INDICATIONS AND USAGE
CINNOVEX (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.
DOSAGE AND ADMINISTRATION
CINNOVEX is administered intramuscularly.
The recommended dose is 30 micrograms once a week. To reduce the incidence and severity of flulike symptoms that may occur when initiating CINNOVEX therapy at a dose of 30 micrograms, CINNOVEX may be started at a dose of 7.5 micrograms and the dose may be increased by 7.5 micrograms each week for the next three weeks until the recommended dose of 30 micrograms is achieved (see Table 1). An AVOSTARTGRIP kit containing 3 titration devices can be used for titration and is to be used only with CINNOVEX Prefilled Syringes.
Table 1: Schedule for Dose Titration
1Dosed once a week, intramuscularly
Important Administration Instructions (All Dosage Forms)
All CINNOVEX dosage forms are single-use (injection of reconstituted solution, prefilled syringe, and prefilled autoinjector). See Patient's Instructions for Use for complete administration instructions.
The first CINNOVEX injection should be performed under the supervision of an appropriately qualified health care professional. If patients or caregivers are to administer CINNOVEX, train them in the proper intramuscular injection technique and assess their ability to inject intramuscularly to ensure the proper administration of CINNOVEX.
Advise patients and caregivers to:
- Rotate sites for intramuscular injections with each injection to minimize the likelihood of injection site reactions
- NOT inject into an area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way
- Check the injection site after 2 hours for redness, swelling, or tenderness
- Contact their doctor or nurse if they have a skin reaction and it does not clear up in a few days
A 25 gauge, 1” needle for intramuscular injection with CINNOVEX prefilled syringe or injection of reconstituted solution may be substituted for the 23 gauge, 1 ¼” needle by the healthcare provider, if deemed appropriate. A 25 gauge, 5/8” needle specific to the prefilled autoinjector is supplied with the CINNOVEX PEN Administration Dose Pack. DO NOT use any other needle with the autoinjector.
Use safe disposal procedures for needles and syringes. Do not re-use needles, syringes, prefilled syringes, or auto injectors. Following the administration of each titrated dose, discard any remaining product.
Premedication for Flu-like Symptoms
Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with CINNOVEX use.
DOSAGE FORMS AND STRENGTHS
- For injection: 30 micrograms lyophilized powder in a single-use vial
- Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled syringe
- Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled Auto-Injector
CINNOVEX is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation.
The lyophilized vial formulation of CINNOVEX is contraindicated in patients with a history of hypersensitivity to albumin (human).
WARNINGS AND PRECAUTIONS
Depression, Suicide, and Psychotic Disorders
Patients treated with CINNOVEX and their caregivers should be advised to report immediately any symptoms of depression, suicidal ideation, and/or psychosis to their prescribing physicians. If a patient develops depression or other severe psychiatric symptoms, cessation of CINNOVEX therapy should be considered. Depression and suicide have been reported to occur with increased frequency in patients receiving CINNOVEX. In Study 1, the incidence of depression was similar in placebo-treated and in CINNOVEXtreated patients, but suicidal tendency was seen more frequently in CINNOVEX-treated patients (4% in CINNOVEX group vs. 1% in placebo group). In Study 2, there was a greater incidence of depression in CINNOVEX-treated patients than in placebo-treated patients (20% in CINNOVEX group vs. 13% in placebo group).
Additionally, there have been post-marketing reports of depression, suicidal ideation, and/or development of new or worsening of other pre-existing psychiatric disorders, including psychosis. For some of these patients, symptoms of depression improved upon cessation of CINNOVEX.
Severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients taking CINNOVEX. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with CINNOVEX. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of CINNOVEX used in combination with known hepatotoxic drugs or other products (e.g., alcohol) should be considered prior to starting CINNOVEX, or before starting hepatotoxic drugs. Patients should be monitored for signs of hepatic injury.
Anaphylaxis and Other Allergic-Reactions
Anaphylaxis has been reported as a rare complication of CINNOVEX use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria. Discontinue CINNOVEX if anaphylaxis or other allergic reactions occur.
Congestive Heart Failure
Patients with pre-existing congestive heart failure should be monitored for worsening of their cardiac condition during initiation of and continued treatment with CINNOVEX. While beta interferons do not have any known direct cardiac toxicity, during the post-marketing period cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported in patients without known predisposition to these events, and without other etiologies being established. In some cases, these events have been temporally related to the administration of CINNOVEX. In some of these instances recurrence upon rechallenge was observed.
Decreased Peripheral Blood Counts
Decreased peripheral blood counts in all cell lines, including rare pancytopenia and thrombocytopenia, have been reported from postmarketing experience in CINNOVEX-treated patients. In some cases, platelet counts were below 10,000/microliter. Some cases recurred with rechallenge. Patients should be monitored for symptoms or signs of decreased blood counts.
Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. In the two placebo-controlled studies in multiple sclerosis (Studies 1 and 2), 4 patients receiving CINNOVEX experienced seizures, while no seizures occurred in the placebo group. Three of these 4 patients had no prior history of seizure. It is not known whether these events were related to the effects of multiple sclerosis alone, to CINNOVEX, or to a combination of both.
Post-marketing reports of autoimmune disorders of multiple target organs in CINNOVEX-treated patients included idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of autoimmune hepatitis. If CINNOVEX-treated patients develop a new autoimmune disorder, consider stopping the therapy.
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended during CINNOVEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Thyroid function should be monitored periodically. If patients have or develop symptoms of thyroid dysfunction (hypo- or hyperthyroidism), thyroid function tests should be performed according to standard medical practice.
Central nervous system: Headache (58% to 70%), fatigue (33% to 41%), depression (18% to 25%), pain (23%), chills (19%), dizziness (14%)
Gastrointestinal: Nausea (23%), abdominal pain (8% to 22%)
- Genitourinary: Urinary tract infection (17%)
- Hematologic & oncologic: Leukopenia (28% to 36%), lymphadenopathy (11% to 12%)
- Hepatic: Increased serum ALT (20% to 27%), increased serum AST (10% to 17%)
- Immunologic: Antibody development (neutralizing; significance not known; Rebif: 24% to 31%; CinnoVex: 5%)
- Local: Injection site reaction (3% to 92%)
- Neuromuscular & skeletal: Myalgia (25% to 29%), back pain (23% to 25%), weakness (24%), skeletal pain (10% to 15%), rigors (6% to 13%)
- Ophthalmic: Visual disturbance (7% to 13%)
- Respiratory: Flu-like symptoms (49% to 59%), sinusitis (14%), upper respiratory tract infection (14%)
- Miscellaneous: Fever (20% to 28%)
1% to 10%:
Cardiovascular: Chest pain (5% to 8%), vasodilation (2%)
Central nervous system: Hypertonia (6% to 7%), migraine (5%), ataxia (4% to 5%), drowsiness (4% to 5%), malaise (4% to 5%), seizure (1% to 5%), suicidal tendencies (4%)
- Dermatologic: Erythematous rash (5% to 7%), maculopapular rash (4% to 5%), alopecia (4%), urticaria
- Endocrine & metabolic: Thyroid disease (4% to 6%)
- Gastrointestinal: Xerostomia (1% to 5%), toothache (3%)
- Genitourinary: Urinary frequency (2% to 7%), urinary incontinence (2% to 4%), urine abnormality (3%)
- Hematologic & oncologic: Thrombocytopenia (2% to 8%), anemia (3% to 5%)
- Hepatic: Hyperbilirubinemia (2% to 3%)
- Infection: Infection (7%)
- Local: Pain at injection site (8%), bruising at injection site (6%), inflammation at injection site (6%), tissue necrosis at injection site (1% to 3%)
- Neuromuscular & skeletal: Arthralgia (9%)
- Ophthalmic: Eye disease (4%), xerophthalmia (1% to 3%)
- Respiratory: Bronchitis (8%)
(Limited to important and life-threatening): Abnormal healing, abscess, abscess at injection site, amnesia, anaphylaxis, arteritis, arthritis, bloody stools, breast fibroadenosis, cardiac arrest, cardiac failure, cellulitis at injection site, conjunctivitis, depersonalization, dermal ulcer, diverticulitis, drug dependence, emphysema, epididymitis, erythema multiforme, facial paralysis, fibrosis at injection site, furunculosis, gallbladder disease, gastritis, gastrointestinal hemorrhage, gingivitis, gynecomastia, hemolytic uremic syndrome, hemorrhage, hepatic failure, hepatic neoplasm, hepatitis, hepatomegaly, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hernia, hypersensitivity reaction at injection site, hyperthyroidism, hypoglycemia, hypokalemia, hypomagnesemia, hypotension, hypothyroidism, immune thrombocytopenia, intestinal obstruction, intestinal perforation, lipoma, lupus erythematosus, menopause, neoplasm, nephrolithiasis, neurological signs and symptoms (transient; may mimic multiple sclerosis exacerbations), nevus, orthostatic hypotension, osteonecrosis, pancytopenia, pelvic inflammatory disease, pericarditis, periodontitis, peripheral vascular disease, Peyronie's disease, pneumonia, postmenopausal bleeding, proctitis, psychiatric disorders (new or worsening; including suicidal ideation), psychoneurosis, pulmonary embolism, pyelonephritis, retinal vascular disease, sepsis, severe weakness (transient), skin photosensitivity, Stevens-Johnson syndrome, synovitis, tachycardia, telangiectasia, testicular disease, thromboembolism, thrombotic thrombocytopenic purpura, uterine fibroids, vaginal hemorrhage, vascular disease, vesicular eruption
USE IN SPECIFIC POPULATIONS
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. CINNOVEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose (based upon a body surface area [mg/m2] comparison), no teratogenic or other adverse effects on fetal development were observed. Abortifacient activity was evident following 3 to 5 doses at this level. No abortifacient effects were observed in monkeys treated at 2 times the recommended weekly human dose (based upon mg/m2).
It is not known whether CINNOVEX is excreted in human milk.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of CINNOVEX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.
CINNOVEX is a 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of CINNOVEX is identical to that of natural human interferon beta.
Using the World Health Organization (WHO) International Standard for Interferon, CINNOVEX has a specific activity of approximately 200 million international units of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). CINNOVEX 30 micrograms contains approximately 6 million international units of antiviral activity using this method. The activity against other standards is not known. Comparison of the activity of CINNOVEX with other interferon betas is not appropriate, because of differences in the reference standards and assays used to measure activity.
CINNOVEX Lyophilized Powder Vial
A vial of CINNOVEX is a sterile, white to off-white lyophilized powder for intramuscular injection after reconstitution with supplied diluent (Sterile Water for Injection, USP). Each vial of reconstituted CINNOVEX contains 30 micrograms of interferon beta-1a; 15 mg Albumin (Human), USP; 5.8 mg Sodium Chloride, USP; 5.7 mg Dibasic Sodium Phosphate, USP; and 1.2 mg Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approximately 7.3.
Mechanism of Action
The mechanism of action by which CINNOVEX exerts its effects in patients with multiple sclerosis is unknown.
Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type I (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN gamma) and type III (IFNlambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells.
Differences in the bioactivites induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors.
Interferon beta exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include 2', 5'-oligoadenylate synthetase, β2-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with CINNOVEX.
Clinical studies conducted in multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased in patients treated with CINNOVEX compared to placebo. Serum IL10 levels maximally were increased by 48 hours after intramuscular injection of CINNOVEX and remained elevated for 1 week. However, no relationship has been established between absolute levels of IL-10 and clinical outcome in multiple sclerosis.
Pharmacokinetics of CINNOVEX in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of CINNOVEX in healthy subjects following doses of 30 micrograms through 75 micrograms have been investigated. Serum levels of CINNOVEX as measured by antiviral activity are slightly above detectable limits following a 30 microgram intramuscular dose, and increase with higher doses.
After an intramuscular dose, serum levels of CINNOVEX typically peak between 3 and 15 hours and then decline at a rate consistent with a 10 hour elimination half-life. Serum levels of CINNOVEX may be sustained after intramuscular administration due to prolonged absorption from the intramuscular site. Systemic exposure, as determined by AUC and Cmax values, is greater following intramuscular than subcutaneous (SC) administration.
Subcutaneous administration of CINNOVEX should not be substituted for intramuscular administration. Subcutaneous and intramuscular administration have been observed to have non-equivalent pharmacokinetic and pharmacodynamic parameters following administration to healthy volunteers.
Biological response markers (e.g., neopterin and β2-microglobulin) are induced by CINNOVEX following parenteral doses of 15 micrograms through 75 micrograms in healthy subjects and treated patients. Biological response marker levels increase within 12 hours of dosing and remain elevated for at least 4 days. Peak biological response marker levels are typically observed 48 hours after dosing. The relationship of serum CINNOVEX levels or levels of these induced biological response markers to the mechanisms by which CINNOVEX exerts its effects in multiple sclerosis is unknown.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis: The carcinogenic potential of CINNOVEX has not been tested in animals.
Mutagenesis: Interferon beta was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test or in an in vitro cytogenetic assay in human lymphocytes.
Impairment of Fertility: In monkeys administered interferon beta by subcutaneous injection (8 to 15 doses of 1.25 mcg/kg or 50 mcg/kg) over the course of one menstrual cycle, menstrual irregularities, anovulation, and decreased serum progesterone levels were observed at the higher dose. These effects were reversible after discontinuation of drug. The no-effect dose (1.25 mcg/kg) is approximately 2 times the recommended weekly dose in humans (30 mcg) on a mg/m2 basis.
HOW SUPPLIED/STORAGE AND HANDLING
CINNOVEX Lyophilized Powder Vial
A vial of CINNOVEX is supplied as a lyophilized powder in a single-use vial containing 33 micrograms (6.6 million international units) of interferon beta-1a; 16.5 mg Albumin (Human), USP; 6.4 mg Sodium Chloride, USP; 6.3 mg Dibasic Sodium Phosphate, USP; and 1.3 mg Monobasic Sodium Phosphate, USP, and is preservative-free. Diluent is supplied in a single-use vial (Sterile Water for Injection, USP). Vials of CINNOVEX should be stored in a 2°C to 8°C (36°F to 46°F) refrigerator. Should refrigeration be unavailable, vials of CINNOVEX can be stored at 25°C (77°F) for a period of up to 30 days. DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the vial. Following reconstitution, it is recommended the product be used as soon as possible within 6 hours stored at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE RECONSTITUTED CINNOVEX. Once the product is removed from the refrigerator, it must not be stored above 25°C (77°F). If the product has been exposed to conditions other than those recommended, DISCARD THE PRODUCT and DO NOT USE. DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the syringe.
DISCARD THE PRODUCT and DO NOT USE. DO NOT EXPOSE TO HIGH TEMPERATURES.
DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the prefilled autoinjector.
Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, trouble with sensation, or trouble with coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially as the disease advances.