Sylatron

Included as part of the PRECAUTIONS section.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• aldesleukin (Proleukin)
• fluoxetine (Prozac, Sarafem, Symbyax)
• methadone (Dolophine, Methadose)
• pegloticase (Krystexxa)
• ribavirin (Copegus, Rebetol, Ribasphere, Virazole)
• telbivudine (Tyzeka)
• theophylline 
• zidovudine (Retrovir, in Combivir, Trizivir)

This is not a complete list of Sylatron drug interactions. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Sylatron there are no specific foods that you must exclude from your diet when receiving Sylatron.

Tell your doctor if you are pregnant or plan to become pregnant. It is not known if Sylatron will harm your unborn baby.

• Store vials in the carton at 59°F to 86°F (15°C to 30°C).
• After mixing, use Sylatron right away or store it in the refrigerator for no longer than 24 hours at 36°F to 46°F (2°C to 8°C).
• Do not freeze Sylatron.

Keep Sylatron and all medicines out of the reach of children.

WARNING: DEPRESSION AND OTHER NEUROPSYCHIATRIC DISORDERS

The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alpha interferons, Sylatron Permanently discontinue peginterferon alfa-2b in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Sylatron.

You should not use this medicine if you have liver failure or autoimmune hepatitis. You should not use peginterferon alfa-2b with ribavirin if you have severe kidney disease, or a hemoglobin blood cell disorder (sickle-cell anemia, thalassemia).

Do not use peginterferon alfa-2b and ribavirin if you are pregnant, or if you are a man and your sexual partner is pregnant. Prevent pregnancy while using this medicine, and for at least 6 months after you stop using it.

Peginterferon alfa-2b may cause serious or fatal side effects, and can worsen a medical condition you already have. Call your doctor if you have symptoms such as mood or behavior changes, chest pain, fast heartbeats, trouble breathing, numbness or weakness, loss of coordination, fever, chills, a cough with mucus, burning when you urinate, or bloody diarrhea.

Get emergency medical help if you have signs of an allergic reaction: hives, or a rash that spreads and causes blistering and peeling; chest pain, anxiety, difficult breathing; swelling of your face, lips, tongue, or throat.

Peginterferon alfa-2b can cause life-threatening infections, autoimmune disorders, serious mood or behavior problems, or a stroke.

Stop using peginterferon alfa-2b and call your doctor at once if you have unusual changes in mood or behavior, such as: depression, irritability, aggression, hallucinations, thoughts about hurting yourself, or falling back into a previous pattern of drug addiction. Once you have had this type of reaction to peginterferon alfa-2b, you may not be able to use it again.

Call your doctor at once if you have other serious side effects, such as:

• vision loss;

• severe stomach pain with bloody diarrhea;

• easy bruising, unusual bleeding;

• high blood sugar--increased thirst or urination, hunger, fruity breath odor, tiredness, weight loss;

• lung problems--sudden chest discomfort, wheezing, trouble breathing;

• nerve problems--numbness, tingling, or burning pain in your arms or legs;

• new or worsened autoimmune disorders--skin problems, joint pain or swelling, cold feeling or pale appearance in your fingers or toes;

• pancreas problems--severe pain in your upper stomach spreading to your back, vomiting, fever;

• signs of infection--fever, chills, body aches, cough with yellow or pink mucus, pain or burning when you urinate, increased urination;

• signs of a stroke or heart attack--chest pain spreading to your jaw or shoulder, fast heartbeats, trouble breathing, sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, loss of coordination;

• thyroid problems--weight changes, skin changes, thinking problems, feeling hot or cold all the time; or

• worsening liver symptoms--upper stomach pain or swelling, loss of appetite, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• flu-like symptoms, weakness, feeling tired;

• mild depression or sadness, feeling anxious or irritable;

• nausea, vomiting, loss of appetite, weight loss;

• thinning hair; or

• redness, swelling, or itching where the medicine was injected.

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.

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 Pegintron® in children younger than 3 years of age. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of Sylatron™ in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of peginterferon alfa-2b injection in the elderly. However, elderly patients are likely to be more sensitive to the effects of this medicine, and are more likely to have age-related kidney problems, which may require caution in patients receiving this medicine.

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 taking 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.

• Thioridazine

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.

• Aminophylline
• Amitriptyline
• Anagrelide
• Caffeine Citrate
• Clomipramine
• Desipramine
• Donepezil
• Doxepin
• Doxorubicin
• Eliglustat
• Flecainide
• Imipramine
• Methadone
• Nortriptyline
• Perphenazine
• Pirfenidone
• Propranolol
• Rasagiline
• Ropivacaine
• Theophylline
• Tizanidine
• Tramadol
• Trimipramine
• Warfarin

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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:

• Allergic reactions (eg, anaphylaxis, bronchoconstriction, Stevens-Johnson syndrome) or
• Autoimmune hepatitis (liver inflammation) or
• Decompensated liver disease—Should not be used in patients with these conditions.

• Angina (severe chest pain) or
• Heart attack, history of or
• Heart or blood vessel disease or
• Heart rhythm problems (eg, arrhythmia , tachycardia), history of or
• Hypotension (low blood pressure)—Use with caution. Patients with these conditions should be closely monitored while using this medicine.

• Bone marrow problems (eg, aplastic anemia) or
• Brain disease (eg, encephalopathy) or
• Breathing problems or other lung diseases (eg, chronic obstructive pulmonary disease or COPD, pneumonia, pulmonary infiltrates, sarcoidosis), or history of or
• Depression or mental illness, history of or
• Diabetes mellitus (sugar diabetes) or
• Diabetic retinopathy (eye problem caused by diabetes) or
• Eye or vision problems (eg, retinopathy, optic neuritis) or
• Hyperglycemia (high blood sugar level) or
• Hypertensive retinopathy (eye problem caused by hypertension or high blood pressure) or
• Hypertriglyceridemia (high triglyceride levels or fats in the blood) or
• Kidney disease or
• Liver disease (including cirrhosis), severe or
• Psoriasis or
• Psychiatric problems, history of or
• Rheumatoid arthritis or
• Systemic lupus erythematosus or
• Thyroid disease or
• Type 1 diabetes—Use with caution. May make these conditions worse.

• Colitis (inflammation of the bowel) or
• Pancreatitis (inflammation of the pancreas)—Peginterferon alfa-2b should be stopped in patients with these conditions.

• Heart disease (severe and unstable), or history of or
• Kidney disease, severe or
• Sickle cell anemia (red blood cell disorder) or
• Thalassemia major (genetic blood disorder)—Peginterferon alfa-2b together with ribavirin should not be used in patients with these conditions.

• Organ transplant (eg, liver)—Use of peginterferon alfa-2b alone or in combination with ribavirin have not been studied in patients with this condition.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Tell your doctor if you have signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• You may have more chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Take good care of your teeth. See a dentist often.
• If you throw up, rinse your mouth out well.
• Avoid drinking alcohol while taking Sylatron.
• Very bad and sometimes deadly pancreas problems (pancreatitis) have happened with this medicine. This could happen at any time during care. Signs of pancreatitis include very bad stomach pain, very bad back pain, or very upset stomach or throwing up. Call your doctor right away if you have any of these signs.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• Very bad and sometimes deadly liver problems have happened with Sylatron. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Tell your doctor if you take a drug that has caffeine, or you eat or drink products that have caffeine, like tea, coffee, cola, or chocolate.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• This medicine may affect growth in children and teens in some cases. They may need regular growth checks. Talk with the doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Sylatron while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flu-like signs.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Not hungry.
• Hair loss.
• Not able to sleep.
• Feeling tired or weak.
• Weight loss.
• Change in taste.
• Dizziness.
• Dry mouth.
• Irritation where the shot is given.
• Muscle or joint pain.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Recommended Dosing

• The recommended starting dose is 6 mcg/kg/week subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously for up to 5 years.
• Premedicate with acetaminophen 500 to 1000 mg orally 30 minutes prior to the first dose of Sylatron and as needed for subsequent doses.
• The recommended starting doses of Sylatron in patients with moderate or severe renal impairment or end-stage renal disease (ESRD) are listed in Table 1 [see Use in Specific Populations (8.7)]. No dose adjustment is needed for patients with a creatinine clearance (CLcr) > 50 mL/min/1.73m2.

Dose Modification Guidelines

Guidelines for Dose Modification provided below are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 2.0).

• Permanently discontinue Sylatron for:
  • Persistent or worsening severe neuropsychiatric disorders
  • Grade 4 non-hematologic toxicity
  • Inability to tolerate a dose of 1 mcg/kg/wk
  • New or worsening retinopathy
• Withhold Sylatron dose for any of the following:
  • Absolute Neutrophil Count (ANC) less than 0.5×109/L
  • Platelet Count (PLT) less than 50×109/L
  • ECOG PS greater than or equal to 2
  • Non-hematologic toxicity greater than or equal to Grade 3
• Resume dosing at a reduced dose (see Table 1) when all of the following are present:
  • Absolute Neutrophil Count (ANC) greater than or equal to 0.5×109/L
  • Platelet Count (PLT) greater than or equal to 50×109/L
  • ECOG PS 0-1
  • Non-hematologic toxicity has completely resolved or improved to Grade 1

Preparation and Administration

Reconstitute Sylatron with 0.7 mL of Sterile Water for Injection, USP. The Sterile Water for Injection supplied contains 5 mL. Each vial of Sterile Water for Injection is intended for single use. Discard any unused Sterile Water for Injection, USP.

• Swirl gently to dissolve the lyophilized powder. DO NOT SHAKE.
• Visually inspect the solution for particulate matter and discoloration prior to administration. Discard if solution is discolored, cloudy, or if particulates are present.
• Do not withdraw more than 0.5 mL of reconstituted solution from each vial.
• Administer Sylatron subcutaneously. Rotate injection sites.
• If reconstituted solution is not used immediately, store at 2°-8°C (36°-46°F) for no more than 24 hours. Discard reconstituted solution after 24 hours. DO NOT FREEZE.
• For single-use only. DISCARD ANY UNUSED PORTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis:

Sylatron has not been tested for its carcinogenic potential. Neither peginterferon alfa-2b nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

Impairment of Fertility:

Sylatron may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m2 peginterferon alfa-2b alone every other day for 1 month (approximately 72 to 144 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of peginterferon alfa-2b treatment. Every other day dosing with 262 mcg/m2 (approximately 3.5 to 7 times the recommended weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of Sylatron on male fertility have not been studied.

See FDA-approved patient labeling (Instructions for Use and Medication Guide).

• Advise patients that Sylatron may be administered with antipyretics at bedtime to minimize common "flu-like" symptoms (including chills, fever, muscle aches, joint pain, headaches, tiredness).
• Advise patients to maintain hydration if experiencing "flu-like" symptoms.
• Advise patients and their caregivers to immediately report any symptoms of depression or suicidal ideation to their healthcare provider during treatment and up to 6 months after the last dose.
• Use Sylatron during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
• Instruct patients to not re-use or share syringes and needles.
• Instruct patients on proper disposal of vials, syringes and needles.
• Advise patients that the Sterile Water for Injection vials supplied contain an excess amount of diluent and only 0.7 mL should be withdrawn to reconstitute Sylatron. Discard the unused portion of sterile water. Do not save or reuse.

Manufactured by:
Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ 08889, USA
U.S. License Number 0002

Revised: 02/2016

For patent information: www.merck.com/product/patent/home.html

BD and Safety-Lok are registered trademarks of Becton, Dickinson and Company.

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk4031-pwi-5ml-1602r004

You should not use Sylatron if you are allergic to peginterferon alfa-2b or other alfa interferons (Intron A, Rebetron, Alferon N, Infergen, Pegasys), or if you have:

• liver failure; or

• autoimmune hepatitis.

You should not use Sylatron if you have:

• severe kidney disease;

• a hemoglobin blood cell disorder such as sickle-cell anemia or thalassemia; or

• if you are pregnant, or if you are a man and your sexual partner is pregnant.

To make sure Sylatron is safe for you, tell your doctor if you have:

• cirrhosis, hepatitis B, or liver problems other than hepatitis C;

• a history of depression, mental illness, suicidal thoughts, alcoholism, or drug addiction;

• heart disease, high blood pressure, or a history of heart attack, stroke, or blood clot;

• lung disease;

• an autoimmune disorder such as rheumatoid arthritis, lupus, or psoriasis;

• any blood cell disorder causing bleeding episodes, infections, or fever-related illness;

• HIV or AIDS;

• diabetes;

• high triglycerides (a type of fat in the blood);

• a thyroid disorder;

• kidney disease (or if you are on dialysis);

• a weak immune system caused by cancer or other conditions;

• ulcerative colitis; or

• a history of organ transplant.

Sylatron may be harmful to an unborn baby. Do not use Sylatron without telling your doctor if you are pregnant. Sylatron should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

It is not known whether peginterferon alfa-2b passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using Sylatron.