Doxil (Pegylated Liposomal Doxorubicin) is anthracycline chemotherapeutic antineoplastic drug that is used to treat multiple myeloma, breast, and ovarian cancer.

Indications of Pegylated liposomal doxorubicin (Doxil):

• AIDS-related Kaposi sarcoma:

  • It is indicated for the treatment of AIDS-related Kaposi sarcoma (after the failure of or intolerance to prior systemic therapy).

• Multiple myeloma:

  • It is used for the treatment of multiple myeloma (in combination with bortezomib) in patients who are bortezomib-naïve and have received at least 1 prior therapy.

• Advanced Ovarian cancer:

  • Treatment of progressive or recurrent ovarian cancer (after platinum-based treatment) can be done by pegylated doxorubicin.

• Off Label Use of Pegylated liposomal doxorubicin in Adults:

  • Breast cancer, metastatic
  • Hodgkin lymphoma (salvage treatment)
  • Cutaneous T-cell lymphomas (mycosis fungoides and Sézary syndrome)
  • Advanced Soft tissue sarcomas
  • Advanced or recurrent Uterine sarcoma

Pegylated liposomal doxorubicin dose in adults:

Liposomal formulations of doxorubicin should NOT be substituted for conventional doxorubicin hydrochloride on an mg-per-mg basis.

Doxil Treatment dose of AIDS-related Kaposi sarcoma:

• 20 mg/m I/V once every 21 days until disease progression or unacceptable toxicity

Doxil Treatment dose of Multiple myeloma:

• 30 mg/m I/V on day 4 every 21 days (in combination with bortezomib) for 8 cycles or until disease progression or unacceptable toxicity.

Doxil Treatment dose of newly diagnosed multiple myeloma (off-label dosing):

• 40 mg/m² I/V on day 1 every 4 weeks (in combination with vincristine and dexamethasone) for at least 4 cycles.

Doxil Treatment dose of advanced Ovarian cancer:

• 50 mg/m² I/V once every 28 days until disease progression or unacceptable toxicity.

Doxil Treatment dose of advanced, recurrent Ovarian cancer, (off- label dosing):

• 40 mg/m² I/V once every 28 days (as monotherapy) until disease progression or unacceptable toxicity or
• 30 mg/m² I/V once every 28 days (in combination with carboplatin) for at least 6 cycles
• or 40 mg/m² once every 28 days (in combination with bevacizumab) until disease progression or unacceptable toxicity.

Doxil Treatment dose of metastatic Breast cancer, (off-label):

• 50 mg/m² I/V every 4 weeks.

Doxil Treatment dose of Cutaneous T-cell lymphomas (off-label):

• 20 mg/m² I/V days 1 and 15 every 4 weeks for 6 cycles or
• 20 mg/m² every 4 weeks.

Doxil Treatment dose of Hodgkin lymphoma, salvage (off-label):

• GVD regimen:
  • 10 mg/m²  I/V (post-transplant patients) or
  • 15 mg/m² I/V (transplant-naive patients) days 1 and 8 every 3 weeks (in combination with gemcitabine and vinorelbine) for 2 to 6 cycles.

Doxil Treatment dose of advanced Soft tissue sarcoma, (off-label):

• 50 mg/m² I/V every 4 weeks for 6 cycles.

Doxil Treatment dose of advanced or recurrent Uterine sarcoma, (off-label):

• 50 mg/m² I/V every 4 weeks until disease progression or unacceptable toxicity.

Use in Children:

Not indicated

Doxil pregnancy Risk Category: D

• Studies on animal reproduction revealed that pregnant women can have adverse outcomes.
• Young women should avoid pregnancy. Men with female partners who have the potential to become pregnant should use effective contraception during treatment and for six months afterwards.
• Doxorubicin liposomal can cause impaired fertility in women and men.
• Doxorubicin may cause oligospermia and azoospermia in men.
• Doxorubicin may cause amenorrhea and premature menstruation in young women.

Use while breastfeeding

• It is not known if breast milk contains Doxorubicin liposomal Secretion.
• Due to the possibility of side effects, it is important that you stop breast-feeding during treatment.

Doxil Dose adjustment in renal disease:

There are no dosage adjustments provided in the manufacturer’s labeling.

Doxil Dose adjustment in liver disease:

• US labeling:

  • There are no dosage adjustments provided in the manufacturer’s labeling.
  • However, doxorubicin is predominantly excreted via liver therefore dose reduction is necessary in patients with serum bilirubin ≥1.2 mg/dL.

• Canadian labeling:

  • AIDS-related Kaposi sarcoma:

    • Bilirubin 1.2 to 3 mg/dL:
      • 50% dose reduction is needed.
    • Bilirubin >3 mg/dL:
      • Reduce dose to 25% of normal dose

  • Breast cancer and ovarian cancer:

    • Bilirubin 1.2 to 3 mg/dL:
      • Initial dose: Reduce dose to 75% of normal dose;
      • if tolerated and no change in bilirubin/hepatic enzymes, may increase to full dose with cycle 2.
    • Bilirubin >3 mg/dL:
      • Initial dose: 50% dose reduction is needed;
      • if tolerated and no change in bilirubin/hepatic enzymes, may increase the dose to 75% of the normal dose for cycle 2;
      • if cycle 2 dose tolerated, may increase to the full dose for subsequent cycles.

Common Side Effects of Pegylated liposomal doxorubicin (Doxil):

• Cardiovascular:

  • Cardiomyopathy
  • Cardiotoxicity
  • Chest Tightness
  • Flushing
  • Hypotension

• Central Nervous System:

  • Fatigue
  • Headache

• Dermatologic:

  • Palmar-Plantar Erythrodysesthesia
  • Skin Rash
  • Alopecia
  • Facial Swelling

• Gastrointestinal:

  • Nausea
  • Stomatitis
  • Vomiting
  • Constipation
  • Diarrhea
  • Anorexia
  • Mucous Membrane Disease
  • Dyspepsia

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Neutropenia
  • Leukopenia
  • Anemia

• Neuromuscular & Skeletal:

  • Weakness
  • Back Pain

• Respiratory:

  • Pharyngitis
  • Dyspnea

• Miscellaneous:

  • Fever
  • Infusion Related Reaction

Rare Side Effects Of Pegylated Liposomal Doxorubicin (Doxil):

• Cardiovascular:

  • Cardiac Arrest
  • Chest Pain
  • Deep Thrombophlebitis
  • Tachycardia
  • Vasodilation

• Central Nervous System:

  • Depression
  • Dizziness
  • Drowsiness
  • Chills

• Dermatologic:

  • Acne Vulgaris
  • Ecchymoses
  • Exfoliative Dermatitis
  • Fungal Dermatitis
  • Furunculosis
  • Herpes Simplex Dermatitis
  • Pruritus
  • Skin Discoloration
  • Vesiculobullous Dermatitis
  • Xeroderma
  • Maculopapular Rash

• Endocrine & Metabolic:

  • Hypercalcemia
  • Hypokalemia
  • Hyponatremia
  • Weight Loss
  • Dehydration
  • Hyperglycemia

• Gastrointestinal:

  • Dysphagia
  • Esophagitis
  • Intestinal Obstruction
  • Oral Candidiasis
  • Oral Mucosa Ulcer
  • Dysgeusia
  • Abdomen Enlarged
  • Glossitis
  • Cachexia

• Genitourinary:

  • Hematuria
  • Hemorrhagic Cystitis
  • Urinary Tract Infection
  • Vulvovaginal Candidiasis

• Hematologic & Oncologic:

  • Rectal Hemorrhage
  • Hemolysis
  • Prolonged Prothrombin Time
  • Bone Marrow Depression
  • Progression Of Cancer

• Hepatic:

  • Hyperbilirubinemia
  • Increased Serum Alkaline Phosphatase
  • Increased Serum ALT

• Hypersensitivity:

  • Hypersensitivity Reaction

• Infection:

  • Infection
  • Herpes Zoster
  • Paresthesia
  • Myalgia
  • Neuropathy
  • Toxoplasmosis

• Ophthalmic:

  • Dry Eye Syndrome
  • Conjunctivitis
  • Retinitis Optic Neuritis

• Respiratory:

  • Epistaxis
  • Pneumonia
  • Rhinitis
  • Sinusitis
  • Increased Cough
  • Cough

Contraindications to Pegylated liposomal doxorubicin (Doxil):

• Severe hypersensitivity (including anaphylaxis), to doxorubicin liposomal or conventionaldoxorubicin or any component of formulation

Canadian labeling: Additional contraindications not in the US labeling

• Breastfeeding

Warnings and precautions

• Suppression of bone marrow

  • Doxorubicin may cause anemia, neutropenia and thrombocytopenia. Therefore, regular CBC monitoring of the patient is necessary.
  • Treatment delay or withdrawal, dose reduction, and/or therapy delay may be necessary.
  • Hematologic toxicities are more common in combination therapy.

• Infusion reactions: [US Boxed Warning]

  • Infusion reactions that can cause life-threatening complications such as rash, pruritus and tachycardia flushing, dizziness, facial swelling, dyspnoea or facial swelling, headaches, back pain or tightness or pain in the chest, throat or chest, hypotension, apnoea were reported in 11% patients with solid tumors treated using doxorubicin.
  • Infusion reactions can occur with the initial infusion, and may require interruption.
  • During infusion, you should have immediate access to medication and equipment for managing infusion reactions.
  • Infusions should begin at 1 mg/minute. The rate can be increased to complete the infusion in 60 minutes if necessary.
  • Infusions should be stopped if there is an infusion reaction. Once symptoms have resolved, you can resume infusions at a lower rate.
  • Grade IV reactions should prompt the discontinuation of therapy

• Myocardial toxicity: [US Boxed Warning]

  • Doxorubicin liposomal, especially at doses exceeding 550 mg/m2, is known to cause myocardial injury (including congestive cardiac failure).
  • A clinical study with 250 patients with advanced cancer was done. The risk of cardiotoxicity was 1.1% for those who received doxorubicin lipsosomal.
  • In order to calculate the cumulative dose, it is important to include any prior use of anthracyclines and anthracenediones.
  • Patients who have received mediastinal radiation are more at risk for cardiomyopathy.
  • Myocardial injury may be manifested as acute left ventricular dysfunction. Cardiotoxicity refers to a decrease of >20% in resting left ventricular ejection percentage (LVEF) from baseline (if LVEF remained within the normal range), or a decrease of >10% from baseline (where LVEF is less than the institution's lower limit).
  • Without evidence of cardiotoxicity, some patients may have signs or symptoms of heart failure.
  • Cardiomyopathy is generally a result of doxorubicin exposure. However, it is unknown if there is a relationship between cumulative doxorubicin dose and risk of cardiotoxicity.
  • Anthracycline-induced cardiotoxicity can be delayed after withdrawal therapy.
  • To detect any acute changes, it is important to monitor with an echocardiogram and a MUGA scan prior and during treatment. This should also be done for delayed events.
  • Only use in patients who have had a history or heart disease.

• Palmar-plantar Erythrodysesthesia (handfoot syndrome)

  • The hand-foot syndrome usually appears after two to three treatment cycles.
  • Grade IV toxicities require dosage reduction or withdrawal.

• Secondary malignancy

  • The tissue distribution of liposomal doxorubicin in comparison to the free doxorubicin could play a role for the development of secondary malignancies.
  • Studies of secondary oral cancers that were treated for longer than one year have shown cases, primarily squamous cells carcinoma.
  • Secondary oral malignancies can occur during treatment or up to six years after.
  • Patients who have used doxorubicin liposomal in the past or current are subject to monitoring and evaluation for any oral ulceration.

• Hepatic impairment

  • It is not clear if pharmacokinetics of patients with hepatic impairment have been well studied.
  • Doxorubicin is excreted in the liver so patients with serum bilirubin greater than 1.2 mg/dL will need to reduce their dose.

Pegylated liposomal doxorubicin: Drug Interaction

Monitoring parameters:

• CBC with differential and platelet count,
• LFTS (ALT/AST, bilirubin, alkaline phosphatase)
• Monitoring of infusion site, infusion reactions
• Side effects including hand-foot syndrome, stomatitis, and oral ulceration/discomfort suggestive of secondary oral malignancy.
• Cardiac function (left ventricular ejection fraction [LVEF]; baseline and periodic); echocardiography, or MUGA scan.

How to administer Doxil (Pegylated liposomal doxorubicin)?

• It should only be given via IV infusion(no IV push) with adequate monitoring.
• If contact with skin/mucosa occurs, wash immediately with soap and water. IVPB should be given over 1 hour.
• The manufacturer recommends infusing the first dose at an initial rate of 1 mg/minute to minimize the risk of infusion reactions; if no infusion-related reactions are observed, then increase the infusion rate for completion over 1 hour.
• It should always be diluted and never infused with in-line filters or mixed with other medications.
• A rapid infusion can cause erythematous streaking along the vein and/or facial flushing.
• For multiple myeloma, administer doxorubicin liposomal after bortezomib on day 4 of each cycle.

Irritant:

• In order to avoid extravasation, monitoring of the infusion site is vital. Proper needle or catheter position is necessary before infusion.

Extravasation management:

• The infusion should be stopped immediately in case of any extravasation, infiltration, or burning/ stinging sensation and disconnected (leave cannula/needle in place).
• The extravasated solution should be slowly aspirated without flushing the line.
• The needle/cannula should be removed and extremity should be elevated.
• Pressure should not be applied to the site. Cold compression should be given to the site for 15 minutes 4 times a day for 3 days.

Mechanism of action of Pegylated liposomal doxorubicin (Doxil):

• Doxorubicin causes steric obstruction and inhibition topoisomerase II at the point DNA cleavage.
• This inhibits DNA and RNA formation due to intercalation of DNA base pairs.
• Doxorubicin can also be used as an iron chelator. 
• Iron-doxorubicin creates free hydroxyl radicals by binding to DNA and cell membranes, resulting in the cleavage DNA.
• Active throughout the entire cell-cycle. Doxorubicin Liposomal, a pegylated formulation, increases blood circulation by protecting the liposomes.

Distribution:

• largely confined to the vascular fluid.

Protein binding plasma:

• Unknown;
• non-liposomal (conventional) doxorubicin: 70%

Half-life elimination:

• Terminal: Distribution: 4.7 to 5.2 hours,
• Elimination: 52 to 55 hours

Metabolism:

• Hepatic and in plasma to doxorubicinol and the sulfate and glucuronide conjugates of 4-demethyl,7-deoxyaglycones

International Brands of Pegylated liposomal doxorubicin:

• Doxil
• Lipodox 50
• Lipodox
• Caelyx
• Bdlypo
• Caelyx
• Doxopeg
• Lipo-Dox
• Myocet
• Zuclodox-DRS

Pegylated liposomal Doxorubicin Brand Names in Pakistan:

No Brands Available in Pakistan.