Ipilimumab

IPILIMUMAB

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use.

Overview and uses

Ipilimumab is used for the treatment of cancer. Ipilimumab is used to treat skin cancer that cannot be treated with surgery, or that has spread to other parts of the body. Ipilimumab is also used to prevent melanoma from coming back after surgery, including lymph node removal.

Indication (uses)

  • Unresectable or Metastatic Melanoma
  • Adjuvant Treatment of Melanoma
    • Ipilimumab is used for the adjuvant treatment of patients with cutaneous melanoma with a pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Pharmacological classification

Anti-cancer

Brand names

YERVOY

Dosage form

  • Ipilimumab is available as injection in strengths of
    • 50 mg/10 mL (5 mg/mL)
    • 200 mg/40 mL (5 mg/mL)

Mechanism of action

CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.

Dosage

Read the package insert for instructions on preparation and administration od Ipilimumab injection.

  • Recommended Dosing for Unresectable or Metastatic Melanoma
    • The recommended dose of Ipilimumab is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses. In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose.
  • Recommended Dosing for Adjuvant Treatment of Melanoma
    • The recommended dose of YERVOY is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years. In the event of toxicity, doses are omitted, not delayed.

Recommended dose modification for immune – mediated adverse reaction (CTCAE v3)

  • Endocrine adverse reactions
    • Symptomatic endocrinopathy
      • Withhold Ipilimumab.
      • Resume Ipilimumab in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.
    • Symptomatic reactions lasting 6 weeks or longer
      • Permanently discontinue Ipilimumab.
    • Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
      • Permanently discontinue Ipilimumab.
    • Ophthalmologic adverse reactions (grade 2 through 4 reactions)
      • Not improving to Grade 1 within 2 weeks while receiving topical therapy.
        • Permanently discontinue Ipilimumab.
      • Requiring systemic treatment.
        • Permanently discontinue Ipilimumab.
      • All other adverse reaction (CTCAE v3)
        • Grade 2
          • Withhold Ipilimumab.
          • Resume Ipilimumab in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.
        • Grade 2 reactions lasting 6 weeks or longer
          • Permanently discontinue Ipilimumab.
        • Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
          • Permanently discontinue Ipilimumab.
        • Grade 3 or grade 4
          • Permanently discontinue Ipilimumab.

Renal dose adjustments

  • No dose adjustment is needed for patients with renal impairment.

Hepatic dose adjustments

  • No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin >1.0 to 1.5 times the upper limit of normal.
  • Data not available for patients with moderate to severe hepatic impairment.

Geriatric dose adjustments

  • Data not available. Dose adjustments may be required.

Pediatric Use

  • Data not available. Dose adjustments may be required.

Overdosage

  • Data not available.

Side effects or adverse effects

Side effects specific to Ipilimumab

  • Immune mediated enterocolitis
    • Immune-mediated enterocolitis, including fatal cases, can occur with Ipilimumab.
    • Symptoms of enterocolitis are diarrhea, abdominal pain, mucus or blood in stool, with or without fever and of bowel perforation are peritoneal signs and ileus.
    • In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
    • Permanently discontinue Ipilimumab in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
    • Consider adding anti-TNF or other immunosuppressant agents for the management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom improvement.
    • Withhold Ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
  • Immune-Mediated Hepatitis
    • Immune-mediated hepatitis, including fatal cases, can occur with Ipilimumab.
    • Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of Ipilimumab.
    • In patients with hepatotoxicity, rule out infectious or malignant causes and increase the frequency of liver function test monitoring until resolution.
    • Permanently discontinue Ipilimumab in patients with Grade 3 to 4 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.
    • When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month.
    • Across the clinical development program for Ipilimumab, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids.
    • Withhold Ipilimumab in patients with Grade 2 hepatotoxicity.
  • Immune-Mediated Dermatitis
    • Immune-mediated Dermatitis, including fatal cases, can occur with Ipilimumab.
    • Permanently discontinue Ipilimumab in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.
    • Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.
    • When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month.
    • Withhold Ipilimumab dosing in patients with moderate to severe signs and symptoms.
    • For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically.
    • Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
  • Immune-Mediated Neuropathies
    • Immune-mediated Neuropathies, including fatal cases, can occur with Ipilimumab.
    • Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia.
    • Permanently discontinue Ipilimumab in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes.
    • Institute medical intervention as appropriate for the management of severe neuropathy.
    • Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies.
    • Withhold Ipilimumab dosing in patients with moderate neuropathy (not interfering with daily activities).
  • Immune-Mediated Endocrinopathies
    • Immune-mediated Endocrinopathies, including fatal cases, can occur with Ipilimumab.
    • Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.
    • Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.
    • Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
    • Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms.
    • In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
    • Withhold Ipilimumab dosing in symptomatic patients and consider referral to an endocrinologist.
    • Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy.
  • Other Immune-Mediated Adverse Reactions, Including Ocular Manifestations
    • Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions.
    • Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
    • Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.
    • Permanently discontinue Ipilimumab for the immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.
  • Embryo-fetal toxicity
    • Ipilimumab can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Other side effects

  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below-mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anticancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and hemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to a reduction in the number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout, and Urate stones may develop in the urinary tract.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.

Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above-mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Ipilimumab can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Contraindications

  • None

Pregnancy & breast feeding warnings

  • Pregnancy
    • Category not assigned.
    • Animal reproduction studies have shown reproductive toxicity.
  • Nursing
    • It is not known whether Ipilimumab is excreted in human breast milk or not.
    • Since many drugs are excreted in milk and because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Concomitant use of Ipilimumab with following drugs/medicines should be strictly avoided.
    • Argatroban may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Ardeparin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Apixaban may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Anisindione may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Betrixaban may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Bivalirudin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Dabigatran may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Danaparoid may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Desirudin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Dicumarol may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Dalteparin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Edoxaban may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Enoxaparin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Fondaparinux may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Heparin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Lomitapide may increase the risk of liver toxicity.
    • Lepirudin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Leflunomide may increase the risk of liver toxicity.
    • Rivaroxaban may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Tinzaparin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Warfarin may increase the risk of serious or life threatening gastrointestinal bleeding complications.
    • Mipomersen may increase the risk of liver toxicity.
    • Teriflunomide may increase the risk of liver toxicity.

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Reference

  • Highlights of prescribing information: 1
By | 2017-12-20T13:12:42+00:00 August 11th, 2017|medicines|0 Comments

About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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