BCG (Intravesical)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension Reconstituted, Intravesical [preservative free]:

TheraCys: 81 mg (1 ea [DSC]) [contains monosodium glutamate (sodium glutamate)]

Tice BCG: 50 mg (1 ea)

Pharmacology

Mechanism of Action

BCG (intravesical) is an attenuated strain of bacillus Calmette-Guérin (Mycobacterium bovis) used as a biological response modifier. BCG, when used intravesicularly for treatment of bladder carcinoma in situ, is thought to cause a local, chronic inflammatory response involving macrophage and leukocyte infiltration of the bladder. BCG (intravesical) is active immunotherapy which stimulates the host's immune mechanism to reject the tumor.

Use: Labeled Indications

Bladder cancer: Treatment and prophylaxis of carcinoma in situ of the urinary bladder; prophylaxis of primary or recurrent superficial or minimally invasive (stage Ta and/or T1) papillary tumors following transurethral resection

Limitations of use: BCG (intravesical) is not recommended for stage Ta low-grade papillary tumors unless judged to be at high risk for recurrence. BCG (intravesical) is not recommended for immunization against tuberculosis.

Contraindications

Known hypersensitivity to BCG (intravesical) or any component of the formulations, hypersensitivity after a previous administration of BCG (intravesical) or after a previous administration of a medicinal product containing the same substances; immunosuppressed patients or persons with congenital or acquired immune deficiencies (eg, HIV infection, leukemia, lymphoma, cancer therapy, immunosuppressive therapy such as corticosteroids); active tuberculosis; concurrent febrile illness, urinary tract infection, or gross hematuria; current symptoms or previous history of a systemic BCG reaction; recent (TheraCys: <14 days; TICE BCG: <7 to 14 days) biopsy, transurethral resection (TUR), or traumatic catheterization

Canadian labeling: Additional contraindications (not in US labeling): Invasive bladder cancer; concomitant use with antituberculosis drugs, including streptomycin, para-aminosalicylic acid, isoniazid, rifampicin, and ethambutol; pregnancy; breast-feeding

Dosage and Administration

Dosing: Adult

Bladder cancer: Intravesicular:

TheraCys: Induction: One dose (81 mg or one vial) instilled into bladder (retain for up to 2 hours) once weekly for 6 weeks beginning at least 14 days after biopsy or transurethral resection, followed by maintenance therapy of 81 mg (one vial) at 3, 6, 12, 18, and 24 months after initial dose.

TICE BCG: Induction: One dose (~50 mg or one vial) instilled into the bladder (retain for 2 hours) once weekly for 6 weeks beginning 7 to 14 days after biopsy (may repeat cycle 1 time if tumor remission not achieved), followed by maintenance therapy of ~50 mg (one vial) approximately once a month for at least 6 to 12 months.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Bacterial urinary tract infection: Withhold treatment until complete resolution.

Persistent fever or acute febrile illness consistent with BCG infection: Discontinue treatment.

Reconstitution

TheraCys: Reconstitute with 3 mL of sterile preservative free saline and shake gently to create a fine, even suspension (avoid foaming). Do not use if flocculation or clumping (that is not dispersed with gentle shaking) occurs after reconstitution. Withdraw contents (~3 mL) and further dilute with sterile preservative free saline to a final volume of 50 mL.

TICE BCG: Reconstitute with 1 mL sterile, preservative free saline using a 3 mL syringe. Add to vial and swirl gently to form a homogenous suspension (forceful agitation may cause clumping). Dilute to a final volume of 50 mL with sterile, preservative free saline. Mix gently prior to intravesical installation.

Administration

For intravesicular (bladder instillation) administration only; do not administer IV, SubQ, IM, or intradermally.

Intravesicular: Patients should not drink fluids for 4 hours prior to instillation. Empty or drain bladder. Instill BCG (intravesical) by gravity; remove catheter after instillation is complete. Retain BCG (intravesical) for as long as possible, up to 2 hours. Patient should lie prone for at least 15 minutes, then rotate positions (lie on right side, left side, abdomen, and back) every 15 minutes to maximize bladder surface exposure (TICE BCG); for TheraCys, patient may be in an upright position after the first 15 minutes. Following bladder instillation, patients should be instructed to void in a seated position in order to avoid the splashing of urine; burning may occur with the first void following therapy. Prior to flushing, disinfect the urine for 15 minutes with an equal amount of household bleach (this should be done for the first 6 hours after therapy). After administration, patients should drink plenty of water in order to flush the bladder.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Protect from sunlight (direct or indirect); minimize exposure to artificial light. Use TheraCys immediately after reconstitution if possible, and do not exceed 2 hours stored at 2°C to 25°C (35°F to 77°F). Store TICE BCG at 2°C to 8°C (36°F to 46°F) and use within 2 hours of reconstitution.

Drug Interactions

Antibiotics: May diminish the therapeutic effect of BCG (Intravesical). Exceptions: Acetic Acid (Otic); Acetic Acid (Topical); Aluminum Acetate; Azithromycin (Ophthalmic); Aztreonam (Oral Inhalation); Bacitracin (Ophthalmic); Bacitracin (Topical); Chlortetracycline; Ciprofloxacin (Ophthalmic); Clindamycin (Topical); Dapsone (Topical); Dibrompropamidine (Ophthalmic); Dibrompropamidine (Topical); Erythromycin (Ophthalmic); Erythromycin (Topical); Fidaxomicin; Framycetin; Fusidic Acid (Ophthalmic); Fusidic Acid (Topical); Gatifloxacin; Gentamicin (Ophthalmic); Gentamicin (Topical); MetroNIDAZOLE (Topical); Mupirocin; Nitrofurazone; Ozenoxacin; Sulfacetamide (Ophthalmic); Tobramycin (Ophthalmic). Avoid combination

Hexaminolevulinate: BCG (Intravesical) may diminish the diagnostic effect of Hexaminolevulinate. Avoid combination

Immunosuppressants: May diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Myelosuppressive Agents: May diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Test Interactions

Use of BCG (intravesical) may result in tuberculin sensitivity. Determine the tuberculin reactivity of patients receiving BCG by PPD skin testing PRIOR to treatment initiation.

Adverse Reactions

>10%:

Central nervous system: Malaise (≤40%), chills (9% to 34%), pain (≤17%)

Gastrointestinal: Nausea (≤16%), vomiting (≤16%), anorexia (≤11%)

Genitourinary: Dysuria (52% to 60%), detrusor hyperreflexia of bladder (50% to 60%), urinary frequency (40% to ≤50%), urinary urgency (6% to ≤50%), hematuria (26% to 39%), cystitis (6% to 30%), urinary tract infection (2% to 18%)

Hematologic & oncologic: Anemia (≤21%)

Respiratory: Flu-like symptoms (24% to 33%)

Miscellaneous: Fever (17% to 38%)

1% to 10%:

Central nervous system: Fatigue (≤7%), dizziness (≤2%), headache (≤2%)

Dermatologic: Diaphoresis (3%), skin rash (≤3%)

Endocrine & metabolic: Weight loss (≤2%)

Gastrointestinal: Diarrhea (≤6%), abdominal pain (2% to 3%)

Genitourinary: Genital pain (10%), nephrotoxicity (10%), hemorrhagic cystitis (9%), bladder spasm (≤8%; including contracted bladder), bladder pain (≤6%), urinary incontinence (2% to 6%), nocturia (5%), bladder contraction (≤5%), urine sedimentation abnormality (debris and tissue; ≤2%), epididymitis (≤1%), orchitis (≤1%), prostatitis (≤1%), pyuria (≤1%), urethritis (≤1%), urinary tract obstruction (≤1%)

Hematologic & oncologic: Leukopenia (≤5%), disorder of hemostatic components of blood (≤1%); thrombocytopenia (≤1%)

Hepatic: Granulomatous hepatitis (≤1%), hepatitis (≤1%)

Hypersensitivity: Hypersensitivity reaction (2%)

Infection: Sepsis (3%; BCG sepsis: ≤1%), abscess (genital; ≤2%)

Neuromuscular & skeletal: Arthritis (≤7%), arthralgia (≤7%), myalgia (≤7%), muscle cramps (≤4%), rigors (3%)

Respiratory: Pulmonary infection (3%), pneumonitis (≤1%)

Miscellaneous: Inflammation (genital; ≤2%)

<1%, postmarketing, and/or case reports: Aneurysm (infective), arthritis (reactive), BCG infection, bladder outflow obstruction, chorioretinitis (granulomatous), conjunctivitis, constipation, cytopenia, erythema nodosum, flank pain, glomerulonephritis, granuloma, increased blood urea nitrogen, increased post-void residual urine volume, increased serum creatinine, interstitial nephritis, interstitial pulmonary disease, iritis, keratitis, localized infection (renal abscess), nephritis, pneumonia, pyelonephritis, renal failure syndrome, urinary retention, uveitis, vasculitis

Warnings/Precautions

Concerns related to adverse effects:

• BCG reaction: A systemic granulomatous illness occurring following exposure to BCG is referred to as a systemic BCG reaction when any of the following are present without another detectable etiology: Fever ≥39.5°C for ≥12 hours or ≥38.5°C for ≥48 hours; pneumonitis; hepatitis; organ dysfunction outside of the GU tract with granulomatous inflammation; clinical signs of sepsis. It may be difficult to determine if reaction is due to infection process or inflammatory hypersensitivity. A systemic BCG reaction is more likely to occur with intravesical administration <14 days after a biopsy, transurethral resection (TUR), or traumatic catheterization. Fatalities have been reported with systemic BCG reactions.
• Bladder irritation: BCG (intravesical) may cause symptoms of bladder irritability which usually begin 4 to 6 hours after instillation and may last 24 to 72 hours; symptoms may increase in severity following each instillation.
• Disseminated infections: [US Boxed Warning]: May cause disseminated (including fatal) infections following intravesical administration. Instillation to actively bleeding mucosa may promote systemic BCG infection or sepsis. To prevent serious infections, avoid trauma and/or introduction of contaminants into the urinary tract; postpone treatment for at least 1 to 2 weeks (depending on product) following TUR, biopsy, traumatic catheterization (may resume original schedule after 14 days), or gross hematuria. Do not use in patients with concurrent infections. Use caution in patients with aneurysms and prosthetic devices; ectopic BCG infection may occur at these sites. If signs and symptoms of a systemic BCG infection occur, permanently discontinue BCG treatment and begin therapy with 2 or more antimycobacterial agents (do not use single-agent therapy) while conducting a diagnostic evaluation. Infection from BCG (intravesical) is not sensitive to pyrazinamide. Do not use prophylactic antimycobacterial therapy to prevent local adverse events during treatment (there is no data to support use and may alter efficacy). Determine PPD status prior to use (rule out active tuberculosis prior to treatment initiation). Prior to intravesical instillation, patients with a positive PPD test should be further assessed for signs and/or symptoms of active or latent tuberculosis. BCG may persist in the urinary tract for several months after treatment; delayed manifestations of disseminated BCG infection may develop months to years after BCG therapy. Patients who receive immunosuppressive therapy after BCG therapy may be at higher risk for disseminated infection. Monitor for signs/symptoms of infection/toxicity after each treatment. Discontinue for persistent fever or acute febrile illness consistent with BCG infection. Some male genitourinary tract infections (orchitis or epididymitis) have been refractory to multiple antituberculosis drug therapies and have required orchiectomy.

Disease-related concerns:

• Small bladder capacity: Intravesical instillation may be associated with increased risk of severe local reactions in the presence of small bladder capacity; use with caution.
• Urinary tract infection: If a bacterial urinary tract infection occurs during therapy, withhold instillation until complete resolution of infection.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Latex: Packaging may contain natural latex rubber.

Special handling:

• Biohazard agent: [US Boxed Warning]: Contains live, attenuated mycobacteria. Use appropriate precautions for handling and disposal. BCG is a biohazard; proper preparation technique, handling, and disposal of all equipment in contact with BCG as a biohazard material is recommended. BCG infections have been reported in health care workers due to accidental exposure (needle stick, skin laceration); nosocomial infections have been reported in patients (including immunosuppressed patients) receiving parenteral medications prepared in areas where BCG was prepared. To avoid cross contamination, do not prepare parenteral medications in an area where BCG has been prepared.

Other warnings/precautions:

• Appropriate use: BCG (intravesical) is not a vaccine for the prevention of cancer. Information is not available for interchanging products used for intravesical administration.

Monitoring Parameters

PPD test prior to treatment

Intravesical treatment: Monitor for signs/symptoms of toxicity/infection following every treatment. Signs that antituberculous therapy may be needed: Flu-like symptoms ≥72 hours, fever ≥101.3°F, systemic symptoms which worsen with each treatment, persistently abnormal liver function tests, prostatitis, epididymitis or orchitis of >2 to 3 day duration

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted. BCG (intravesical) is not recommended for use in pregnant women. Women of childbearing potential should be advised to avoid pregnancy while on BCG (intravesical) therapy.

Patient Education

What is this drug used for?

• It is used to treat bladder cancer.

Frequently reported side effects of this drug

• Bladder irritation
• Passing a lot of urine
• Nausea
• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Flu-like symptoms longer than 2 days
• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Severe dizziness
• Passing out
• Chest pain
• Joint pain
• Eye pain
• Eye irritation
• Vomiting
• Unable to pass urine
• Change of amount of urine passed
• Painful urination
• Blood in the urine
• Severe fever
• Loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.