Triptodur

Triptorelin is a man-made form of a hormone that regulates many processes in the body. Triptorelin overstimulates the body's own production of certain hormones, which causes that production to shut down temporarily.

The Trelstar brand of triptorelin is used in men to treat the symptoms of prostate cancer. Trelstar treats only the symptoms of prostate cancer and does not treat the cancer itself.

The Triptodur brand of triptorelin is used to treat precocious puberty in boys and girls who are at least 2 years old.

Triptorelin may also be used for purposes not listed in this medication guide.

Triptorelin is injected into a muscle. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to give the injection and properly dispose of used needles and syringes.

Triptorelin is usually given once every 4, 12, or 24 weeks. Your dose schedule will depend on the strength and brand of triptorelin you are using.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Triptorelin is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

Triptorelin can increase certain hormones when you first start using this medicine or after each new injection. This may cause symptoms of prostate cancer or precocious puberty to get worse for a short time. These side effects should get better within 1 to 2 months. Call your doctor if your symptoms do not improve, or if they get worse while using triptorelin.

While using triptorelin, you may need frequent medical tests.

Each single-use vial (bottle) of this medicine is for one use only. Throw it away after one use, even if there is still medicine left inside.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Store at room temperature away from moisture and heat. Do not freeze.

Call your doctor for instructions if you miss a dose, or if you miss an appointment for your triptorelin injection.

Get emergency medical help if you have signs of an allergic reaction: hives, red skin rash, severe itching, sweating; dizziness, fast heartbeats; trouble breathing or swallowing; swelling of your face, lips, tongue, or throat.

Triptorelin can cause a temporary increase in certain hormones, especially when you first start using this medicine. This may cause side effects that are similar to the condition being treated. Call your doctor at once if you have:

• painful or difficult urination, burning when you urinate, blood in the urine;

• bone pain;

• (in children) new or worsening signs of puberty;

• a seizure;

• chest pain or pressure, pain spreading to your jaw or shoulder;

• sudden numbness or weakness, slurred speech;

• loss of movement in any part of your body;

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor; or

• nerve problems--back pain, muscle weakness, problems with balance or coordination, severe numbness or tingling in your legs or feet, loss of bladder or bowel control.

Common side effects may include:

• pain, swelling, itching, or redness where an injection was given;

• hot flashes;

• decreased interest in sex, impotence, trouble having an orgasm;

• headache, bone pain, pain or swelling in your legs;

• nausea, vomiting, diarrhea, upset stomach;

• vaginal bleeding; or

• cold or flu symptoms (stuffy nose, sneezing, cough, sore throat, ear pain).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Initial Rise of Gonadotropins and Sex Steroid Levels

During the early phase of initial therapy or after subsequent doses, gonadrotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug [see Clinical Pharmacology (12.2)]. Therefore, a transient increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses.

Psychiatric Events

Psychiatric events have been reported in patients taking GnRH agonists, including triptorelin. Postmarketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with Triptodur [see Adverse Reactions (6)].

Convulsions

Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including triptorelin. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above [see Adverse Reactions (6)].

There is no experience with overdosage in clinical trials of triptorelin. If overdosage occurs, therapy should be discontinued and appropriate supportive and symptomatic treatment administered.

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 (5.2)]. 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 (8.6)].

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 (8.7)].

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.

In a single-arm open-label study, 44 children 2 to 9 years of age with CPP, 39 females and 5 males, all naïve 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.

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 (5.2) and Adverse Reactions (6.1)].

Applies to triptorelin: intramuscular powder for suspension

Along with its needed effects, triptorelin (the active ingredient contained in Triptodur) 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 while taking triptorelin:

• 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 of triptorelin 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