids, like olive oil. Avoid grilled meat, red meat, and saturated fat from animal products, including milk and dairy. Exercise regularly to manage weight, as obesity is a known risk factor for prostate cancer. Eat at regular intervals and opt for a diet rich in whole grains, veggies, fruits,and low-fat dairy products.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity: Anyone previously experienced hypersensitivity to any of the product's constituents.
• Pregnancy or women who may become pregnant.

1. Hypersensitivity Reactions: Triptorelin administration has been associated with hypersensitivity reactions, including anaphylactic shock and angioedema. Immediate discontinuation of triptorelin, followed by appropriate supportive care, is crucial in such cases.

2. Transient Increase in Serum Testosterone: Upon initial use, triptorelin, like other GnRH agonists, induces a transient rise in serum testosterone. Some patients may experience exacerbated signs and symptoms of prostate cancer during the initial weeks, such as bone pain, neuropathy, hematuria, or urinary obstruction.

3. Metastatic Vertebral Lesions and Urinary Tract Obstruction: GnRH agonists, including triptorelin, have been linked to spinal cord compression, potentially leading to weakness or paralysis. Vigilant monitoring is necessary for patients with metastatic vertebral lesions and urinary tract obstruction, with prompt intervention for complications.

4. Effect on QT/QTc Interval: Androgen deprivation therapy, including triptorelin, may prolong the QT/QTc interval. Providers should carefully weigh the benefits against potential risks, particularly in patients with congenital long QT syndrome, heart failure, or electrolyte imbalances. Monitoring of electrocardiograms and electrolytes is advisable.

5. Hyperglycemia and Diabetes: GnRH agonists, like triptorelin, may contribute to hyperglycemia and an increased risk of diabetes. Regular blood glucose and HbA1c monitoring is essential, and management should align with current practices for hyperglycemia or diabetes.

6. Cardiovascular Diseases:m Men using GnRH agonists, including triptorelin, may face an elevated risk of myocardial infarction, sudden cardiac death, and stroke. Evaluation of cardiovascular risk factors is crucial when deciding on prostate cancer treatment, and patients should be monitored for signs of cardiovascular disease.

7. Laboratory Tests: Monitoring the response to TRELSTAR involves periodic measurement of testosterone levels. Continuous triptorelin administration can impact diagnostic tests assessing pituitary-gonadal function, potentially leading to misleading results.

8. Embryo-Fetal Toxicity: According to animal studies, Triptorelin poses a risk of fetal harm. Pregnant women and females of reproductive potential should be informed of potential risks, considering maternal toxicity and embryo-fetal toxicities observed in animal studies.

It is unsafe to consume Triptorelin with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

Limit intake of saturated fats and consume nutrient-rich, high-fibre,omega-3 foods.

The adverse reactions related to Triptorelin can be categorized as

•Common Adverse Effects: Hot flushes, injection site pain, headache, skeletal pain, nasopharyngitis and injection site redness.

•Less Common Adverse Effects: Impotence, hypertension, generalized pain, vomiting, fatigue, insomnia, urinary tract infection (UTI), diarrhoea, pruritus, upper respiratory infection, vaginal bleeding and cough

•Rare Adverse Effects: Spinal cord compression and injection site pruritus.

Reports on Postmarketing

Apoplexy in the pituitary

convulsions

Interstitial lung disease

thromboembolic events, such as thrombophlebitis, pulmonary emboli, CVA, MI, and DVT

Non-alcoholic fatty liver disease

Idiopathic intracranial hypertension is known as pseudotumor cerebri

The clinically relevant drug interactions of Triptorelin are briefly summarized here.

• Drug-Drug Interaction: Triptorelin may interact with medications that address heart rhythm issues, such as antipsychotics, antibiotics, procainamide, amiodarone, and sotalol, as well as opioid pain relievers like methadone and quinidine.
• Drug-Food Interaction: None have been identified or established.
• Drug-Disease Interaction: People with high cholesterol, depression, brain tumours, electrolyte imbalance, diabetes, liver or renal problems, heart disease, recent heart attack, weak bones, fits, and seizures should use triptorelin with caution.

The common side effects of Triptorelin include weakness, diminished sexual desire, increased sweating, back pain, testicular shrinkage, breast tenderness or swelling, dizziness, erectile dysfunction, headaches, flu-like symptoms, nausea, vomiting, diarrhoea, upset stomach, leg swelling, paresthesia (tingling or prickling), and hot flashes.

• Pregnancy

Pregnancy Category X (FDA): The risks outweigh the potential benefits. Safer alternatives exist.

Pregnant women who receive therapy may experience fetal harm due to the mechanism of action and findings from animal studies; pregnancy loss is more likely due to expected hormonal changes associated with treatment; in animal developmental and reproductive toxicology studies, daily drug administration to pregnant rats during organogenesis caused maternal toxicity and embryo-fetal toxicities, including pregnancy loss, at doses as low as 0.2, 0.8, and 8 times estimated daily human dose based on body surface area; pregnant patients and females of reproductive potential should be advised of the potential risk to fetus.

Treatment may reduce fertility in males capable of reproducing, depending on the mode of action.

• Nursing Mothers

In females, the safety and effectiveness of triptorelin have not been proven. No information is available regarding triptorelin's presence in human milk, the medication's effects on milk production, or the drug's effects on a breastfed infant. Given the risk of severe side effects in a breastfed child from triptorelin, the mother's need for the medication must be taken into consideration while deciding whether to stop nursing or stop taking it altogether.

• Pediatric Use

As per the FDA, the safety and efficacy in patients under 2 years of age have not been established.

Dosage adjustment

Central Precocious Puberty

<2 years: Safety and efficacy not established

≥2 years: 22.5 mg IM q6Months

Considerations for Dosing

Once puberty has reached the appropriate age, discontinue.

Monitor on

LH levels at the start of therapy, every month or two after that, and with each new dosage.

Every three to six months, measure height and periodically check bone age.

The preputial process may be impacted by irregular gonadotropin and/or sex steroid levels due to noncompliance or insufficient dose. Insufficient dosage can necessitate transferring to a different GnRH agonist.

• Geriatric Use

The safety and efficacy of Triptorelin in the geriatric population have been established for conditions like prostate cancer and endometriosis. It effectively manages hormonal imbalances with a favourable safety profile, improving older individuals' health outcomes.

Prostate cancer occurs primarily in the older population. Clinical studies with Triptorelin have been conducted mainly in patients ≥ 65 years.

Dose Adjustment in Kidney Impairment Patients:

Renal impairment: Not studied

Dose Adjustment in Hepatic Impairment Patients:

Hepatic impairment: Not studied

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Triptorelin.

Overdosage in clinical studies has yet to be reported. Triptorelin's subcutaneous LD50 in mice and rats was 400 mg/kg and 250 mg/kg in rats, respectively, in single-dose toxicity studies. This is roughly 500 and 600 times the anticipated monthly human dose based on body surface area.

Overdosing has no known cure; hence, the option for therapy is to stop the treatment immediately, followed by symptomatic treatment. If the patient is awake, it is possible to induce vomiting. It is recommended to provide general supportive care, which includes regular vital sign monitoring and careful patient observation.

Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

Following the first administration of triptorelin, a transient surge of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and testosterone occurs. The time, peak, and decline of testosterone vary with the administered dose. This surge can exacerbate symptoms of prostate cancer in its early stages, such as urethral or bladder outlet obstruction, bone pain, spinal cord injury, and hematuria. A sustained decrease in FSH and LH and a significant reduction in testicular steroidogenesis typically occur 2-4 weeks post-initiation of therapy. This leads to a reduction in serum testosterone levels comparable to those in surgically castrated men, rendering tissues and functions dependent on these hormones inactive. The effects of triptorelin are usually reversible upon discontinuation of the drug.

Pharmacokinetics:

• Absorption: Following a single intramuscular injection of Triptorelin in prostate cancer patients, peak serum concentrations occurred 1 to 3 hours post-injection. The 3.75 mg, 11.25 mg, and 22.5 mg dosage strength resulted in mean peak serum concentrations of 28.4 ng/mL, 38.5 ng/mL, and 44.1 ng/mL, respectively.

• Distribution: In healthy male volunteers receiving a 0.5 mg intravenous bolus dose of triptorelin peptide, the volume of distribution ranged from 30 to 33 L. Notably, triptorelin does not exhibit evidence of binding to plasma proteins at clinically relevant concentrations.

• Metabolism: The metabolic pathways of triptorelin in humans remain unknown, with minimal likelihood of involving hepatic microsomal enzymes such as cytochrome P-450. The impact of triptorelin on other drug-metabolizing enzymes is also unclear. Currently, no identifiable metabolites of triptorelin have been recognized. Pharmacokinetic data suggest that C-terminal fragments produced during tissue degradation are either fully degraded within the tissues or rapidly cleared by the kidneys.

• Excretion: Triptorelin undergoes elimination via the liver and kidneys, primarily excreted in the urine, with 42% as intact peptides. The elimination half-life is approximately 2.8 ± 1.2 hours, reflecting the efficient triptorelin clearance from the body.

• Zenaty D, Blumberg J, Liyanage N, Jacqz-Aigrain E, Lahlou N, Carel JC; Co-Investigators. A 6-Month Trial of the Efficacy and Safety of Triptorelin Pamoate (11.25 mg) Every 3 Months in Children with Precocious Puberty: A Retrospective Comparison with Triptorelin Acetate. Horm Res Paediatr. 2016;86(3):188-195. doi: 10.1159/000448840. Epub 2016 Sep 7. PMID: 27603324.
• Choktanasiri W, Boonkasemsanti W, Sittisomwong T, Kunathikom S, Suksompong S, Udomsubpayakul U, Rojanasakul A. Long-acting triptorelin for the treatment of endometriosis. Int J Gynaecol Obstet. 1996 Sep;54(3):237-43. doi: 10.1016/0020-7292(96)02698-7. PMID: 8889631.
• Alshehre SM, Duffy S, Jones G, Ledger WL, Metwally M. A prospective, single-centre, single-arm, open label study of the long term use of a gonadotropin releasing hormone agonist (Triptorelin SR, 11.25 mg) in combination with Tibolone add-back therapy in the management of chronic cyclical pelvic pain. Reprod Biol Endocrinol. 2020 Apr 14;18(1):28. doi: 10.1186/s12958-020-00586-z. PMID: 32290838; PMCID: PMC7155249.
• Kong H, Hu L, Nie L, Yu X, Dai W, Li J, Chen C, Bu Z, Shi H, Wu Q, Guan Y, Sun Y. A multi-center, randomized controlled clinical trial of the application of a shortened protocol of long-acting Triptorelin down-regulated prior to IVF/ICSI among patients with endometriosis: A protocol. Reprod Health. 2018 Dec 20;15(1):213. doi: 10.1186/s12978-018-0639-8. PMID: 30572916; PMCID: PMC6302481.

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