Siltuximab (Sylvant) inhibits the Interleukin 6 triggered-inflammatory cascade like Tocilizumab. It is used in the treatment of Castleman disease.

Siltuximab (Sylvant) Uses:

• Castleman disease:

  • It is indicated for the treatment of multicentric Castleman disease in patients who are human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8) negative.
• Limitations of use:
  • It has not been studied in HIV or HHV-positive patients. It does not bind to virally produced Interleukin.
  • Siltuximab has not been studied in patients with MCD who are HIV positive or HHV-8 positive because in a nonclinical study, siltuximab did not bind to virally produced IL-6.

Sylvant (Siltuximab) Use in the Treatment of COVID 19 Pneumonia:

FDA has granted permission for the clinical phase III trials of Siltuximab in patients with COVID19 pneumonia. The proposed mechanism is the inhibition of Interleukin 6 triggered cascade by the drug (like Tocilizumab or Actemra). The SISCO study conducted in Italy has shown some positive results with its use in COVID-19 pneumonia [Ref].

My personal point of view ...

As mentioned previously in its uses above, I personally don't think this drug is going to work in COVID 19 pneumonia as it does not inhibit virally induced interleukin 6 (in HIV and HHV-positive patients). Likewise, it may not suppress the IL-6 triggered cascade in SARS-CoV 2 or COVID 19 associated infection.

Siltuximab (Sylvant) Dose in Adults

Note:

• The first dose should be delayed if the:
  • ANC is less than 1000/mm³,
  • platelet counts is less than 75,000/mm³, and
  • hemoglobin ≥17 g/dL;
• The subsequent doses may be delayed if the:
  • ANC < 1000/mm³,
  • platelets <50,000/mm³, and
  • hemoglobin ≥17 g/dL.
• The dose of therapy should not be reduced.

Siltuximab (Sylvant) Dose in the treatment of multicentric Castleman disease (in patients who are HIV and HHV-8 negative):

• 11 mg/kg intravenous once every three weeks until treatment failure.
• Corticosteroids may be used as an adjunct to the treatment followed by a slow taper over 4 - 8 weeks for initial disease control.
• Highly symptomatic patients may require higher doses followed by a more gradual taper.

Siltuximab (Sylvant) Dose in the treatment of Severe disease in critically ill patients (off-label dosing):

• 11 mg/kg intravenous once a week for one month, followed by 11 mg/kg once every three weeks until treatment failure.
• High-dose corticosteroids followed by a slow taper may be administered initially for disease control.

Use in Children:

The safety and efficacy of the drug in children have not been established.

Pregnancy Risk Factor C

• Negative fetal outcomes in animal reproduction studies have not been documented.
• Pregnant animals and their offspring showed a decrease in the levels of globulins.
• The risk of infection was higher in infants born to mothers who had received the drug during pregnancy.
• Manufacturers recommend that pregnant women use it only if they feel the benefits are greater than the risks.
• Effective contraception should be used during treatment, and for at least three months after it is stopped.

Siltuximab use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• However, immunoglobulins can be excreted in breastmilk so the manufacturer suggests that you discontinue the drug and continue breastfeeding. This is to balance the risks and the benefits.

Siltuximab (Sylvant) Dose in Kidney Disease:

• CrCl ≥15 mL/minute:
  • Initial dose adjustment is not necessary.
• CrCl <15 mL/minute:
  • The manufacturer has not provided any adjustments in the dose in patients with severe hepatic impairment (it has not been studied).
• End-stage renal disease (ESRD):
  • The manufacturer has not provided any adjustments in the dose in patients with severe hepatic impairment (it has not been studied).

Siltuximab (Sylvant) Dose in Liver disease:

• Mild to moderate hepatic impairment (Child-Pugh class A or B):
  • Initial dose adjustment is not necessary.
• Severe hepatic impairment (Child-Pugh class C):
  • The manufacturer has not provided any adjustments in the dose in patients with severe hepatic impairment (it has not been studied).

Common Side Effects of Siltuximab (Sylvant):

• Cardiovascular:

  • Edema

• Dermatologic:

  • Pruritus
  • Skin Rash

• Endocrine & Metabolic:

  • Weight Gain
  • Hyperuricemia

• Local:

  • Localized Edema

• Respiratory:

  • Upper Respiratory Tract Infection

Less Common Side Effects of Siltuximab (Sylvant):

• Cardiovascular:

  • Hypotension

• Central Nervous System:

  • Headache

• Dermatologic:

  • Eczema
  • Psoriasis
  • Skin Hyperpigmentation
  • Xeroderma

• Endocrine & Metabolic:

  • Hypertriglyceridemia
  • Hypercholesterolemia

• Gastrointestinal:

  • Constipation

• Hematologic & Oncologic:

  • Thrombocytopenia

• Hypersensitivity:

  • Hypersensitivity Reaction

• Immunologic:

  • Antibody Development

• Renal:

  • Renal Insufficiency

• Respiratory:

  • Lower Respiratory Tract Infection
  • Oropharyngeal Pain

• Miscellaneous:

  • Infusion Related Reaction

Rare Side effects of Siltuximab (Sylvant):

• Cardiovascular:

  • Hypertension

• Central Nervous System:

  • Dizziness

• Gastrointestinal:

  • Abdominal Pain
  • Diarrhea
  • Gastroesophageal Reflux Disease
  • Nausea
  • Oral Mucosa Ulcer
  • Vomiting

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Neutropenia

• Respiratory:

  • Nasopharyngitis

Contraindications to Siltuximab (Sylvant):

Hypersensitivity to any drug or component of the formulation

Warnings and precautions

• Gastrointestinal perforation:

  • It is possible for gastrointestinal perforation to occur.
  • Patients must be evaluated for their risk, and patients at high risk of perforation should not be given the drug.
  • Patients with new abdominal symptoms must be evaluated immediately.

• Hemoglobin levels:

  • Patients with multicentric Castleman syndrome may experience an increase in hemoglobin.
  • Before administering the first dose, and every subsequent dose thereafter, blood counts should be checked.
  • Sometimes, patients may need to be treated indefinitely.

• Infection

  • Sometimes, the clinical signs of inflammation and infection may not be apparent. In some cases, patients may not experience a fever or raise inflammatory markers (Creactive Protein) even though they have active infection and inflammation.
  • Patients with active infections should be advised not to take the drug until the infection has resolved.
  • During treatment, monitor patients for signs and symptoms of infection.
  • When indicated, initiate appropriate antimicrobial treatment immediately.

• Hypersensitivity and infusion-related reactions

  • When administering the drug, you may experience anaphylactic reactions and other drug reactions.
  • The patient must stop receiving treatment immediately and for a permanent period if they develop any symptoms of an allergic reaction. The patient must stop receiving treatment.
  • If the patient experiences cytokine release syndrome or infusion site reactions, treatment must be stopped immediately.
  • Patients with mild or moderate infusion reactions may be treated at a lower dose after their initial symptoms have resolved.
  • Prior to infusions, it is possible to pre-medication with an antihistamine or corticosteroid or acetaminophen.
  • Infusion reactions can occur in patients who are not receiving the appropriate dose reductions or premedications. Treatment may be stopped permanently.
  • Anaphylactic reactions must be managed in the setting where Siltuximab is administered. Life-saving medicines (bronchodilators, epinephrine, antihistamines, and corticosteroids) must be available when administering the drug.

Siltuximab: Drug Interaction

Monitoring parameters:

• Blood counts along with differential counts should be monitored before each dose for the first 12 months and after every 3-dose cycle thereafter, or as clinically indicated.
• Monitor the patient for anaphylaxis and infusion-related adverse drug reactions. Observe the patient for the clinical features of gastrointestinal perforation and cytokine-release syndrome.

How to administer Siltuximab (Sylvant)?

• It is intended for intravenous use only.
• It should be administered as an intravenous infusion over one hour using the administration sets that are line with polyvinyl chloride (PVC), polyurethane, or polyethylene that contains a 0.2-micron inline polyethersulfone filter.
• Avoid infusing the drug in the same line with other medications.
• Once the injection is diluted, the reconstituted solution should be infused within four hours.

Mechanism of action of Siltuximab (Sylvant):

• It is a monoclonal chimeric antibody with a high affinity for Interleukin-6.
• It blocks IL-6 binding to membrane-bound and soluble receptors.
• In Castleman's disease, most manifestations are caused by an overproduction of interleukin-6.
• This causes the synthesis and activation of C-reactive proteins.
• The symptoms can be improved by inhibiting IL-6.

Initial:

• After 3-4 doses, treatment response can be observed.
• The lymph nodes take approximately five months to regress.

Half-life elimination:

• About 21 days (ranging from 14.2 to 29.7 days)

International Brands of Siltuximab:

• Sylvant

Siltuximab Brand Names in Pakistan:

No Brands Available in Pakistan.