Sylatron

Name: Sylatron

Indications

SYLATRON™ is an alpha interferon indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

Clinical pharmacology

Mechanism Of Action

Peginterferon alfa-2b is a pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.

Pharmacokinetics

The pharmacokinetics was studied in 32 patients receiving adjuvant therapy for melanoma with SYLATRON according to the recommended dose and schedule (6 mcg/kg/week for 8 doses, followed by 3 mcg/kg/week thereafter). At a dose of 6 mcg/kg/week once weekly, the geometric mean Cmax was 4.4 ng/mL (CV 51%) and the geometric mean AUCtau was 430 ng•hr/mL (CV 35%) at week 8. The mean terminal half-life was approximately 51 hours (CV 18%). The mean accumulation from week 1 to week 8 was 1.7. After administration of 3 mcg/kg/week once weekly, the mean geometric Cmax was 2.5 ng/mL (CV 33%) and the geometric mean AUCtau was 228 ng•hr/mL (CV 24%) at week 4. The mean terminal half-life was approximately 43 hours (CV 19%).

Renal Impairment

Renal clearance accounts for approximately 30% of total peginterferon alfa-2b clearance. The effect of renal impairment on the pharmacokinetics of peginterferon alfa-2b was studied in 24 subjects with normal or impaired renal function after a single 4.5 mcg/kg dose. Compared to subjects with normal renal function (CLcr > 80 mL/min/1.73 m²), the geometric mean AUClast to peginterferon alfa-2b increased by 1.4-fold in subjects with moderate renal impairment (CLcr 30 to 50 mL/min/1.73m²) and 2.1-fold in subjects with severe renal impairment (CLcr < 30 mL/min/1.73m²) or ESRD requiring dialysis [see Use in Specific Populations].

No clinically meaningful amounts of peginterferon alfa-2b were removed during hemodialysis following a single 1 mcg/kg dose in subjects with renal impairment.

Drug Interactions

Peginterferon alfa-2b inhibits CYP1A2 and CYP2D6 activity. In a drug interaction study, healthy subjects received a dose of 200 mg of caffeine (CYP1A2 substrate), 2 mg of midazolam (CYP3A4 substrate), 500 mg of tolbutamide (CYP2C9 substrate), or 50 mg of desipramine (CYP2D6 substrate) before and after two doses of SYLATRON administered subcutaneously at a dose of 3 mcg/kg. The geometric mean AUClast was increased by 36% for caffeine and 30% for desipramine when coadministered with SYLATRON compared to caffeine or desipramine administered alone. No clinically meaningful changes in CYP2C9 activity and CYP3A4 activity were observed. [See DRUG INTERACTIONS]

Clinical Studies

The safety and effectiveness of SYLATRON were evaluated in an open-label, multicenter, randomized (1:1) study conducted in 1256 patients with surgically resected, AJCC Stage III melanoma within 84 days of regional lymph node dissection. Patients were randomized to observation (no therapy) (n=629) or to SYLATRON (n=627) at a dose of 6 mcg/kg by subcutaneous injection once weekly for 8 doses followed by a 3 mcg/kg subcutaneous injection once weekly for a period of up to 5 years total treatment. The dose of SYLATRON was adjusted to maintain an ECOG Performance Status of 0 to 1.

The median age of the population was 50 years with 11% of patients 65 years or older, and 42% were female. Forty percent of the study population had microscopic, nonpalpable nodal involvement and 59% had clinically palpable nodes prior to lymphadenectomy. A total of 54% of subjects had one pathologically positive lymph node, 34% had 2 to 4 positive nodes, and 12% had 5 or more. Most subjects had no second primary lesion (98%). Ulceration of the primary lesion was present in 30% of subjects (52% had no ulceration of the primary lesion, and the status was missing/unknown for 18% of subjects). The most common sites were the trunk (43%) or the leg (32%). Eighty-four percent had an International Prognostic Index (IPI) score of 0 and 16% had an IPI score of 1. The main outcome measure was relapse-free survival (RFS), defined as the time from randomization to the earliest date of any relapse (local, regional, in-transit, or distant), or death from any cause. Secondary outcome measures included overall survival.

Patients in the SYLATRON arm received 6 mcg/kg/week for a median of 8.0 weeks. Less than 1% of patients took longer than 9 weeks to complete the 6 mcg/kg/week dosing regimen. Approximately one-third (36%) of patients required dose reductions and 29% of patients required a dose delay, with an average delay of 1.2 weeks, during the initial 8 weeks of SYLATRON. Ninety-four patients (16%) did not continue on to the 3 mcg/kg/week dosing regimen.

Patients who continued on SYLATRON after the initial 8 doses, received 3 mcg/kg/week for a median duration of treatment of 14.3 months. Approximately half (52%) of the patients underwent dose reductions and 70% required dose delays (average delay 2.2 weeks).

Based on 696 RFS events, determined by the Independent Review Committee, median RFS was 34.8 months (95% CI: 26.1, 47.4) and 25.5 months (95% CI: 19.6, 30.8) in the SYLATRON and observation arms, respectively. The estimated hazard ratio for RFS was 0.82 (95% CI: 0.71, 0.96; unstratified log-rank p =0.011) in favor of SYLATRON. Figure 1 shows the Kaplan-Meier curves of RFS.

FIGURE 1: Kaplan-Meier Curves for Relapse-Free Survival

There was no statistically significant difference in survival between the SYLATRON and the observation arms. Based on 525 deaths, the estimated hazard ratio of SYLATRON versus observation was 0.98 (95% CI: 0.82, 1.16).

What should i avoid while using peginterferon alfa-2b (pegintron, pegintron redipen, sylatron)?

Treatment with this medication does not prevent spread of the hepatitis virus to other people. Follow your doctor's instructions about how to prevent passing the disease to another person.

Uses of Sylatron

Sylatron is a prescription medicine that is used alone to prevent malignant melanoma (a kind of skin cancer) from coming back after it has been removed by surgery. Sylatron should be started within 84 days of surgery to remove lymph nodes containing cancer.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using peginterferon alfa-2b?

Using this medicine will not prevent you from passing hepatitis to other people. Follow your doctor's instructions about how to prevent passing the disease to another person.

Avoid coffee, tea, cola, energy drinks, or other products that contain caffeine.

What other drugs will affect peginterferon alfa-2b?

Other drugs may interact with peginterferon alfa-2b, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Precautions While Using Sylatron

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

Using peginterferon alfa-2b together with ribavirin while you are pregnant can harm your unborn baby. These medicines may also cause birth defects if the father is using it when his sexual partner becomes pregnant. If a pregnancy occurs while you are using these medicines, tell your doctor right away.

A negative pregnancy test is needed in women who are of childbearing age before starting treatment with this medicine and ribavirin. Female patients and female partners of male patients must use 2 forms of birth control during therapy and for 6 months after therapy ends. Female patients must have regular pregnancy tests during combination therapy.

This medicine can increase thoughts of suicide in people with or without a history of a mental illness. This medicine may also cause relapse in people with a history of substance abuse. Tell your doctor right away if you start to feel more depressed or exhibit aggressive behavior. Also tell your doctor right away if you have thoughts of hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure your caregiver knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell your doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. If you, your child, or your caregiver notice any of these side effects during treatment and up to 6 months after treatment, tell your doctor or your child's doctor right away.

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

Serious allergic reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loose skin, fever or chills, hives or welts, red skin lesions, severe acne or skin rash, or sores or ulcers on the skin while you or your child are using this medicine.

Check with your doctor right away if blurred vision, difficulty in reading, eye pain, or any other change in vision occurs during or after treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Peginterferon alfa-2b injection combined with ribavirin can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets in the blood, which are necessary for proper blood clotting. If this occurs, there are certain precautions you or your child can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

  • If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
  • Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
  • Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
  • Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
  • Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
  • Avoid contact sports or other situations where bruising or injury could occur.

Check with your doctor right away if you or your child have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Peginterferon alfa-2b injection when used together with ribavirin may cause teeth and gum problems. These medicines may cause dryness of the mouth, and a dry mouth may damage your teeth and gums if you take these medicines for a long time. To help prevent this condition, carefully brush your teeth at least two times a day and have regular visits with your dentist. For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute.

Check with your doctor right away if you or your child have symptoms that could lead to pancreatitis. This includes sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Children who use peginterferon alfa-2b and ribavirin combination may have weight loss and slowed growth. Most children have a growth spurt and gain weight after therapy ends. If you have questions about this, talk to your doctor.

Peripheral neuropathy may occur if you use this medicine together with telbivudine (Tyzeka®). Check with your doctor right away if you or your child are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Uses of Sylatron

  • It is used to treat skin cancer.

What do I need to tell my doctor BEFORE I take Sylatron?

  • If you have an allergy to this medicine or any part of Sylatron.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have ever had any of these health problems: Autoimmune hepatitis or liver disease.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Sylatron with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Sylatron - Clinical Pharmacology

Mechanism of Action

Peginterferon alfa-2b is a pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.

Pharmacokinetics

The pharmacokinetics was studied in 32 patients receiving adjuvant therapy for melanoma with Sylatron according to the recommended dose and schedule (6 mcg/kg/week for 8 doses, followed by 3 mcg/kg/week thereafter). At a dose of 6 mcg/kg/week once weekly, the geometric mean Cmax was 4.4 ng/mL (CV 51%) and the geometric mean AUCtau was 430 ng∙hr/mL (CV 35%) at week 8. The mean terminal half-life was approximately 51 hours (CV 18%). The mean accumulation from week 1 to week 8 was 1.7. After administration of 3 mcg/kg/week once weekly, the mean geometric Cmax was 2.5 ng/mL (CV 33%) and the geometric mean AUCtau was 228 ng∙hr/mL (CV 24%) at week 4. The mean terminal half-life was approximately 43 hours (CV 19%).

Renal Impairment:

Renal clearance accounts for approximately 30% of total peginterferon alfa-2b clearance. The effect of renal impairment on the pharmacokinetics of peginterferon alfa-2b was studied in 24 subjects with normal or impaired renal function after a single 4.5 mcg/kg dose. Compared to subjects with normal renal function (CLcr > 80 mL/min/1.73 m2), the geometric mean AUClast to peginterferon alfa-2b increased by 1.4-fold in subjects with moderate renal impairment (CLcr 30 to 50 mL/min/1.73m2) and 2.1-fold in subjects with severe renal impairment (CLcr < 30 mL/min/1.73m2) or ESRD requiring dialysis [see Use in Specific Populations (8.7)].

No clinically meaningful amounts of peginterferon alfa-2b were removed during hemodialysis following a single 1 mcg/kg dose in subjects with renal impairment.

Drug Interactions:

Peginterferon alfa-2b inhibits CYP1A2 and CYP2D6 activity. In a drug interaction study, healthy subjects received a dose of 200 mg of caffeine (CYP1A2 substrate), 2 mg of midazolam (CYP3A4 substrate), 500 mg of tolbutamide (CYP2C9 substrate), or 50 mg of desipramine (CYP2D6 substrate) before and after two doses of Sylatron administered subcutaneously at a dose of 3 mcg/kg. The geometric mean AUClast was increased by 36% for caffeine and 30% for desipramine when coadministered with Sylatron compared to caffeine or desipramine administered alone. No clinically meaningful changes in CYP2C9 activity and CYP3A4 activity were observed. [See Drug Interactions (7).]

Important information

Sylatron can cause life-threatening infections, autoimmune disorders, serious mood or behavior problems, or a stroke.

Stop using Sylatron and call your doctor at once if you have any unusual changes in mood or behavior, such as: depression, irritability, aggression, or thoughts about suicide or hurting yourself.

How should I use Sylatron?

Sylatron is usually given once per week as an injection under the skin (subcutaneously). You may be shown how to use injections at home. Do not self inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes. Also be sure you understand how to properly mix and store the medicine.

Do not shake a vial of mixed Sylatron or you may ruin the medicine. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

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.

While using Sylatron, you may need frequent medical tests and eye exams.

Store Sylatron vials (bottles) at room temperature away from moisture and heat. Do not freeze. Do not reuse a vial.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using Sylatron?

Avoid coffee, tea, cola, energy drinks, or other products that contain caffeine.

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