Triptodur

Name: Triptodur

What special precautions should I follow?

Before receiving triptorelin injection,

  • tell your doctor and pharmacist if you are allergic to triptorelin, goserelin (Zoladex), histrelin (Supprelin LA, Vantas), leuprolide (Eligard, Lupron), nafarelin (Synarel), any other medications, or any of the ingredients in triptorelin injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone); bupropion (Aplenzin, Wellbutrin, Zyban); carbamazepine (Tegretol, Teril, others); methyldopa (in Aldoril); metoclopramide (Reglan); reserpine, or selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac, Sarafem), sertraline (Zoloft), and paroxetine (Paxil). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you or anyone in your family has ever had long QT syndrome (condition that increases the risk of developing an irregular heartbeat that may cause fainting or sudden death). Also tell your doctor if you have or have ever had diabetes; cancer that has spread to the spine (backbone),; urinary obstruction (blockage that causes difficulty urinating), a low level of potassium, calcium, or magnesium in your blood, a heart attack; heart failure; a mental illness; a seizure or epilepsy; a stroke, mini-stroke, or other brain problems; a brain tumor; or heart, kidney, or liver disease.
  • you should know that triptorelin is not to be used in women who are pregnant or who can become pregnant. Tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you think you have become pregnant while using triptorelin injection, call your doctor immediately. Triptorelin injection can harm the fetus.

What side effects can this medication cause?

Triptorelin injection may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • headache
  • heartburn
  • constipation
  • hot flashes (a sudden wave of mild or intense body heat), sweating, or clamminess
  • decreased sexual ability or desire
  • mood changes such as crying, irritability, impatience, anger, and aggression
  • leg or joint pain
  • breast pain
  • depression
  • pain, itching, swelling, or redness at the place where injection was given
  • difficulty falling asleep or staying asleep
  • cough

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

  • hives
  • rash
  • itching
  • difficulty breathing or swallowing
  • swelling of the face, eyes, mouth, throat, tongue, or lips
  • hoarseness
  • seizures
  • chest pain
  • pain in the arms, back, neck, or jaw
  • slow or difficult speech
  • dizziness or fainting
  • weakness or numbness of an arm or leg
  • not able to move legs
  • bone pain
  • painful or difficult urination
  • blood in urine
  • frequent urination
  • extreme thirst
  • weakness
  • blurred vision
  • dry mouth
  • nausea
  • vomiting
  • breath that smells fruity
  • decreased consciousness

In children receiving triptorelin injection (Triptodur) for central precocious puberty, new or worsening symptoms of sexual development may occur during the first few weeks of treatment. In girls, the onset of menstruation or spotting (light vaginal bleeding) may occur during the first two months of this treatment. If bleeding continues beyond the second month, call your doctor.

Triptorelin injection may cause other side effects. Call your doctor if you have any unusual problems while using this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

How supplied

Dosage Forms And Strengths

For extended-release injectable suspension: 22.5 mg of triptorelin as a lyophilized white to slightly yellow powder cake in a single-dose vial for reconstitution with the co-packaged 2 mL of diluent (Sterile Water) for Injection.

Storage And Handling

Each TRIPTODUR 22.5 mg single-use kit (NDC 24338-150-20) contains:

  • One single-dose vial of TRIPTODUR 22.5 mg (NDC 24338-150-01) with a Flip-Off seal containing sterile lyophilized white to slightly yellow powder cake
  • One sterile, glass syringe with Luer Lock prefilled with 2 mL of Sterile Water for Injection (NDC 24338-150-02)
  • Two sterile 21 gauge, 1.” needles (thin-wall) with safety cover
  • One Package Insert

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Do not freeze.

Distributed by: Arbor Pharmaceuticals, LLC Atlanta, GA 30328. Revised: June 2017

Clinical pharmacology

Mechanism Of Action

Triptorelin is a GnRH agonist.

Pharmacodynamics

Following the first administration, there is a transient surge in circulating levels of LH, FSH, testosterone, and estradiol [see WARNINGS AND PRECAUTIONS]. After chronic and continuous administration, by 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction in sex steroids are observed.

Pharmacokinetics

Absorption

After an initial intramuscular TRIPTODUR 22.5 mg injection and a second 22.5 mg intramuscular injection 24 weeks later in children 2 to 9 years old with CPP, triptorelin peaked 4 hours postdose with a geometric mean Cmax of 39.9 and 36.5 ng/mL, respectively. No apparent accumulation of triptorelin occurred after the second injection. Absorption occurred in two phases, a burst phase followed by a maintenance release phase. In children with CPP, following the burst phase after the first 22.5 mg injection, geometric mean serum triptorelin levels were 0.11, 0.17, 0.05 and 0.03 ng/mL at Months 1, 2, 3, and 6, respectively.

Distribution

There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins.

Elimination

Metabolism

The metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P450). Thus far no metabolites of triptorelin have been identified. Pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys.

Excretion

Triptorelin is eliminated by both the liver and the kidneys. Following intravenous administration of 0.5 mg triptorelin peptide to six healthy male volunteers with a creatinine clearance of 149.9 mL/min, 41.7% of the dose was excreted in urine as intact peptide with a total triptorelin clearance of 211.9 mL/min. This percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 mL/min). It has also been observed that the nonrenal clearance of triptorelin (patient anuric, Clcreat = 0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver.

Specific Populations

Renal Impairment

After intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by renal impairment. However, renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in the elimination half-life. Adult male subjects with moderate or severe renal impairment had approximately 2-fold higher exposure (AUC values) than young healthy adult males (see Table 1) [see Use In Specific Populations].

Hepatic Impairment

After intravenous bolus injection of 0.5 mg triptorelin in adults, the two distribution half-lives were unaffected by hepatic impairment. In adult males with hepatic insufficiency, triptorelin clearance was reduced and exposure (AUC) was increased 3.7-fold compared to young healthy adult males (Table 2) [see Use In Specific Populations].

Table 2 Pharmacokinetic Parameters (Mean ± SD) in Healthy Adults, Adults with Renal Impairment, and Adults with Hepatic Impairment Following an I.V. Bolus of 0.5 mg Triptorelin in Solution

Group Cmax
(ng/mL)
AUCinf
(h·ng/mL)
Clp
(mL/min)
Clrenal
(mL/min)
t1/2
(h)
Clcreat
(mL/min)
6 healthy male volunteers 48.2 ±11.8 36.1 ±5.8 211.9 ±31.6 90.6 ±35.3 2.81 ±1.21 149.9 ±7.3
6 males with moderate renal impairment 45.6 ±20.5 69.9 ±24.6 120.0 ±45.0 23.3 ±17.6 6.56 ±1.25 39.7 ±22.5
6 males with severe renal impairment 46.5 ±14.0 88.0 ±18.4 88.6 ±19.7 4.3 ±2.9 7.65 ±1.25 8.9 ±6.0
6 males with liver disease 54.1 ±5.3 131.9 ±18.1 57.8 ±8.0 35.9 ±5.0 7.58 ±1.17 89.9 ±15.1

Drug-Drug Interactions

In Vitro Assessment Of Drug Interactions

Drug Metabolizing Enzyme Inhibition

Triptorelin did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 or 2D6, or CYP 3A4/5 at clinically relevant concentrations.

Drug Metabolizing Enzyme Induction

In fresh human hepatocytes from three human donors, triptorelin did not induce CYP1A2 or CYP3A4/5 activity.

Transporters

Triptorelin was a poor P-gp substrate and had no inhibitory effect toward P-gp.

Clinical Studies

In a single-arm open-label study, 44 children 2 to 9 years of age with CPP, 39 females and 5 males, all naive to previous GnRH agonist treatment, were administered TRIPTODUR 22.5 mg at a dosing interval of 24 weeks. Subjects were evaluated over two dosing intervals for a total of 12 months.

TRIPTODUR 22.5 mg suppressed pituitary release of LH and FSH and, consequently, gonadal secretion of estradiol in girls and testosterone in boys (Table 3). At all timepoints evaluated, ≥93% of children achieved LH suppression to prepubertal levels (i.e., serum LH ≤5 IU/L 30 minutes after GnRH agonist stimulation), ≥79% of girls achieved prepubertal levels of estradiol (i.e., <20 pg/mL), and ≥80% of boys achieved prepubertal levels of testosterone (i.e., <30 ng/dL). TRIPTODUR arrested or reversed progression of clinical signs of puberty with 95% of children showing no increase in the bone age/chronological age ratio, and 89% showing stabilization of sexual maturation at Month 12.

Table 3 Efficacy of TRIPTODUR 22.5 mg Administered Every 6 Months to Children with CPPa

Endpoint % (n/N) of Children Achieving Endpoint
Month 1 Month 2 Month 3 Month 6 Month 9 Month 12
% with prepubertal LH (GnRH-stim LH ≤5 IU/L) 95% (42/44) 95% (42/44) 95% (42/44) 93%b (41/44) 95% (42/44) 98% (43/44)
% girls with prepubertal estradiol (<20 pg/mL) 87% (34/39) 89% (34/38) 92% (36/39) 79% (31/39) 82% (32/39) 79% (31/39)
% boys with prepubertal testosterone (<30 ng/dL) 80% (4/5) 80% (4/5) 100% (5/5) 100% (5/5) 80% (4/5) 80% (4/5)
% with no increase in BA/CAc ratio vs. baseline       64% (28/44)   95% (42/44)
% achieving stabilization of sexual maturation       91% (40/44)   89% (39/44)
% girls with regression of uterine length       69% (27/39)   77% (30/39)
% boys with no progression in testis volumes       100% (5/5)   100% (5/5)
a-Intent-to-Treat population
b-Primary efficacy endpoint.
c-Bone Age/Chronological Age

Following the second TRIPTODUR injection, 22 children (all girls) were assessed for evidence of an acute-on-chronic phenomenon (i.e., increase in basal LH >5 IU/L or serum estradiol level >20 pg/mL 48 hours after the second triptorelin injection). Of these, one girl who achieved prepubertal hormone levels prior to the second injection showed biochemical evidence of acute-on-chronic phenomenon [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Side effects

The following serious adverse reactions are described here and elsewhere in the label:

  • Initial Rise of Gonadotropins and Sex Steroid Levels [see WARNINGS AND PRECAUTIONS]
  • Psychiatric Events [see WARNINGS AND PRECAUTIONS]
  • Convulsions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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 trials of another drug and may not reflect the rates observed in practice.

The safety of TRIPTODUR was evaluated in one uncontrolled, open-label single arm clinical trial in which 44 children with central precocious puberty received two doses of TRIPTODUR and were observed for 12 months. The median age of the study population was 8 years (range 2-9 years) at treatment start; 88.6% of subjects were female, 59.1% were White, 27.3% were Black and 4.5% were Asian. Table 1 shows all the adverse reactions that occurred in at least 2 patients (≥4.5%) during the open-label single-arm trial.

Table 1: Adverse Reactions1 Occurring in ≥2 Patients Treated with TRIPTODUR in an Open-Label Single-Arm Trial

Adverse Reactions Number of Patients Reporting Event (%)
(Total N=44)
Infections & Infestations
  Bronchitis 2 (4.5)
  Gastroenteritis 3 (6.8)
  Influenza 2 (4.5)
  Nasopharyngitis 6 (13.6)
  Otitis externa 2 (4.5)
  Pharyngitis 2 (4.5)
  Sinusitis 2 (4.5)
  Upper respiratory tract infection 4 (9.1)
Nervous System Disorders
  Headache 6 (13.6)
Reproductive system & breast disorders
  Menstrual (Vaginal bleeding)2 3 (7.7)
Respiratory, thoracic & mediastinal disorder
  Cough 3 (6.8)
Vascular disorders
  Hot flush 2 (4.5)
1Injection site reactions are presented separately
2Includes % of patients with vaginal bleeding or menstrual disorder (“menstrual cycle returned”) in 39 females out of N=44.

Other Selected Adverse Reactions:

Injection site reactions

Injection site reactions occurring in patients immediately and/or 2 hours after injection include pain (45%), redness (14%), pruritus (2.3%) and swelling (2.3%).

Psychiatric Disorders

Anxiety (2.3%) and mood altered (2.3%)

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions were reported from postmarketing experience of triptorelin in patients with CPP:

Hypersenstivity Reactions: Anaphylactic shock, anaphylactoid reaction, angioedema, urticaria.

Cardiovascular: Hypertension.

Psychiatric: Emotional lability, such as crying, irritability, impatience, anger, and aggression, has been observed with GnRH agonists, including triptorelin [see WARNINGS AND PRECAUTIONS]; Depression, including rare reports of suicidal ideation and attempt, has been reported for GnRH agonists in children treated for CPP. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.

Nervous System: Convulsions [see WARNINGS AND PRECAUTIONS]

Vision disorders: Visual impairment, visual disturbance

Read the entire FDA prescribing information for Triptodur (Triptorelin for Extended-release Injectable Suspension)

Read More »

Dosage Forms and Strengths

For extended-release injectable suspension: 22.5 mg of triptorelin as a lyophilized white to slightly yellow powder cake in a single-dose vial for reconstitution with the co-packaged 2 mL of diluent (Sterile Water) for Injection.

Contraindications

  • Hypersensitivity: Triptodur is contraindicated in individuals with a known hypersensitivity to triptorelin, any other component of the product, or other GnRH agonists or GnRH [see Adverse Reactions (6.2)].
  • Pregnancy: Triptodur may cause fetal harm [see Use in Specific Populations (8.1)].

How Supplied/Storage and Handling

Each Triptodur 22.5 mg single-use kit (NDC 24338-150-20) contains:

  • One single-dose vial of Triptodur 22.5 mg (NDC 24338-150-01) with a Flip-Off seal containing sterile lyophilized white to slightly yellow powder cake
  • One sterile, glass syringe with Luer Lock prefilled with 2 mL of Sterile Water for Injection (NDC 24338-150-02)
  • Two sterile 21 gauge, 1½" needles (thin-wall) with safety cover
  • One Package Insert

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. Do not freeze.

For Healthcare Professionals

Applies to triptorelin: intramuscular powder for injection, intramuscular powder for injection extended release

General

The most common adverse events were hot flushes, impotence, decreased libido, skeletal pain, and headache.[Ref]

Cardiovascular

Very common (10% or more): Hot flush (up to 73%), hypertension (14.2%)
Common (1% to 10%): Dependent edema
Uncommon (0.1% to 1%): Embolism
Rare (less than 0.1%): Hypotension
Postmarketing reports: Blood pressure increased, thromboembolic events including, but not limited to, pulmonary emboli, cerebrovascular accident, myocardial infarction, deep venous thrombosis, transient ischemic attack, and thrombophlebitis[Ref]

Genitourinary

Very common (10% or more): Impotence (30 to 40%), urinary tract infection (11.6%), erectile dysfunction (10%), dysuria; women: dyspareunia, dysmenorrhea, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, vulvovaginal dryness, bleeding/spotting, genital hemorrhage (including menorrhagia and metrorrhagia)
Common (1% to 10%): Testicular atrophy, breast pain, gynecomastia, urinary retention, vaginal bleeding (children)
Uncommon (0.1% to 1%): Testicular pain, vaginal discharge (children)
Rare (less than 0.1%): Ejaculation failure
Frequency not reported: Testosterone levels increased, testosterone levels decreased, worsening of urethral or bladder outlet obstruction, worsening of symptoms of endometriosis
Postmarketing reports: Amenorrhea[Ref]

At the beginning of treatment, endometriosis symptoms including pelvic pain and dysmenorrhea are commonly exacerbated due to an initial transient increase in plasma estradiol levels. These symptoms are transient and usually disappear in one to two weeks.[Ref]

Psychiatric

Very common (10% or more): Decreased libido (30 to 40%), sleep disorders, mood changes
Common (1% to 10%): Insomnia, emotional lability, loss of libido, depression, depressed mood, irritability
Rare (less than 0.1%): Confusional state, decreased activity, euphoric mood
Postmarketing reports: Anxiety, affect lability, nervousness[Ref]

Hematologic

Very common (10% or more): Decreased hemoglobin, decreased red blood count
Common (1% to 10%): Anemia
Frequency not reported: Increased lymphocyte count[Ref]

Hepatic

Very common (10% or more): Increased AST, increased ALT, increased alkaline phosphatase, increased hepatic transaminases
Common (1% to 10%): Abnormal hepatic function
Uncommon (0.1% to 1%): Gama-glutamyl transferase increased
Rare (less than 0.1%): Blood alkaline phosphatase increased[Ref]

Metabolic

Very common (10% or more): Increased glucose
Common (1% to 10%): Diabetes mellitus/hyperglycemia, anorexia
Uncommon (0.1% to 1%): Weight increased, gout, increased appetite, weight decreased[Ref]

Renal

Very common (10% or more): Increased BUN
Uncommon (0.1% to 1%): Blood creatinine increased
Frequency not reported: Worsening hematuria, decreased kidney function[Ref]

Respiratory

Very common (10% or more): Influenza (15.8%)
Common (1% to 10%): Bronchitis, coughing, dyspnea, pharyngitis
Uncommon (0.1% to 1%): Asthma aggravated
Rare (less than 0.1%): Orthopnea, epistaxis, nasopharyngitis[Ref]

Musculoskeletal

Very common (10% or more): Skeletal pain (13.2%), back pain (10.8%)
Common (1% to 10%): Pain in extremity, arthralgia, edema in legs, leg cramps, myalgia, musculoskeletal pain, muscle spasms
Uncommon (0.1% to 1%): Muscle cramp, muscular weakness
Rare (less than 0.1%): Joint stiffness, joint swelling, musculoskeletal stiffness, osteoarthritis
Frequency not reported: Worsening of bone pain, increased bone loss, osteoporosis, bone fracture, bone disorder, epiphysiolysis, slipped capital femoral epiphysis
Postmarketing reports: Bone pain[Ref]

Nervous system

Very common (10% or more): Paresthesia in lower limbs
Common (1% to 10%): Headache, dizziness, fatigue
Uncommon (0.1% to 1%): Tinnitus, somnolence, paresthesia
Rare (less than 0.1%): Vertigo, dysstasia, memory impairment
Frequency not reported: Worsening of neuropathy, spinal cord compression with weakness or paralysis of the lower extremities
Postmarketing reports: Convulsions[Ref]

Other

Very common (10% or more): Asthenia
Common (1% to 10%): Leg pain, peripheral edema, leg pain, back pain, fatigue, chest pain, edema
Uncommon (0.1% to 1%): Lethargy, pain, rigors, blood lactate dehydrogenase increased, blood cholesterol increased
Rare (less than 0.1%): Pyrexia, influenza like illness, body temperature increased
Frequency not reported: Chills
Postmarketing reports: Malaise[Ref]

Dermatologic

Very common (10% or more): Hyperhidrosis
Common (1% to 10%): Rash, pruritus
Uncommon (0.1% to 1%): Acne, alopecia, hypotrichosis
Rare (less than 0.1%): Purpura, blister
Postmarketing reports: Angioneurotic edema, urticaria[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity reaction
Uncommon (0.1% to 1%): Allergic reactions
Rare (less than 0.1%): Anaphylactic reaction, hypersensitivity
Frequency not reported: Anaphylactic shock, angioedema[Ref]

Local

Common (1% to 10%): Injection site pain, injection site reactions, injection site erythema, injection site inflammation[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, vomiting, constipation, dyspepsia, diarrhea, abdominal pain, abdominal discomfort
Uncommon (0.1% to 1%): Abdominal pain upper, dry mouth
Rare (less than 0.1%): Abdominal distension, dysgeusia, flatulence
Frequency not reported: Gastralgia[Ref]

Ocular

Common (1% to 10%): Eye pain, conjunctivitis
Rare (less than 0.1%): Abnormal sensation in eye, visual disturbance
Postmarketing reports: Vision blurred[Ref]

Oncologic

Frequency not reported: Tumor flare, exacerbation of disease symptoms
Postmarketing reports: Pituitary adenoma[Ref]

Tumor flare occurred in 5% or less of patients, usually manifested by an increase in urinary symptoms and metastatic pain.[Ref]

Endocrine

Postmarketing reports: Pituitary apoplexy[Ref]

The majority of pituitary apoplexy cases occurred within 2 weeks of the first dose, some within the first hour. In these cases, pituitary apoplexy presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.[Ref]

Some side effects of Triptodur may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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