EXTAVIA (Page 2 of 7)

5.4 Congestive Heart Failure

Monitor patients with preexisting congestive heart failure (CHF) for worsening of their cardiac condition during initiation of and continued treatment with EXTAVIA. While beta interferons do not have any known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of interferon beta-1b. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of EXTAVIA if worsening of CHF occurs with no other etiology.

5.5 Injection Site Reactions Including Necrosis

Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including EXTAVIA. Injection site necrosis (ISN) was reported in 4% of interferon beta-1b-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions (6.1)]. Typically, ISN occurs within the first four months of therapy, although postmarketing reports have been received of ISN occurring over one year after initiation of therapy. The necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions, debridement, and/or skin grafting have been required. In most cases, healing was associated with scarring.

In controlled clinical trials, injection site reactions occurred in 78% of patients receiving interferon beta-1b with injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%), and nonspecific reactions were significantly associated with interferon beta-1b treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies.

Injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including EXTAVIA. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating injection sites with each dose. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with EXTAVIA after injection site necrosis has occurred, avoid administration of EXTAVIA into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.

5.6 Leukopenia

In controlled clinical trials, leukopenia was reported in 18% of patients receiving interferon beta-1b (compared to 6% on placebo), leading to a reduction of the dose of interferon beta-1b in some patients [see Adverse Reactions (6.1)]. Monitoring of complete blood and differential white blood cell counts is recommended. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

5.7 Thrombotic Microangiopathy

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including EXTAVIA.

Cases have been reported several weeks to years after starting interferon beta products. If clinical symptoms and laboratory findings consistent with TMA occur and a relationship to EXTAVIA is suspected, discontinue treatment and manage as clinically indicated.

5.8 Pulmonary Arterial Hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including EXTAVIA. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.

Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.

5.9 Flu-like Symptom Complex

In controlled clinical trials, the rate of flu-like symptom complex for patients on interferon beta-1b was 57% [see Adverse Reactions (6.1)]. The incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. The median duration of flu-like symptom complex in Study 1 was 7.5 days [see Clinical Studies (14)]. Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with EXTAVIA use.

5.10 Seizures

Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. It is not known whether these events were related to a primary seizure disorder, the effects of MS alone, the use of beta interferons, other potential precipitants of seizures (e.g., fever), or to some combination of these.

5.11 Drug-induced Lupus Erythematosus

Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including EXTAVIA. Signs and symptoms of drug-induced lupus reported in EXTAVIA-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded DNA antibody testing). If EXTAVIA-treated patients develop new signs and symptoms characteristic of this syndrome, EXTAVIA therapy should be stopped.

5.12 Monitoring for Laboratory Abnormalities

In addition to those laboratory tests normally required for monitoring patients with MS, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of EXTAVIA therapy, and then periodically thereafter in the absence of clinical symptoms.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in more details in other sections of labeling:

  • Hepatic Injury [see Warnings and Precautions (5.1)]
  • Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.2)]
  • Depression and Suicide [see Warnings and Precautions (5.3)]
  • Congestive Heart Failure [see Warnings and Precautions (5.4)]
  • Injection Site Reactions Including Necrosis [see Warnings and Precautions (5.5)]
  • Leukopenia [see Warnings and Precautions (5.6)]
  • Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
  • Pulmonary Arterial Hypertension [see Warnings and Precautions (5.8)]
  • Flu-like Symptom Complex [see Warnings and Precautions (5.9)]
  • Seizures [see Warnings and Precautions (5.10)]
  • Drug-induced Lupus Erythematosus [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical trials of interferon beta-1b cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice.

Among 1407 patients with MS treated with interferon beta-1b 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on interferon beta-1b than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of interferon beta-1b, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.

Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of interferon beta-1b every other day by subcutaneous injection in the pooled placebo-controlled trials (Studies 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients [see Clinical Studies (14)].

Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4
Abbreviations: SGPT, serum glutamic-pyruvic transaminase; SGOT, serum glutamic-oxaloacetic transaminase.a “Injection site reaction” comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy.b “Flu-like symptom (complex)” denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating.
Adverse Reaction Placebo (N = 965) Interferon beta-1b (N = 1407)
Blood and lymphatic system disorders
Lymphocytes count decreased (< 1500/mm3) 66% 86%
Absolute neutrophil count decreased (< 1500/mm3) 5% 13%
White blood cell count decreased (< 3000/mm3) 4% 13%
Lymphadenopathy 3% 6%
Nervous system disorders
Headache 43% 50%
Insomnia 16% 21%
Incoordination 15% 17%
Vascular disorders
Hypertension 4% 6%
Respiratory, thoracic, and mediastinal disorders
Dyspnea 3% 6%
Gastrointestinal disorders
Abdominal pain 11% 16%
Hepatobiliary disorders
Alanine aminotransferase increased(SGPT > 5 times baseline) 4% 12%
Aspartate aminotransferase increased(SGOT > 5 times baseline) 1% 4%
Skin and subcutaneous tissue disorders
Rash 15% 21%
Skin disorder 8% 10%
Musculoskeletal and connective tissue disorders
Hypertonia 33% 40%
Myalgia 14% 23%
Renal and urinary disorders
Urinary urgency 8% 11%
Reproductive system and breast disorders
Metrorrhagia 7% 9%
Impotence 6% 8%
General disorders and administration-site conditions
Injection site reactiona 26% 78%
Asthenia 48% 53%
Flu-like symptoms (complex)b 37% 57%
Pain 35% 42%
Fever 19% 31%
Chills 9% 21%
Peripheral edema 10% 12%
Chest pain 6% 9%
Malaise 3% 6%
Injection site necrosis 0% 4%

In addition to the adverse reactions listed in Table 2, the following adverse reactions occurred more frequently on interferon beta-1b than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase.

Laboratory Abnormalities

In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in interferon beta-1b- and placebo-treated groups, respectively. No patients were withdrawn or dose-reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose-reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of interferon beta-1b patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1 to 4, nine (0.6%) patients were withdrawn from treatment with interferon beta-1b for any laboratory abnormality, including four (0.3%) patients following dose reduction.

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