Valrubicin: Illuminating Efficacy and Safety in Bladder Cancer Treatment

Overview:

Valrubicin is a chemotherapy drug used typically in the treatment of bladder cancer. Bladder cancer refers to all forms of cancer arising from the cells and tissues of the urinary bladder. Valrubicin belongs to a group of semisynthetic drugs called anthracyclines. This drug is administered by infusion straight into the urinary bladder.

This drug was launched in the United States in 1999 for intravesical treatment of Bacillus Calmette-Guerin (a vaccine primarily administered against tuberculosis). BCG-refractory carcinoma in situ of the bladder in people whose cystectomy (surgical removal of the urinary bladder) might be associated with unfavorable mortality or morbidity. This drug was voluntarily withheld in 2002 due to certain manufacturing problems. Valrubicin was recalled in September 2009.

For Patients:

What Is Bladder Cancer?

Bladder cancer is a common form of cancer occurring in the cells of the bladder. The bladder is a storage organ of urine. This cancer begins mostly in the urothelial cells lining the inside portion of the bladder. This cancer occurs due to changes or mutations in the deoxyribonucleic acid (DNA) of the cells of the lining of the bladder. Over time, the abnormal cells can break apart and metastasize (spread) to adjacent structures of the body. The common signs and symptoms associated with bladder cancer include:

• Hematuria (blood in the urine).

• Frequent urination.

• Back pain.

• Painful urination.

• Dark-colored urine.

How Does Valrubicin Work?

Valrubicin solution for intravesical (through bladder) injection is used to treat a form of bladder cancer called carcinoma in situ (CIS) that has not been effectively treated with other therapies like Bacillus Calmette-Guerin (BCG) therapy in individuals who can not have the surgery done straight away. It is an anthracycline antibiotic used only in chemotherapy cancer treatments. This drug works by slowing or inhibiting the growth of bladder tumor cells in the body.

What Is the Dosage of Valrubicin?

The recommended adult dosage of Valrubicin for bladder cancer is 800 milligrams administered intravesically (through the bladder) once a week for six weeks.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Inform the doctor if one has or develops allergic reactions to Valrubicin or other ingredients of the given formulation.

• Inform the healthcare provider about the prescription and over-the-counter medication one takes or intends to take in the future. This includes pharmaceutical drugs, herbal products, vitamin supplements, nutritional products, and other products.

• Inform the doctor if one has or has ever had medical conditions, particularly bladder perforation (tear or hole in the bladder), urinary tract infection, overactive bladder, urinary incontinence (loss of bladder control), and leakage.

• Inform the doctor if one has ever had bladder surgery.

• Be certain to inform the doctor if one has difficulty holding large concentrations of urine in the bladder.

How Is Valrubicin Administered?

The drug Valrubicin is given by healthcare providers in the hospital or clinic settings. This drug is not meant for self-administration. This medicine is generally given once a week or six weeks.

• The drug Valrubicin is administered directly into the bladder through a catheter.

• The catheter is inserted into the tube that helps pass the urine out of the bladder, called the urethra.

• Valrubicin is given in a solution for several minutes. The recommended dosage is administered into the bladder.

• Then, the individual must hold the injected solution for two hours. One should avoid voiding urine during this time.

• Inform the doctor if one has trouble holding the medicine for two hours.

Important Note:

Only one in five individuals is known to show a complete response to the drug Valrubicin. The bladder should be surgically removed after three months of treatment in individuals showing no response. This helps prevent the spread of cancer to other parts. The spreading or metastasis of cancer is generally fatal.

What Are the Side Effects of Valrubicin?

Valrubicin is a safe and effective drug therapy for bladder cancer, but it can induce certain unpleasant reactions. The common side effects of Valrubicin are listed below. These symptoms could resolve on their own. However, one should seek professional help if these symptoms persist, distressing the daily function.

• Bladder pain.

• Bladder spasm.

• Red or pink urine in the first 24 hours after the administration.

• Painful or difficult urination.

• Increased urination during the night.

• Nausea.

• Stomach pain.

• Urine leakage.

• Increased urge for urination.

Valrubicin can induce certain serious side effects. In such a case, one should get prompt medical attention and treatment. The serious side effects of Valrubicin include:

• Blood in the urine.

• Painful urination lasts more than 24 hours.

• Pain or burning sensation while urinating.

• Low white blood cell counts.

• Fever.

• Mouth sores.

• Skin sores.

• Cough.

• Trouble breathing.

• Sore throat.

• Changes in the amount of urine.

• Inability to pass urine.

Significant allergic reactions can occur with Valrubicin, like other drugs. The signs of allergic or hypersensitivity reaction include:

• Rash.

• Hives.

• Itching.

• Swelling of lips or throat.

• Selling of face.

• Peeling skin.

• Wheezing.

• Trouble breathing.

• Difficulty swallowing.

• Unusual hoarseness.

• Tightness feeling in the chest.

Dietary Considerations:

Follow the doctor’s advice, feeding the restrictions and considerations on food and beverages. However, one should drink plenty of fluids following every time of Valrubicin administration. So, staying hydrated is essential during Valrubicin therapy.

Missed Dose:

Missed dose is less likely to happen with Valrubicin therapy since it is given in hospital settings. However, call the healthcare provider for information if one misses the appointment for a Valrubicin injection.

Overdose:

Overdose is unlikely to occur because Valrubicin is given by healthcare providers. But, this drug can sometimes worsen the symptoms associated with irritable bladder. The doctors conscientiously monitor and give appropriate care during the therapy.

For Doctors:

Clinical Data of Valrubicin:

• Drug Name: Valrubicin.

• Generic Name: Valrubicin.

• Drug Class: Anthracyclines.

• Route of Administration: Intravesical.

• Chemical Formula: C34H36F3NO13.

• Molar Mass: 723.651 g.mol -1.

Indication:

Valrubicin is typically indicated for the treatment of bladder cancer.

Associated Conditions:

• Bladder cancer.

• In situ Bacillus Calmette-Guerin BCG-refractory bladder cancer.

Dose:

The drug Valrubicin is available as an intravesical solution with a strength of 40 milligrams per milliliter.

• This drug is indicated for intravesical therapy of BCG-refractory bladder cancer in situ.

• The recommended dosage for bladder cancer is 800 mg intravesically once a week for six weeks.

• It is to be retained in the bladder for about two hours prior to voiding.

Storage:

The intact vials should be stored at two to eight degrees Celsius. Nevertheless, one should not freeze them. Store them in the original carton or container. The Valrubicin solution diluted in the normal saline is generally stable for around 12 hours at a temperature of less than 25 degrees Celsius.

Administration and Dosing Considerations:

Reconstitution:

The vials should be kept warm at room temperature before each use. Check for a clear solution, and do not use the coils if any particulate is seen. Then, dilute 800 milligrams or 20 milliliters with about 55 millimeters of normal saline. It is recommended to use non-PVC (Polyvinyl chloride) infusion sets and containers in order to avoid leakage of di(2-ethylhexyl phthalate) plasticizers. Moreover, this solution is not meant to mix with other drugs.

Administration:

This drug must be administered through a non-PVC infusion tube due to the polyoxyl castor oil component. For intravesical instillation, a urinary catheter is inserted under aseptic conditions. Then, the bladder is drained. This is followed by the instillation of 800 mg/75 mL solution gradually by gravity flow for minutes. Then, the catheter can be removed. Ask the patient to retain them in the bladder for about two hours and then void them. Adequate hydration should be considered eventually with the treatment.

NOTE: Valrubicin is strictly for intravesical use. So, it should not be used for intravenous (IV) and intramuscular (IM) use.

Dosing Considerations:

• Consider temporary discontinuation or delay of treatment for Grade 3 Dysgeusia and Grade 2 or Grade 3 hematuria.

• For local toxicities less than Grade 4 (dysuria, bladder spasm), topical anesthesia or anticholinergics can be administered before subsequent installations.

• Monitor for the progression and recurrence of carcinoma in situ (CIS) thrice every month.

• Delay the treatment for a minimum of two weeks following transurethral resection or fulguration.

Clinical Pharmacology

Mechanism of Action:

Valrubicin sorts with the class of drugs called anthracyclines. They generally influence a wide range of interrelated biological functions, particularly nucleic acid metabolism. Valrubicin penetrates the cells and undergoes DNA intercalation, after which it inhibits the integration process of nucleotides into nucleic acids. This results in profound chromosomal damage while arresting the cell cycle involved in G2. Valrubicin does not possess strong bonding or adherence with normal DNA. However, the significant mechanism of action merited by the metabolites of Valrubicin has a marked interference with the normal DNA, showing the breaking and resealing action of DNA topoisomerase-2 alpha.

Pharmacokinetics

Absorption:

• Valrubicin penetrates the bladder cell wall following intravesical infusion.

• This drug shows negligible systemic absorption that can be dependent on the condition of the bladder wall.

• So, trauma or infection to the bladder mucosa and bladder wall perforation might crucially influence the rate of absorption.

Distribution:

• The protein binding capacity of Valrubicin is known to be greater than 99 percent.

Metabolism:

• Valrubicin is usually negligible following intravesical instillation and two-hour retention.

• However, this drug is metabolized by two chief metabolites, namely N-trifluoroacetyl adriamycin and N-trifluoroacetyl adriamycin.

Elimination:

• The route of elimination of Valrubicin is through urine after a two-hour period of retention.

• The intact drug is eliminated in 98.6 percent with about 0.4 percent of its primary metabolite N-trifluoroacetyl adriamycin.

Toxicity:

The suspected complications of overdosage of Valrubicin intravesical complications might be certain irritable bowel symptoms. Myelosuppression can occur if Valrubicin is unpromptedly given through systemic administration or in case of any marked systemic exposure occurring after intravesical administration. The maximum tolerated dose of Valrubicin in humans is 600 mg/m2 by intravenous and intraperitoneal infusion.

Contraindications

The contraindications of Valrubicin are as follows:

• Hypersensitivity to Valrubicin and other anthracyclines.

• Hypersensitivity to polyoxyl castor oil and other ingredients of the prescribed formulation.

• Perforated bladder mucosa.

• Active urinary tract infections.

• Minimal bladder capacity or in individuals who are unable to tolerate installation of 75 milliliters.

Adverse Effects:

The common adverse effects experienced in greater than ten percent of individuals taking Valrubicin therapy include:

• Urinary urgency.

• Urinary frequency.

• Bladder spasms.

• Dysuria.

• Hematuria.

• Bladder pain.

• Urinary tract infections

• Urinary incontinence.

• Cystitis.

About one to ten percent of patients are known to experience any of the following adverse reactions.

• Nausea.

• Abdominal pain.

• Malaise.

• Headache.

• Back pain.

• Urinary retention.

• Rash.

• Anemia.

• Diarrhea.

• Chest pain.

• Headache.

• Pneumonia.

• Vasodilation.

• Asthenia.

• Dizziness.

Warnings and Precautions:

1. Bladder Irritation: Irritable bowel symptoms are more common with the installation and retention of Valrubicin. The spasms and associated symptoms can sometimes persist for a brief period, even after voiding. Hence, clamping the urinary catheter is not recommended. Use the Valrubicin therapy with caution in people having irritable bowel concerns.

2. Urine Discoloration: In major cases, red-colored urine might occur for the first 24 hours following Valrubicin installation. But, prolonged urine discoloration requires prompt medical advice and treatment.

3. Risk of Metastatic Bladder Cancer: Valrubicin has been known to show complete responses in only one in five individuals. Moreover, delaying cystectomy can potentially result in the development of metastatic bladder cancer, which can be lethal. Inform the patient about the possible risk of metastatic bladder cancer versus the cystectomy procedure.

4. Embryo-Fetal Toxicity: Females of reproductive potential should be aware of the potential risks of Valrubicin to the fetus. Advise them to use effective contraceptives during the therapy and for a minimum of six months following the final dosage.

5. Other Warnings: The complete response is noticed in only about 20 percent of individuals taking Valrubicin therapy. The following cautions should be considered for any instance.

• • Valrubicin is not for patients with bladder perforation or in individuals with compromised integrity of the bladder wall or mucosa.

• • Evaluate closely the status of the bladder prior to intravesical instillation.
  • Felt the Valrubicin treatment for about two weeks following fulguration or transurethral resection.
  • Use the Valrubicin medication with caution in individuals having symptoms of irritable bowel.
  • Advise dental patients of reproductive potential about the risks to the fetus. Addedly, advise them to use effective contraception.
  • Valrubicin constitutes polyoxyl castor oil, and it can be associated with certain hypersensitivity reactions. Use cautiously in patients with predetermined hypersensitivity.

Specific Considerations:

• Lactation: Advise women not to breastfeed during Valrubicin treatment and for about two weeks following the last dosage.

• Pregnancy: In utero exposure to Valrubicin might harm the fetus, as per the mechanism of action and animal-based reproduction research. Systemic exposure to conditions like bladder perforation during pregnancy can induce significant harm to the fetus. It is recommended to use it with caution in pregnant women.

• Reproductive Considerations: Females of reproductive ability should use effective birth control aids during the treatment and for a minimum of six months following the final dosage. Males with female partners of reproductive ability should also consider effective measures during and for three months following the treatment.

Geriatrics: This medicine is not studied specifically in the geriatric population. However, Valrubicin has been given for older adults greater than 60 years of age and is mostly not known to cause varied side effects in younger adults.