Anatac

Anatac may be available in the countries listed below.

Ingredient matches for Anatac

Carbocisteine

Carbocisteine is reported as an ingredient of Anatac in the following countries:

• Spain

International Drug Name Search

Penicillamine

Class: Heavy Metal Antagonists
ATC Class: M01CC01
VA Class: AD300
CAS Number: 52-67-5
Brands: Cuprimine, Depen

• 
  

  Only clinicians familiar with the toxicity, special dosage considerations, and therapeutic benefits should prescribe penicillamine.^{a b} Do not use casually.^{a b}

  
  


• 
  

  Closely monitor patients.^{a b}

  
  


• 
  

  Inform patients to promptly report symptoms suggestive of toxicity to their clinician.^{a b}

  
  

Introduction

Heavy metal antagonist; a disease-modifying antirheumatic drug (DMARD).^c

Uses for Penicillamine

Wilson’s Disease

Promotes excretion of copper in the treatment of Wilson’s disease.^{a b c}

Used in conjunction with a low copper diet.^{a b c}

Improves neurologic, corneal, hepatic, and psychiatric manifestations in symptomatic patients.^{a b c}

Prevents signs and symptoms of the disease in asymptomatic patients.^{a b}

Cystinuria

Use in conjunction with conventional measures (urine dilution and alkalinization) to reduce excretion of cystine and prevent renal calculi in patients with cystinuria when conventional measures alone are not successful.^{a b c}

Rheumatoid Arthritis

Management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of NSAIAs.^{a b c 206 207}

Because penicillamine can cause severe adverse reactions, restrict use to patients with severe disease.^{a b}

Lead Poisoning

Has been used for the treatment of lead poisoning†.^{204 d}

AAP considers penicillamine a third-line agent for the treatment of lead poisoning.^{204 d}

Penicillamine Dosage and Administration

General

• 
  

  Individualize dosage according to the condition being treated and patient response.^{a b c}

  
  


• 
  

  When used for cystinuria, high fluid intake (e.g., 500 mL of water at bedtime and again during the night) needed.^{a b c} The greater the fluid intake, the lower the penicillamine dosage required.^{a b c}

  
  

Administration

Oral Administration

Administer orally on an empty stomach (i.e., at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk).^{a b c} Administer the last dose of the day ≥3 hours after the evening meal.^c Administration on an empty stomach ensures maximum absorption and reduces the potential for inactivation of penicillamine by metals in the GI tract.^{a b}

If used in individuals who cannot swallow capsules, contents may be administered in 15–30 mL of chilled pureed fruit or fruit juice.^c

When used for rheumatoid arthritis, administer dosages >500 mg daily in divided doses.^{a b c}

Dosage

Pediatric Patients

Wilson’s Disease

Oral

Optimal dosage determined by measuring urinary copper excretion and/or serum free copper concentrations.^{a b c}

20 mg/kg daily given in divided doses.^c

Cystinuria

Oral

Individualize dosage based on urinary cystine excretion.^{a b c}

30 mg/kg daily given in 4 equal doses.^{a b c} If 4 equal doses are not feasible, give larger dose at bedtime.^{a b c} If dosage reduced because of adverse effects, retain bedtime dose.^{a b c}

Lead Poisoning†

Oral

20–30 mg/kg daily has been recommended.^c

Adults

Wilson’s Disease

Oral

Optimal dosage determined by measuring urinary copper excretion and/or serum free copper concentrations.^{a b c}

Initially, 250 mg 4 times daily.^{a b c} For patients who do not tolerate an initial dosage of 1 g daily, initiate with 250 mg daily and gradually increase dosage.^{a b c}

If tolerated, a dosage of 0.75–1.5 g daily should be continued for 3 months; this dosage produces an initial 24-hour cupruresis of >2 mg.^{a b c} Subsequent dosage based on serum free copper concentrations.^{a b c}

Dosages >2 g daily are seldom necessary.^{a b c}

Cystinuria

Oral

Individualize dosage based on urinary cystine excretion.^{a b c}

Initiate with 250 mg daily and gradually increase dosage to provide close control and minimize adverse reactions.^{a b c}

Usual dosage is 2 g daily given in 4 equal doses; range is 1–4 g daily.^{a b c} If 4 equal doses are not feasible, give larger dose at bedtime.^{a b c} If dosage reduced because of adverse effects, retain bedtime dose.^{a b c}

Rheumatoid Arthritis

Initial Therapy

Oral

Initially, 125–250 mg daily; increase by 125–250 mg daily at 1–3 month intervals as patient response and tolerance allow.^{a b c} Many patients achieve remission with dosage of 500–750 mg daily.^c

If remission is achieved, continue dosage; if no improvement and no signs of serious toxicity noted with 500–750 mg daily, increase by 250 mg daily at 2–3 month intervals until remission occurs or toxicity develops.^{a b c}

Discontinue penicillamine if improvement not observed after 3–4 months of treatment with 1–1.5 g daily.^{a b c}

Maintenance Therapy

Oral

Usual dosage 500–750 mg daily; in patients who respond, but have incomplete suppression of disease after the first 6–9 months of therapy, increase daily dosage by 125–250 mg daily at 3 month intervals to a maximum of 1–1.5 g daily.^{a b c}

Optimum duration of therapy not established; attempt to reduce dosage by 125–250 mg daily at 3 month intervals in patients with remission of symptoms ≥6 months, ^{a b c}

Exacerbation Therapy

Oral

If exacerbation does not subside within 3 months, consider increasing penicillamine dosage.^{a b c}

Prescribing Limits

Adults

Wilson’s Disease

Oral

Maximum 2 g daily.^{a b c}

Rheumatoid Arthritis

Oral

Maximum 1 g daily; occasionally 1.5 g daily required.^{a b c}

Special Populations

Pregnancy

If penicillamine is used in pregnant women with Wilson's disease, the manufacturers recommend a maximum dosage of 0.75–1 g daily.^{a b} If cesarean section is planned, the recommended dosage is 250 mg daily during the last 6 weeks of pregnancy; this dosage is continued postoperatively until wound healing is complete.^{a b} (See Contraindications and Mucocutaneous Effects under Cautions.)

Surgical Candidates

Reduce dosage to 250 mg daily in patients considering surgery.^{a b} Do not reinitiate full dosage until wound healing is complete.^{a b} (See Contraindications and Mucocutaneous Effects under Cautions.)

Cautions for Penicillamine

Contraindications

• 
  

  Known or suspected pregnancy except when used for the treatment of Wilson’s disease or in certain individuals with cystinuria.^{a b} (See Fetal/Neonatal Morbidity and Mortality and Pregnancy under Cautions.)

  
  


• 
  

  Breast-feeding.^{a b} (See Lactation under Cautions.)

  
  


• 
  

  History of penicillamine-related aplastic anemia or agranulocytosis.^{a b c}

  
  


• 
  

  Rheumatoid arthritis patients with current or history of renal insufficiency.^{a b c}

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Aplastic anemia, agranulocytosis, and thrombocytopenia (sometimes fatal) reported.^{a b c} Leukopenia and thrombocytopenia reported.^{a b c}

For the first 6 months, monitor WBC counts, hemoglobin, and platelet counts every 2 weeks; after 6 months, monitor monthly.^{a b} Discontinue penicillamine if WBC count decreases to <3500/mm³.^{a b} Temporarily interrupt therapy if platelet count decreases to <100,000/mm³.^{a b}

Temporarily interrupt therapy if platelet or WBC counts progressively decrease in 3 successive determinations, even if values are still within normal range.^{a b c}

Iron deficiency anemia reported, especially in children or premenopausal women.^{a b c} Iron therapy may be administered for short periods.^{a b c} (See Iron Supplements under Interactions.)

Renal Effects

Slight to moderate proteinuria (<2 g/24 hours) common; may improve spontaneously or following dosage reduction.^c

Hematuria or proteinuria may be warning signs of membranous glomerulopathy that can progress to nephrotic syndrome; essential to closely observe patients who develop hematuria or proteinuria.^{a b}

For the first 6 months, perform urinalysis every 2 weeks; after 6 months, perform monthly.^{a b}

Determine quantitative 24-hour urinary protein levels every 1–2 weeks in patients with rheumatoid arthritis who develop moderate proteinuria; do not increase penicillamine dosage in these patients.^{a b} Reduce dosage or discontinue penicillamine for proteinuria >1 g/24 hours or progressive increases in proteinuria.^{a b} Discontinue therapy if gross hematuria or persistent microscopic hematuria develops.^{a b}

Weigh risks versus benefits of continued therapy in patients with Wilson's disease or cystinuria who develop urinary abnormalities.^{a b c}

Discontinue immediately if abnormal urinary findings associated with hemoptysis and pulmonary infiltrates develop.^{a b c} (See Goodpasture's Syndrome under Cautions.)

Following discontinuance of penicillamine, ≥1 year may be required for urinary abnormalities to resolve.^{a b c}

Annual radiograph of the kidneys advised to check for renal stones in patients with cystinuria.^{a b}

Hepatotoxicity

Intrahepatic cholestasis and toxic hepatitis reported rarely.^{a b} Monitor liver function every 3–6 months.^{a b}

Pulmonary Effects

Obliterative bronchiolitis reported rarely.^{a b}

Goodpasture’s Syndrome

Goodpasture’s syndrome reported rarely.^{a b c} Discontinue immediately if abnormal urinary findings associated with hemoptysis and pulmonary infiltrates occur.^{a b c}

Myasthenia Gravis

Myasthenic syndrome, sometimes progressing to myasthenia gravis, reported.^{a b c} Symptoms typically resolve after discontinuation of penicillamine.^{a b c}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; congenital cutis laxa and associated birth defects reported.^{a b c}

Decisions regarding use of penicillamine in pregnant women should be individualized based on the condition being treated.^{a b} (See Pregnancy under Cautions.)

Advise women who become pregnant while taking penicillamine that there is a potential hazard to the fetus.^{a b}

Sensitivity Reactions

Hypersensitivity Reactions

Drug fever, sometimes accompanied by macular cutaneous eruption, reported; usually occurs after 2–3 weeks of therapy.^{a b c} Temporarily interrupt therapy if drug fever develops in patients with Wilson’s disease or cystinuria; restart with low dosage and gradually increase to full dosage once fever subsides.^{a b c} Discontinue if drug fever occurs in patients with rheumatoid arthritis; initiate alternative therapy for rheumatoid arthritis.^{a b c}

If pruritus or rash accompanied by fever, arthralgia, lymphadenopathy, or other allergic manifestations develop, discontinue penicillamine.^{a b c}

Cross-sensitivity

Potential for cross-sensitivity between penicillamine and penicillin.^{a b c}

Dermatologic Reactions

Most forms of pemphigus reported; pemphigus vulgaris and pemphigus foliaceus reported most frequently.^{a b c} Discontinue if pemphigus suspected.^{a b c}

Rash may occur early in therapy or, less frequently, after many months of therapy.^{a b c} Observe skin and mucous membranes for allergic reactions.^{a b} Generalized pruritic, erythematous, maculopapular, or morbilliform rash occurs early; usually resolves following discontinuance of penicillamine and does not recur when drug is restarted at lower dosage.^{a b c} Late rash with intense pruritus reported after ≥6 months therapy.^{a b c} If late rash occurs, discontinue penicillamine.^{a b} Rash may recur if the drug is restarted.^{a b c}

Antinuclear Antibodies

Possible positive antinuclear antibody (ANA) titers; patients with increases in ANA titers may develop a syndrome resembling systemic lupus erythematosus.^{a b c} Monitor patients who develop an abnormal ANA test; not necessary to discontinue penicillamine.^{a b c}

General Precautions

Mucocutaneous Effects

Potential increased skin friability at pressure or trauma sites (i.e., shoulders, elbows, knees, toes, and buttocks);^{a b c} may progress to purpuric or vesicular ecchymoses.^c Occurs most frequently with dosages >2 g daily;^c does not require discontinuance.^{a b c}

May affect wound healing; dosage adjustment recommended in patients undergoing surgery.^{a b} (See Pregnancy and Surgical Candidates under Dosage and Administration.)

Oral ulcerations with the appearance of aphthous stomatitis reported; rarely, cheilosis, glossitis, gingivostomatitis, and ulceration of the vulva and vagina reported.^{a b c}

Pyridoxine

Penicillamine increases pyridoxine requirement; pyridoxine 25–50 mg daily recommended for patients with Wilson’s disease or cystinuria; also recommended for rheumatoid arthritis patients with impaired nutrition.^{a b c}

Effects on Taste

Hypogeusia reported; may last ≥2–3 months; may progress to full loss of taste; usually self-limiting.^{a b c}

Specific Populations

Pregnancy

Category D.^a (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Contraindicated in women with rheumatoid arthritis who are pregnant.^{a b c} (See Contraindication under Cautions.)

If administered to women with Wilson's disease during pregnancy, dosage adjustment needed.^{a b} (See Pregnancy under Dosage and Administration.)

Use in pregnant women with cystinuria not recommended.^{a b} If stone formation continues, consider benefits to the mother versus risk to the fetus.^{a b}

Use in women of childbearing potential only if potential benefits outweigh risks.^{a b}

Lactation

Discontinue nursing because of potential risk to nursing infants.^{a b c} (See Contraindications under Cautions.)

Pediatric Use

Efficacy not established for treatment of juvenile rheumatoid arthritis.^{a b c}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.^a Select dosage with caution, starting at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.^a May be useful to monitor renal function.^a

Skin rash and taste disturbances reported more frequently in geriatric individuals than in younger adults.^a

Renal Impairment

Contraindicated for the treatment of rheumatoid arthritis in patients with current or a history of renal insufficiency.^{a b c}

Common Adverse Effects

Early and late rashes^{a b c} , taste disturbances, ^{a b c} proteinuria, ^{a b c} anorexia, ^{a b c} epigastric pain, ^{a b c} nausea, ^{a b c} vomiting, ^{a b c} diarrhea, ^{a b c} leukopenia, ^{a b c} thrombocytopenia. ^{a b c}

Interactions for Penicillamine

Specific Drugs

Drug	Interaction	Comments
Antacids	Possible decreased plasma penicillamine concentrationsa	Separate administration by ≥1 hoursa
Antimalarials	Potential additive hematologic and/or adverse renal effectsa b c	Concomitant use not recommendeda b c
Cytotoxic agents	Potential additive hematologic and/or adverse renal effectsa b c	Concomitant use not recommendeda b c
Gold therapy	Potential additive hematologic and/or adverse renal effectsa b c	Concomitant use not recommended a b c
Iron supplements	Possible decreased plasma penicillamine concentrationsa b	Separate administration by ≥2 hoursa b
Zinc supplements	Possible decreased plasma penicillamine concentrationsa	Separate administration by ≥1 hoursa

Penicillamine Pharmacokinetics

Absorption

Bioavailability

Absorption from the GI tract is variable; 40–70% of an oral dose (given as capsules) absorbed.^a Peak plasma concentrations usually attained within 1–3 hours.^{a c}

Food

Presence of food in the GI tract decreases extent of absorption.^{a b}

Distribution

Extent

Crosses the placenta.^c

Plasma Protein Binding

80% (mainly albumin and ceruloplasmin).^a

Elimination

Metabolism

Metabolized in the liver to inactive metabolites.^{a c}

Elimination Route

Excreted principally in urine as disulfides.^{a c}

Stability

Storage

Oral

Capsules and Tablets

15–30°C.^c

ActionsActions

• 
  

  Chelates copper, iron, mercury, and lead to form stable soluble complexes that are excreted by the kidney.^{a b c} Removes excess copper in patients with Wilson's disease.^{a b c}

  
  


• 
  

  Combines with cystine to form penicillamine-cysteine disulfide, a complex that is more soluble than cystine.^{a b c} Reduces concentration of cystine in urine of patients with cystinuria.^{a b c}

  
  


• 
  

  Mechanism of anti-inflammatory effects in rheumatoid arthritis not fully determined; inhibits collagen formation; reduces immunoglobulin M rheumatoid factor; depresses T-cell activity; depolymerizes some macroglobulins; does not reduce B-cell activity.^{a b c}

  
  


• 
  

  Inhibits pyridoxal-dependent enzymes.^c

  
  

Advice to Patients

• 
  

  Importance of advising patients to seek immediate medical attention if signs and symptoms of toxicity (e.g., fever, sore throat, chills, bruising, bleeding) develop.^{a b}

  
  


• 
  

  Importance of taking penicillamine on an empty stomach (at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk).^{a b c}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.^{a b}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; apprise women of potential risks to fetus.^{a b} Importance of women of childbearing potential informing clinician of missed period(s).^{a b}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{a b} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Penicillamine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	125 mg	Cuprimine	Merck
		250 mg	Cuprimine	Merck
	Tablets	250 mg	Depen Titratable (with povidone; scored)	MedPoint

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

200. Merck. Cuprimine (penicillamine) capsules prescribing information (dated 1997 Feb). In: Physicians’ desk reference. 53rd ed. Montvale, NJ; Medical Economics Company Inc; 1999:1766-9.

201. Ramselaar ACP, Dekker AW, Huber-Bruning O et al. Acquired sideroblastic anaemia after aplastic anemia caused by D-penicillamine therapy for rheumatoid arthritis. Ann Rheum Dis. 1987; 46:156-8. [IDIS 226248] [PubMed 3827338]

202. Craig HR. Penicillamine induced mammary hyperplasia: report of a case and review of the literature. J Rheumatol. 1988; 15:1294-7. [PubMed 3184079]

203. Reid DM, Martynoga AG, Nuki G. Reversible gynecomastia associated with d-penicillamine in a man with rheumatoid arthritis. BMJ. 1982; 285:1083-4. [IDIS 159628] [PubMed 6812755]

204. Committee on Drugs, American Academy of Pediatrics. Treatment guidelines for lead exposure in children. Pediatrics. 1995; 96:155-60. [IDIS 349805] [PubMed 7596706]

205. Shannon M, Graef J, Lovejoy FH. Efficacy and toxicity of d-penicillamine in low-level lead poisoning. J Pediatr. 1988; 112:799-804. [IDIS 241344] [PubMed 3361395]

206. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002; 46:358-46.

207. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64. [PubMed 10887424]

a. Merck. Cuprimine (penicillamine) capsules prescribing information. Whitehouse Station, NJ; Oct 2004.

b. MedPointe Healthcare Inc. Depen (penicillamine) tablets prescribing information. Somerset, NJ; 2003 Dec.

c. AHFS Drug Information 2007. McEvoy GK, ed. Penicillamine. Bethesda, MD: American Society of Health-System Pharmacists; 2007. From .

d. American Academy of Pediatrics, Committee on Environmental Health. Lead exposure in children: prevention, detection, and management. Pediatrics. 2005; 116:1036-46. [PubMed 16199720]

More Penicillamine resources

• Penicillamine Side Effects (in more detail)
• Penicillamine Use in Pregnancy & Breastfeeding
• Penicillamine Drug Interactions
• Penicillamine Support Group
• 1 Review for Penicillamine - Add your own review/rating

• Penicillamine Professional Patient Advice (Wolters Kluwer)


• Penicillamine MedFacts Consumer Leaflet (Wolters Kluwer)


• penicillamine Concise Consumer Information (Cerner Multum)


• penicillamine Advanced Consumer (Micromedex) - Includes Dosage Information


• Cuprimine Prescribing Information (FDA)


• Depen Prescribing Information (FDA)

Compare Penicillamine with other medications

• Cystinuria
• Rheumatoid Arthritis
• Wilson's Disease

Poly-Tussin DHC

Generic Name: brompheniramine, dihydrocodeine, and phenylephrine (BROM fen IR a meen, dye HYE dro KOE deen, FEN il EFF rin)

Brand Names: Poly-Tussin DHC

What is Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

Brompheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Dihydrocodeine is a narcotic cough suppressant.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of brompheniramine, dihydrocodeine, and phenylephrine is used to treat nasal congestion, sneezing, runny nose, and cough caused by the common cold.

Dihydrocodeine will not treat a cough that is caused by smoking, asthma, or emphysema.

Brompheniramine, dihydrocodeine, and phenylephrine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

Do not use this medication if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough and cold medicine before the MAO inhibitor has cleared from your body. You should not use brompheniramine, dihydrocodeine, and phenylephrine if you are allergic to it, or if you have peptic ulcer, severe or uncontrolled high blood pressure, severe coronary artery disease, ischemic heart disease (reduced circulation of blood to the heart), narrow-angle glaucoma, if you are breast-feeding a baby, or if you are unable to urinate.

Before taking this medication, tell your doctor if you have heart disease or high blood pressure, asthma or other breathing disorder, diabetes, a thyroid disorder, glaucoma, kidney or liver disease, gallbladder disease, pancreatitis, Addison's disease or other adrenal gland disorder, a seizure disorder, head injury or brain tumor, an enlarged prostate, problems with urination, mental illness, or a history of drug or alcohol addiction.

Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children. Brompheniramine, dihydrocodeine, and phenylephrine should not be given to a child younger than 6 years old.

What should I discuss with my healthcare provider before taking Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

Do not use this medication if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough and cold medicine before the MAO inhibitor has cleared from your body. You should also not take codeine if you are having an asthma attack or if you have a bowel obstruction called paralytic ileus. You should not use brompheniramine, dihydrocodeine, or phenylephrine, if you have ever had an allergic reaction to it, or if you have:

• 
  

  severe or uncontrolled high blood pressure;

  
  


• 
  

  severe coronary artery disease;

  
  


• 
  

  narrow-angle glaucoma;

  
  


• 
  

  peptic ulcer;

  
  


• 
  

  if you are unable to urinate;

  
  


• 
  

  if you are pregnant;

  
  


• 
  

  if you are having an asthma attack.

  
  

If you have certain conditions, you may need a dose adjustment or special tests to safely take brompheniramine, dihydrocodeine, and phenylephrine. Before taking this medication, tell your doctor if you have:

• 
  

  heart disease or high blood pressure;

  
  


• 
  

  ischemic heart disease (reduced circulation of blood to the heart);

  
  


• 
  

  asthma, COPD, or other breathing disorder;

  
  


• 
  

  glaucoma;

  
  


• 
  

  diabetes;

  
  


• kidney or liver disease;


• 
  

  a thyroid disorder;

  
  


• 
  

  enlarged prostate, urination problems;

  
  


• 
  

  gallbladder disease or pancreatitis;

  
  


• 
  

  Addison's disease or other adrenal gland disorders;

  
  


• 
  

  a history of head injury or brain tumor;

  
  


• 
  

  epilepsy or other seizure disorder;

  
  


• 
  

  mental illness; or

  
  


• 
  

  a history of drug or alcohol addiction.

  
  

FDA pregnancy category C. This medication may be harmful to an unborn baby. Dihydrocodeine may cause breathing problems or addiction/withdrawal symptoms in a newborn. Tell your doctor if you are pregnant or plan to become pregnant while you are taking this medication. This medication can pass into breast milk and may harm a nursing baby. The use of dihydrocodeine by some nursing mothers may lead to life-threatening side effects in the baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Older adults may be more sensitive to the side effects of this medication. Dihydrocodeine may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction. Keep the medication in a secure place where others cannot get to it.

How should I take Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label. Cold medicine is usually taken for only a short time until your symptoms clear up.

Always ask a doctor before giving cough or cold medicine to a child. Death can occur from the misuse of cough or cold medicine in very young children. Brompheniramine, dihydrocodeine, and phenylephrine should not be given to a child younger than 6 years old. Take the medicine with a full glass of water.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache or skin rash. Store brompheniramine, dihydrocodeine, and phenylephrine at room temperature away from moisture and heat.

Keep track of how much of this medicine has been used from the bottle. Dihydrocodeine is a drug of abuse and you should be aware if any person in the household is using this medicine improperly or without a prescription.

What happens if I miss a dose?

Since cough and cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of dihydrocodeine can be fatal.

Overdose symptoms may include extreme drowsiness, pinpoint pupils, cold and clammy skin, limp muscles, fainting, seizure (convulsions), shallow breathing or breathing that stops.

What should I avoid while taking Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol while you are taking this medication. Alcohol can add to the side effects of brompheniramine, dihydrocodeine, and phenylephrine.

Tell your doctor if you regularly use other medicines that make you sleepy (such as pain medication, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by brompheniramine, dihydrocodeine, and phenylephrine.

Do not use any other over-the-counter cold, allergy, or pain medication without first asking your doctor or pharmacist. Brompheniramine or phenylephrine are contained in many medicines available over the counter. If you take certain products together you may accidentally take too much of a certain drug. Read the label of any other medicine you are using to see if it contains brompheniramine or phenylephrine.

Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  fast or pounding heartbeat;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  weak or shallow breathing;

  
  


• 
  

  confusion, hallucinations;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  seizure (convulsions); or

  
  


• 
  

  painful or difficult urination.

  
  

Less serious side effects may include:

• 
  

  dizziness, drowsiness, headache, tired feeling;

  
  


• 
  

  feeling excited or restless;

  
  


• 
  

  increased dreaming;

  
  


• 
  

  increased sweating or urination;

  
  


• 
  

  nausea, vomiting, diarrhea, constipation, loss of appetite;

  
  


• 
  

  dry mouth;

  
  


• 
  

  blurred vision, dry eyes; or

  
  


• 
  

  mild skin rash or itching.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Poly-Tussin DHC (brompheniramine, dihydrocodeine, and phenylephrine)?

Tell your doctor about all other medicines you use, especially:

• 
  

  methyldopa (Aldomet);

  
  


• 
  

  mecamylamine (Inversine);

  
  


• 
  

  reserpine;

  
  


• 
  

  promethazine (Phenergan, Adgan, Anergan 50, Pentazine);

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others; or

  
  


• 
  

  an antidepressant such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

This list is not complete and there may be other drugs that can interact with brompheniramine, dihydrocodeine, and phenylephrine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Poly-Tussin DHC resources

• Poly-Tussin DHC Side Effects (in more detail)
• Poly-Tussin DHC Use in Pregnancy & Breastfeeding
• Poly-Tussin DHC Drug Interactions
• Poly-Tussin DHC Support Group
• 0 Reviews for Poly-Tussin DHC - Add your own review/rating

Compare Poly-Tussin DHC with other medications

• Cold Symptoms
• Cough and Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about brompheniramine, dihydrocodeine, and phenylephrine.

See also: Poly-Tussin DHC side effects (in more detail)

Pegasys

peginterferon alfa-2a

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

 Alpha interferons, including Pegasys (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping Pegasys therapy [see Warnings and Precautions (5.2, 5.5, 5.8, 5.11, 5.14, 5.16), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)].

Use with Ribavirin

Ribavirin, including COPEGUS®, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. [See COPEGUS Package Insert for additional information and other WARNINGS.]

Indications and Usage for Pegasys

Chronic Hepatitis C

 Pegasys, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count greater than 100 cells/mm3.

 The following points should be considered when initiating therapy with Pegasys and COPEGUS:

•  Use of Pegasys monotherapy is not recommended for treatment of CHC unless a patient has a contraindication to or significant intolerance to ribavirin. Combination therapy provides substantially better response rates than monotherapy [see Clinical Studies (14)].


•  Safety and efficacy have not been demonstrated for treatment longer than 48 weeks.


•  The safety and efficacy have not been established in liver or other organ transplant recipients [see Use in Specific Populations (8.7)].

Chronic Hepatitis B

Pegasys is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B infection who have compensated liver disease and evidence of viral replication and liver inflammation.

Pegasys Dosage and Administration

Pegasys is administered by subcutaneous injection in the abdomen or thigh. See COPEGUS Package Insert for all instructions regarding COPEGUS dosing and administration.

Chronic Hepatitis C

Adult Patients

Pegasys Monotherapy:

The recommended dose of Pegasys monotherapy for chronic hepatitis C is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

Pegasys/COPEGUS Combination Therapy:

The recommended dose of Pegasys when used in combination with ribavirin for chronic hepatitis C is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly. The recommended dose of COPEGUS and duration for Pegasys/COPEGUS therapy is based on viral genotype (see Table 1).

The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses.

COPEGUS should be taken with food.

Table 1 Pegasys and COPEGUS Dosing Recommendations

Hepatitis C virus Genotype	Pegasys Dose (once weekly)	COPEGUS Dose (daily)	Duration
Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 13).
Data on genotypes 5 and 6 are insufficient for dosing recommendations.
Genotypes 1, 4	180 mcg	<75 kg = 1000 mg ≥75 kg = 1200 mg	48 weeks 48 weeks
Genotypes 2, 3	180 mcg	800 mg	24 weeks

Pediatric Patients

 Pegasys/COPEGUS Combination Therapy:

 Pegasys is administered as 180 mcg/1.73 m2 × BSA subcutaneously once weekly, to a maximum dose of 180 mcg, and should be given in combination with COPEGUS. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

 COPEGUS is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. COPEGUS should be administered with food. The recommended doses for COPEGUS are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.

Table 2 COPEGUS Dosing Recommendations for Pediatric Patients

Body Weight in kilograms (kg)	COPEGUS Daily Dose*	COPEGUS Number of Tablets
* approximately 15 mg/kg/day
23 – 33	400 mg/day	1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M.
34 – 46	600 mg/day	1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M.
47 – 59	800 mg/day	2 × 200 mg tablets A.M. 2 × 200 mg tablets P.M.
60 – 74	1000 mg/day	2 × 200 mg tablets A.M. 3 × 200 mg tablets P.M.
≥75	1200 mg/day	3 × 200 mg tablets A.M. 3 × 200 mg tablets P.M.

Chronic Hepatitis C with HIV Coinfection

Adult Patients

Pegasys Monotherapy:

The recommended dose of Pegasys monotherapy for chronic hepatitis C in patients coinfected with HIV is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

Pegasys/COPEGUS Combination Therapy:

The recommended dose when used in combination with ribavirin is Pegasys 180 mcg once weekly and COPEGUS 800 mg orally daily given in two divided doses for a total of 48 weeks, regardless of genotype.

Since COPEGUS absorption increases when administered with a meal, patients are advised to take COPEGUS with food.

Chronic Hepatitis B

Adult Patients

Pegasys Monotherapy:

The recommended dose of Pegasys monotherapy for hepatitis B is 180 mcg (1 mL vial, 0.5 mL prefilled syringe or 0.5 mL disposable autoinjector) once weekly for 48 weeks.

Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination Pegasys/COPEGUS therapy, the dose should be modified until the adverse reactions abate. If intolerance persists after dose adjustment, Pegasys/COPEGUS therapy should be discontinued. Table 3, Table 4, Table 5, and Table 6 provide guidelines for dose modifications and discontinuation of Pegasys/COPEGUS based on laboratory abnormalities, patient's depression status, and cardiac status.

Adult Patients

When dose modification of Pegasys is required for adverse reactions (clinical and/or laboratory), initial dose reduction to 135 mcg (which is 0.75 mL for the vials or adjustment to the corresponding graduation mark for the prefilled syringes) is recommended. Dose modification to 135 mcg per week can also be achieved by using a 135 mcg/0.5 mL strength disposable autoinjector. Dose reduction to 90 mcg (which is 0.5 mL for the vials or adjustment to the corresponding graduation mark for the prefilled syringes) may be needed if the adverse reaction persists or recurs. Following improvement of the adverse reaction, re-escalation of the dose may be considered [see Warnings and Precautions (5) and Adverse Reactions (6)].

Table 3 Pegasys Hematological Dose Modification Guidelines

Laboratory Values	Recommended Dose
ANC <750 cells/mm3	Reduce to 135 mcg
ANC <500 cells/mm3	Discontinue treatment until ANC values return to more than 1000 cells/mm3. Reinstitute at 90 mcg and monitor ANC.
Platelet <50,000 cells/mm3	Reduce to 90 mcg
Platelet <25,000 cells/mm3	Discontinue treatment

Table 4 Guidelines for Modification or Discontinuation of Pegasys and for Scheduling Visits for Adult Patients with Depression

Depression Severity	Initial Management (4-8 weeks)		Depression Status
	Dose modification	Visit schedule	Remains stable	Improves	Worsens
Mild	No change	Evaluate once weekly by visit and/or phone	Continue weekly visit schedule	Resume normal visit schedule	(See moderate or severe depression)
Moderate	Decrease Pegasys dose to 135 mcg (in some cases dose reduction to 90 mcg may be needed)	Evaluate once weekly (office visit at least every other week)	Consider psychiatric consultation. Continue reduced dosing	If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced dosing or return to normal dose	(See severe depression)
Severe	Discontinue Pegasys permanently	Obtain immediate psychiatric consultation	Psychiatric therapy necessary

Pediatric Patients

 If toxicities occur which may be related to Pegasys or COPEGUS administration, the dose of one or both drugs can be modified. Additionally, COPEGUS or Pegasys plus COPEGUS combination therapy can be discontinued. COPEGUS should never be given as monotherapy. Recommendations for dose modifications in pediatric patients for toxicities associated with Pegasys administration are presented in Table 5.

 When dose modification is required for moderate to severe adverse reactions (clinical or laboratory), modification to 135 mcg/1.73 m2 × BSA is generally adequate. However, in some cases, dose modification to 90 mcg/1.73 m2 × BSA or 45 mcg/1.73 m2 × BSA may be needed. Up to 3 dose modifications for toxicity can be made before discontinuation is considered. These modifications apply to pediatric patients with depression, who can be managed similar to the algorithm for adult patients outlined in Table 4.

 Guidelines for dose modification based on neutropenia, increased ALT levels, and decreased platelet counts for pediatric patients are provided in Table 5.

Table 5 Pegasys Dose Modification for Neutropenia, Increased ALT and Decreased Platelets in Pediatric Patients

	Pegasys Dose Modification
Neutropenia	750-999 cells/mm3: Week 1-2 — immediate modification to 135 mcg/1.73 m2 × BSA; Week 3-48: no modification.
	500-749 cells/mm3: Week 1-2 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 135 mcg/1.73 m2 × BSA, assess weekly × 3 to verify WBC's >750 cells/mm3; Week 3-48 — immediate modification to 135 mcg/1.73 m2 × BSA.
	250-499 cells/mm3: Week 1-2 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 90 mcg/1.73 m2 × BSA; Week 3-48 — delay or hold dose until >750 cells/mm3 then resume dose with a modification to 135 mcg/1.73 m2 × BSA.
	<250 cells/mm3 (or febrile neutropenia): discontinue treatment.
Increased alanine transaminase (ALT)	For persistent or increasing elevations ≥5 but <10 × ULN, modify dose with a modification to 135 mcg/1.73 m2 × BSA. Monitor weekly, further modifying dose if necessary, until stable or ALT level decreases.
	For persistent ALT values ≥10 × ULN discontinue treatment.
Decreased platelet count	Platelet <50,000 cells/mm3: Modify dose to 90 mcg/1.73 m2 × BSA.

COPEGUS Dose Modifications

 See COPEGUS Package Insert for all instructions regarding COPEGUS dosing and administration.

Adult and Pediatric Patients

Table 6 COPEGUS Dose Modification Guidelines for Adults and Pediatric Patients

Body weight in kilograms (kg)	Laboratory Values
	Hemoglobin <10 g/dL in patients with no cardiac disease, or   Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease	Hemoglobin <8.5 g/dL in patients with no cardiac disease, or   Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease
Adult Patients older than 18 years of age
Any weight	1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M.	Discontinue COPEGUS
Pediatric Patients 5 to 18 years of age
23 – 33 kg	1 × 200 mg tablet A.M.	Discontinue COPEGUS
34 – 46 kg	1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M.
47 – 59 kg	1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M.
60 – 74 kg	1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M.
≥75 kg	1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M.

 The guidelines for COPEGUS dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that COPEGUS be increased to the original dose (1000 mg or 1200 mg).

Pediatric Patients

 Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in COPEGUS dose to the original dose may be attempted depending upon the physician's judgment. If COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at one-half the full dose.

Renal Impairment

 In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg Pegasys is recommended. Signs and symptoms of interferon toxicity should be closely monitored. If severe adverse reactions or laboratory abnormalities develop, the dose of Pegasys may be reduced to 90 mcg until the adverse reactions abate. If intolerance persists after dose adjustment, Pegasys/COPEGUS therapy should be discontinued.

 Renal function should be evaluated in all patients on COPEGUS. The dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].

Table 7 Dose Modification for Renal Impairment

Creatinine Clearance	Pegasys Dose (once weekly)	COPEGUS Dose (daily)
30 to 50 mL/min	180 mcg	Alternating doses, 200 mg and 400 mg every other day
< 30 mL/min	135 mcg	200 mg daily
Hemodialysis	135 mcg	200 mg daily

 No data are available for pediatric subjects with renal impairment.

Liver Function

Adult Patients

If ALT increases are progressive despite dose reduction or accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be immediately discontinued.

In chronic hepatitis C patients with progressive ALT increases above baseline values, the dose of Pegasys should be reduced to 135 mcg and more frequent monitoring of liver function should be performed. After Pegasys dose reduction or withholding, therapy can be resumed after ALT flares subside.

In chronic hepatitis B patients with elevations in ALT (greater than 5 × ULN), more frequent monitoring of liver function should be performed and consideration should be given to either reducing the dose of Pegasys to 135 mcg or temporarily discontinuing treatment. After Pegasys dose reduction or withholding, therapy can be resumed after ALT flares subside.

In adult patients with persistent, severe (ALT greater than 10 times above the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.

Discontinuation of Dosing

Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of therapy or undetectable HCV RNA after 24 weeks of therapy [see Clinical Studies (14)].

During treatment, patients' clinical status and hepatic function should be closely monitored, and Pegasys treatment should be immediately discontinued if decompensation is observed [see Contraindications (4)].

Patients should be monitored for serious adverse reactions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn [see Boxed Warning].

Preparation and Administration

A patient should self-inject Pegasys only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique [see illustrated FDA Approved Medication Guide for directions on injection site preparation and injection instructions].

Pegasys should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Vials, prefilled syringes, and disposable autoinjectors with particulate matter or discoloration should be returned to the pharmacist.

 Discard the unused portion of Pegasys in single-use vials or prefilled syringes in excess of the labeled volume. Use only one vial or prefilled syringe or disposable autoinjector per dose.

Dosage Forms and Strengths

• Vial for single use: 180 mcg/mL


• Prefilled Syringe for single use: 180 mcg/0.5 mL


• Autoinjector for single use: 180 mcg/0.5 mL


• Autoinjector for single use: 135 mcg/0.5 mL

Contraindications

Pegasys is contraindicated in patients with:

• Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome to alpha interferons, including Pegasys, or any of its components.


• Autoimmune hepatitis


•  Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment


•  Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment

Pegasys is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants.

Pegasys/COPEGUS combination therapy is additionally contraindicated in:

• Women who are pregnant


• Men whose female partners are pregnant


• Patients with known hypersensitivity (urticaria, angioedema, bronchoconstriction, and anaphylaxis) to COPEGUS or to any component of the tablet


• Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)


• Combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions (7.4)].

Warnings and Precautions

Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn [see Boxed Warning].

Use with Ribavirin including COPEGUS

Pregnancy

COPEGUS may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking Pegasys and COPEGUS combination therapy. COPEGUS therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time [see Boxed Warning, Contraindications (4), Patient Counseling Information (17) and COPEGUS Package Insert].

Anemia

The primary toxicity of COPEGUS is hemolytic anemia. Hemoglobin less than 10 g/dL was observed in approximately 13% of COPEGUS and Pegasys treated subjects in chronic hepatitis C clinical trials.  The anemia associated with COPEGUS occurs within 1 to 2 weeks of initiation of therapy with maximum drop in hemoglobin observed during the first eight weeks. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pre-treatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by COPEGUS. Patients should be assessed for underlying cardiac disease before initiation of COPEGUS therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.6)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS [see COPEGUS Package Insert].

Neuropsychiatric

Life-threatening or fatal neuropsychiatric reactions may manifest in all patients receiving therapy with Pegasys and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with and without previous psychiatric illness.

Pegasys should be used with extreme caution in all patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders, and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted [see Adverse Reactions (6.1) and Dosage and Administration (2.5)].

Cardiovascular Disorders

Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with Pegasys. Pegasys should be administered with caution to patients with pre-existing cardiac disease. Because cardiac disease may be worsened by ribavirin-induced anemia, patients with a history of significant or unstable cardiac disease should not receive Pegasys/COPEGUS [see Warnings and Precautions (5.1) and COPEGUS Package Insert].

Bone Marrow Suppression

Pegasys suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including Pegasys. Very rarely, alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy [see Warnings and Precautions (5.1)].

Pegasys/COPEGUS should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm3, with baseline platelet counts less than 90,000 cells/mm3 or baseline hemoglobin less than 10 g/dL. Pegasys therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts [see Dosage and Administration (2.6)].

Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding [see Adverse Reactions (6.1)].

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Pegasys, COPEGUS, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7)].

Autoimmune Disorders

Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. Pegasys should be used with caution in patients with autoimmune disorders.

Endocrine Disorders

Pegasys causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with Pegasys. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin Pegasys therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of Pegasys therapy.

Ophthalmologic Disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment are induced or aggravated by treatment with Pegasys or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including Pegasys. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alfa-based therapies and these events is difficult to establish.

Hepatic Failure and Hepatitis Exacerbations

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Pegasys. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 6 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic subjects receiving HAART, 14 (11%) of these subjects across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 subjects were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk.  During treatment, patients' clinical status and hepatic function should be closely monitored, and Pegasys/COPEGUS treatment should be immediately discontinued in patients with hepatic decompensation [see Contraindications (4)].

Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 10-fold higher than the upper limit of normal) during Pegasys treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive subjects, respectively. Marked transaminase flares while on Pegasys therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. Pegasys dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of Pegasys dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, Pegasys should be immediately discontinued [see Adverse Reactions (6.1) and Dosage and Administration (2.5)].

Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by Pegasys or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. Pegasys combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

Infections

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, or fungal), some fatal, have been reported during treatment with alpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Colitis

Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. Pegasys should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.

Pancreatitis

Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. Pegasys/COPEGUS should be suspended if symptoms or signs suggestive of pancreatitis are observed. Pegasys/COPEGUS should be discontinued in patients diagnosed with pancreatitis.

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with Pegasys/COPEGUS should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving Pegasys with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

Impact on Growth in Pediatric Patients

 Pediatric subjects treated with Pegasys plus COPEGUS combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.

Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and Pegasys as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.

Laboratory Tests

Before beginning Pegasys or Pegasys/COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Pegasys/COPEGUS.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found.  In a pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of Pegasys may be considered as a guideline to acceptable baseline values for initiation of treatment:

• Platelet count greater than or equal to 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV subjects with cirrhosis or 70,000 cells/mm3 in subjects with CHC and HIV)


• Absolute neutrophil count (ANC) greater than or equal to 1,500 cells/mm3


• Serum creatinine concentration less than 1.5 × upper limit of normal


• TSH and T4 within normal limits or adequately controlled thyroid function


• CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 copies/mL in subjects coinfected with HIV


• Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected subjects


• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in subjects with CHC and HIV

Adverse Reactions

In clinical trials, a broad variety of serious adverse reactions were observed in 1,010 subjects who received Pegasys at doses of 180 mcg for 48 weeks, alone or in combination with COPEGUS [see Boxed Warning and Warnings and Precautions (5)]. The most common life-threatening or fatal events induced or aggravated by Pegasys and COPEGUS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects [see Warnings and Precautions (5.9)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in 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 clinical practice.

Adult Subjects

In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving Pegasys alone or in combination with COPEGUS. The most common serious adverse reactions (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of less than 1% and included: suicide, suicidal ideation, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

In clinical trials, 98 to 99 percent of subjects experienced one or more adverse reactions. For hepatitis C subjects, the most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 8 displays pooled rates of adverse reactions occurring in greater than 5% of subjects in the Pegasys monotherapy and Pegasys/COPEGUS combination therapy clinical trials.

Overall 11% of CHC monoinfected subjects receiving 48 weeks of therapy with Pegasys either alone or in combination with COPEGUS discontinued therapy; 16% of CHC/HIV coinfected subjects discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders, and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of subjects with CHC or CHC/HIV required modification of Pegasys and/or COPEGUS therapy. The most common reasons for dose modification of Pegasys in CHC and CHC/HIV subjects was for neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of COPEGUS in CHC and CHC/HIV subjects was anemia (22% and 16%, respectively). Pegasys dose was reduced in 12% of subjects receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of subjects receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of subjects