Trelstar LA

In the U.S.

• Trelstar
• Trelstar Depot
• Trelstar LA
• Triptodur

Available Dosage Forms:

• Powder for Suspension, 6 Month
• Powder for Suspension

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Luteinizing Hormone Releasing Hormone Agonist

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of triptorelin to treat advanced prostrate cancer in the pediatric population. Safety and efficacy have not been established.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of triptorelin to treat central precocious puberty in children 2 years of age and older. Safety and efficacy have not been established in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of triptorelin to treat advanced prostrate cancer in the elderly.

Use of triptorelin injection to treat central precocious puberty in geriatric patients is not indicated.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Mesoridazine
• Pimozide
• Piperaquine
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin
• Amiodarone
• Amitriptyline
• Anagrelide
• Apomorphine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Asenapine
• Astemizole
• Atazanavir
• Azithromycin
• Bedaquiline
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Crizotinib
• Cyclobenzaprine
• Dabrafenib
• Dasatinib
• Delamanid
• Desipramine
• Deutetrabenazine
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Doxepin
• Droperidol
• Ebastine
• Efavirenz
• Eribulin
• Erythromycin
• Escitalopram
• Famotidine
• Felbamate
• Fingolimod
• Flecainide
• Fluconazole
• Fluoxetine
• Formoterol
• Foscarnet
• Fosphenytoin
• Galantamine
• Gatifloxacin
• Gemifloxacin
• Granisetron
• Halofantrine
• Haloperidol
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Iloperidone
• Imipramine
• Itraconazole
• Ivabradine
• Ketoconazole
• Lapatinib
• Levofloxacin
• Lumefantrine
• Mefloquine
• Methadone
• Metronidazole
• Mifepristone
• Mizolastine
• Moxifloxacin
• Nelfinavir
• Nilotinib
• Norfloxacin
• Octreotide
• Ofloxacin
• Olanzapine
• Ondansetron
• Paliperidone
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Pentamidine
• Perphenazine
• Pimavanserin
• Pipamperone
• Pitolisant
• Posaconazole
• Probucol
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Ranolazine
• Ribociclib
• Rilpivirine
• Risperidone
• Ritonavir
• Sertindole
• Sevoflurane
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• Sulpiride
• Sunitinib
• Tacrolimus
• Tamoxifen
• Telaprevir
• Telavancin
• Telithromycin
• Tetrabenazine
• Tizanidine
• Tolterodine
• Toremifene
• Trazodone
• Trimipramine
• Vandetanib
• Vardenafil
• Vemurafenib
• Venlafaxine
• Vilanterol
• Vinflunine
• Voriconazole
• Vorinostat
• Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bladder blockage or
• Depression, history of or
• Diabetes or
• Heart or blood vessel disease or
• Hyperglycemia (high blood sugar) or
• Mental illness, history of or
• Spinal cord problems—Use with caution. May make these conditions worse.

• Brain or brain vessel problems or tumors, history of or
• Seizures, history of—May increase the risk for seizures.

• Congestive heart failure or
• Electrolyte imbalance or
• Heart rhythm problems (eg, congenital long QT syndrome)—May cause side effects to become worse.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

This medicine may cause a serious type of allergic reaction, called anaphylaxis. This can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after you receive the medicine.

Patients receiving triptorelin injection for advanced prostrate cancer:

• When you first start using this medicine, some of your symptoms might get worse or you might have new symptoms for a short time. Tell your doctor right away if you have bone pain, back pain, a tingling or numbness in the body, blood in the urine, or trouble urinating.
• Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem, such as QT prolongation.
• This medicine may cause changes in your blood sugar levels. Check with your doctor if you notice a change in the results of your blood or urine sugar tests.
• This medicine may increase your risk of having a heart attack or stroke. Call your doctor right away if you have chest pain or discomfort, pain or discomfort in the arms, jaw, back, or neck, shortness of breath, nausea, sweating, or vomiting.

Patients receiving triptorelin injection for central precocious puberty (CPP):

• This medicine can cause a brief increase in blood levels of some hormones. During this time, you may notice more signs of puberty in your child, including light vaginal bleeding in girls. If your child's symptoms do not improve within 2 months, or if they get worse, call your doctor.
• Monitor your child's height every 3 to 6 months while on treatment with this medicine.
• This medicine may cause your child to be agitated, irritable, or display other abnormal behaviors. Make sure the doctor knows if your child has trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if your child has sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. If you or your caregiver notice any of these side effects, tell your doctor right away.
• Using this medicine may increase your child's risk of having seizures. Check with your doctor right away if your child starts to have convulsions, muscle spasm or jerking of all extremities, sudden loss of consciousness, or loss of bladder control.

Before you have any medical tests, tell the medical doctor in charge that you are using this medicine. The results of some tests may be affected by this medicine.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Diarrhea
• loss of appetite
• nausea
• stomach pain
• weakness

• Anxiety
• body aches or pain
• chills
• cough
• cough producing mucus
• difficulty with breathing
• ear congestion
• fever
• general feeling of discomfort or illness
• headache
• joint pain
• loss of voice
• mood or mental changes, including abnormal crying, aggression, agitation, delusions, irritability, nervousness, or restlessness
• muscle aches and pains
• nasal congestion
• runny nose
• shivering
• sneezing
• sore throat
• sweating
• tightness in the chest
• trouble sleeping
• unusual tiredness or weakness
• vomiting

• Bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• chest pain
• cough producing mucus
• decrease in urine volume or frequency of urination
• difficult or labored breathing
• difficult, burning, or painful urination
• difficulty in passing urine
• dizziness
• dry mouth
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• loss of consciousness
• lower back or side pain
• nausea
• nervousness
• pale skin
• pounding in the ears
• rapid weight gain
• slow or fast heartbeat
• stomach ache
• sweating
• tightness in the chest
• tingling of the hands or feet
• troubled breathing
• troubled breathing with exertion
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• vomiting

• Blurred or loss of vision
• depression
• difficulty with swallowing
• disturbed color perception
• dizziness
• double vision
• halos around lights
• hives, itching, skin rash
• nervousness
• night blindness
• overbright appearance of lights
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• seizures
• slow or fast heartbeat
• thoughts of killing oneself

• Anxiety
• changes in skin color
• changes in vision
• chest discomfort
• cold, clammy, or pale skin
• confusion
• dizziness or lightheadedness
• fainting
• inability to speak
• irregular heartbeat
• numbness or tingling in the face, arms, or legs
• pain
• pain or discomfort in the arms, jaw, back, or neck
• pain, redness, or swelling in the arm or leg
• seizures
• severe or sudden headache
• slow heart rate
• slurred speech
• sudden shortness of breath or troubled breathing
• temporary blindness
• tenderness
• trouble speaking, thinking, or walking
• weakness in the arm or leg on one side of the body, sudden and severe

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• stuffy or runny nose

• Bone pain
• chills
• decrease in testicle size
• decreased interest in sexual intercourse
• diarrhea
• feeling of warmth or redness of the face, neck, arms, and occasionally, upper chest
• fever
• general feeling of discomfort or illness
• inability to have or keep an erection
• joint pain
• leg pain
• loss in sexual ability, desire, drive, or performance
• loss of appetite
• muscle aches and pains
• redness of the face, neck, arms, and occasionally, upper chest
• runny nose
• shivering
• sore throat
• sudden sweating
• trouble sleeping

• Change in hearing
• dryness or soreness of the throat
• ear drainage
• earache
• hoarseness
• itching of the ears
• pain or tenderness around the eyes and cheekbones
• tender, swollen glands in the neck
• voice changes

• Back pain
• belching
• body aches or pain
• breast pain
• burning, dry, or itching eyes
• congestion
• crying
• depersonalization
• difficulty having a bowel movement
• difficulty with moving
• discharge or excessive tearing
• dysphoria
• euphoria
• eye pain
• heartburn
• hoarseness
• indigestion
• injection site pain
• itching or rash
• lack or loss of strength
• leg cramps
• loss of appetite
• muscle aching or cramping
• muscle pains or stiffness
• paranoia
• quick to react or overreact emotionally
• rapidly changing moods
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• runny nose
• stomach discomfort, upset, or pain
• swelling of the breasts or breast soreness in both females and males
• swollen joints
• tender, swollen glands in the neck
• trouble swallowing
• voice changes
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Mechanism of Action

Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Following the first administration, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol (see ADVERSE REACTIONS). After chronic and continuous administration, usually 2 to 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction of testicular and ovarian steroidogenesis is observed. In men, a reduction of serum testosterone concentration to a level typically seen in surgically castrated men is obtained. Consequently, the result is that tissues and functions that depend on these hormones for maintenance become quiescent. These effects are usually reversible after cessation of therapy.

Following a single intramuscular (IM) injection of Trelstar LA to men with advanced prostate cancer, serum testosterone levels first increased, peaking on days 2-3, and declined thereafter to low levels by weeks 3-4.

Pharmacokinetics

Results of pharmacokinetic investigations conducted in healthy men indicate that after intravenous (IV) bolus administration, triptorelin is distributed and eliminated according to a 3-compartment model and corresponding half-lives are approximately 6 minutes, 45 minutes, and 3 hours.

Triptorelin pamoate is not active when given orally. The pharmacokinetic parameters following a single IM injection of 11.25 mg of Trelstar LA to 13 patients with prostate cancer are listed in Table 1. Triptorelin did not accumulate over 9 months of treatment.

The volume of distribution following a single IV bolus dose of 0.5 mg of triptorelin peptide was 30-33 L in healthy male volunteers. There is no evidence that triptorelin, at clinically relevant concentrations, binds to plasma proteins.

The metabolism of triptorelin in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P-450). However, the effect of triptorelin on the activity of other drug metabolizing enzymes is unknown. 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.

Triptorelin is eliminated by both the liver and the kidneys. Following IV administration of 0.5 mg triptorelin peptide to 6 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, CIcreat=0) was 76.2 mL/min, thus indicating that the nonrenal elimination of triptorelin is mainly dependent on the liver (see Special Populations).

Special Populations:

After an IV bolus injection of 0.5 mg triptorelin peptide, the two distribution half-lives were unaffected by renal and hepatic impairment, but renal insufficiency led to a decrease in total triptorelin clearance proportional to the decrease in creatinine clearance as well as an increase in volume of distribution and consequently an increase in elimination half-life (Table 2). The decrease in triptorelin clearance was more pronounced in subjects with liver insufficiency, but the half-life was prolonged similarly in subjects with renal insufficiency, since the volume of distribution was only minimally increased. Patients with renal or hepatic impairment had 2- to 4-fold higher exposure (AUC values) than young healthy males.

The effects of age and race on triptorelin pharmacokinetics have not been systematically studied. However, pharmacokinetic data obtained in young healthy male volunteers aged 20 to 22 years with an elevated creatinine clearance (approximately 150 mL/min) indicates that triptorelin was eliminated twice as fast in this young population (see Special Populations, Renal and Hepatic Impairment) as compared to patients with moderate renal insufficiency. This is related to the fact that triptorelin clearance is partly correlated to total creatinine clearance, which is well known to decrease with age.

No pharmacokinetic drug-drug interaction studies have been conducted with triptorelin (see PRECAUTIONS, Drug Interactions).

Clinical Trials

Trelstar LA was studied in a randomized, active control trial of 346 men with advanced prostate cancer in South Africa. The clinical trial population consisted of 48% Caucasian, 38% Black, and 15% Other. Men were between 45 and 96 years of age (71 mean). Patients received either Trelstar LA (n = 174) every 84 days for a total of up to 3 doses (maximum treatment period of 252 days) or Trelstar Depot (n = 172) every 28 days for a total of up to 9 doses. The primary efficacy endpoints were both achievement of castration by Day 29 and maintenance of castration from Day 57 through Day 253.

Castration levels of serum testosterone (≤ 1.735 nmol/L) were achieved at Day 29 in 167 of 171 (97.7%) of patients treated with Trelstar LA.

Maintenance of castration levels of serum testosterone from Day 57 through Day 253 was found in 94.4% of patients treated with Trelstar LA.

Trelstar LA is indicated in the palliative treatment of advanced prostate cancer. It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration are either not indicated or unacceptable to the patient.

Rare reports of anaphylactic shock and angioedema related to triptorelin administration have been reported. In the event of a reaction, therapy with Trelstar LA should be discontinued immediately and the appropriate supportive and symptomatic care should be administered.

Initially, triptorelin, like other LHRH agonists causes a transient increase in serum testosterone levels. As a result, isolated cases of worsening of signs and symptoms of prostate cancer during the first weeks of treatment have been reported with LHRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LHRH agonists.

If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.

In the majority of patients, testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment. The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, hematuria, and bladder outlet obstruction. Isolated cases of spinal cord compression with weakness or paralysis of the lower extremities have occurred (see WARNINGS).

In a controlled, comparative clinical trial, the following adverse reactions were reported to have a possible or probable relationship to therapy as ascribed by the treating physician in 1% or more of the patients receiving triptorelin (Table 3). Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not drug-related or unlikely to be related are excluded.

Changes in Laboratory Values During Treatment: The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients at the Day 253 visit: decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase. The relationship of these changes to drug treatment is difficult to assess in this population.

Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

Trelstar LA Must Be Administered Under the Supervision of a Physician.

The recommended dose of Trelstar LA is 11.25 mg incorporated in a long acting formulation administered every 84 days as a single intramuscular injection administered in either buttock. The lyophilized microgranules are to be reconstituted in sterile water. No other diluent should be used. Reconstitute in accord with the following:

For Trelstar LA:

1. Using a syringe fitted with a sterile 20-gauge needle, withdraw 2 mL sterile water for injection, USP, and after removing the flip-off seal from the vial, inject into the vial.

2. Shake well to thoroughly disperse particles to obtain a uniform suspension. The suspension will appear milky.

3. Slowly withdraw the entire contents of the reconstituted suspension into the syringe.

4. Inject the patient in either buttock with the contents of the syringe.

For the Trelstar LA Clip'n'Ject® single-dose delivery system, see adjacent INSTRUCTIONS FOR CLIP'N'JECT® USE section.

The suspension should be discarded if not used immediately after reconstitution.

As with other drugs administered by intramuscular injection, the injection site should be altered periodically.

Before you begin read complete instructions.

Clip'n'Ject® Preparation

Wash your hands with soap and hot water and put on gloves immediately prior to preparing the injection. Place the package containing the Clip'n'Ject system and the Trelstar® vial on a clean, flat surface that is covered with a sterile pad or cloth. Peel the Tyvek® cover away from the blister package, and place the vial, connector, alcohol swab, and plunger rod on the prepared surface. Be sure to begin by removing the Flip-Off® button from the top of the vial, revealing the rubber stopper. Disinfect the rubber portion of the vial cap with the alcohol swab. Discard the alcohol swab and let the alcohol dry. Proceed to Clip'n'Ject Activation.

Clip'n'Ject® Activation

Clip'n'Ject® Disposal

After administering Trelstar®, dispose of the Clip'n'Ject system as follows:

1. Place Clip'n'Ject with attached vial in standing upright position on a flat surface.

2. Using one hand, replace the syringe into the Clip'n'Ject connector.

3. Dispose of syringe and attached Clip'n'Ject connector with vial into a suitable sharps container.