What Is Irinotecan Hydrochloride (Campto)? FDA Approval, Licensing in Turkey, and Reimbursement Status

• FDA Approval: Yes (Initial approval: 1996)
• Brand Name: Campto (also: Camptosar, irinotecan hydrochloride injection)
  
• Active Ingredient: Irinotecan hydrochloride
  
• Route of Administration: Intravenous injection (IV)
  
• Class: Chemotherapeutic agent / Topoisomerase I inhibitor
  
• Category: Antineoplastic (cytotoxic drug)
  
• Manufacturer: Pfizer (Campto); other generic manufacturers are available
• Availability in Turkey: Available and included on the SGK reimbursement list
• Approved Cancers: Metastatic colorectal cancer, cervical cancer (in combination therapy), non-small cell lung cancer

What Is Irinotecan Hydrochloride? How Does It Work?

Irinotecan hydrochloride is a chemotherapy drug used to treat various solid tumors, particularly metastatic colorectal cancer. It is derived from a natural compound called camptothecin and is a synthesized semisynthetic derivative. In clinical practice, it is usually administered by intravenous injection.

This drug targets DNA synthesis to inhibit tumor cell proliferation. It is administered alone or, frequently, in combination with other chemotherapeutic agents such as 5-fluorouracil and folinic acid.

How does it work?

• Irinotecan is converted in the body into its active metabolite, SN-38. SN-38 inhibits topoisomerase I, an enzyme that plays a critical role during cell division.
• Topoisomerase I helps cells regulate DNA replication and transcription by temporarily cutting the supercoiled structure of DNA. Irinotecan prevents this enzyme from repairing the temporary breaks it makes in DNA. Consequently, DNA strand breaks develop, causing damage that the cell cannot repair. Damaged cells are eliminated through apoptosis (programmed cell death).
• Although this effect is particularly pronounced in rapidly dividing tumor cells, it can also cause toxic effects in normal cells. Careful dose adjustments and patient monitoring are therefore important during irinotecan treatment.

FDA (United States Food and Drug Administration) Approval History

• June 14, 1996: The FDA approved Camptosar (irinotecan hydrochloride injection), manufactured by Pfizer, for the treatment of metastatic colorectal cancer.
• October 22, 1998: The FDA expanded the use of Camptosar, approving irinotecan as first-line treatment for patients with previously untreated metastatic colorectal cancer.
• October 22, 2015: The FDA approved Onivyde, manufactured by Ipsen Biopharmaceuticals, in combination with 5-fluorouracil and leucovorin for patients with metastatic pancreatic adenocarcinoma that had progressed following gemcitabine-based therapy.
• February 13, 2024: The FDA approved Onivyde in combination with oxaliplatin, 5-fluorouracil, and leucovorin as first-line treatment for patients with metastatic pancreatic adenocarcinoma. This approval was based on the results of the phase III clinical trial NAPOLI 3.

Licensing in Turkey

The situations in which irinotecan hydrochloride is licensed in Turkey / its therapeutic indications are specified as follows:

Therapeutic Indications

• For the treatment of advanced colorectal cancer: In combination with 5-FU and folinic acid in patients who have not previously received chemotherapy for advanced disease.
• It is used as a single agent in patients who have not responded to treatment regimens containing 5-FU.
• As 2nd-line treatment in patients with recurrent or treatment-resistant small cell lung cancer,
• It is used as a single agent or in combination regimens as 2nd-line treatment for small cell lung cancer that recurs or is resistant after first-line chemotherapy.

Is Irinotecan Hydrochloride Reimbursed?

The licensed uses of irinotecan in Turkey focus particularly on the treatment of advanced colorectal cancer and small cell lung cancer. The use of other variants, such as liposomal formulations, has not yet been licensed in Turkey.

Price: Campto 100 mg vial 1064.7 TL; a Campto 40 mg vial costs 454.58 TL.

Mechanisms of Resistance

• Irinotecan is a potent chemotherapeutic agent that disrupts DNA synthesis in cells. However, some tumor cells can develop resistance to this drug over time. This resistance arises through various biological changes at the cellular level. The main mechanisms of irinotecan resistance are:
• Impaired Conversion to the Drug's Active Form (Metabolic Resistance): Irinotecan acts after liver enzymes convert it into its active form, SN-38. If this conversion slows or insufficient SN-38 is formed, the drug's effectiveness decreases. This is usually associated with low activity of the carboxylesterase enzyme in the liver.
• Increased Drug Efflux (Efflux Pumps): Some tumor cells begin to produce excessive amounts of transporter proteins (particularly ABCB1 / P-gp and ABCG2) that pump irinotecan and SN-38 out of the cell. These proteins prevent the drug from accumulating sufficiently inside the cell, reducing its effect.
• Reduced Topoisomerase I Sensitivity: Mutations in the structure of topoisomerase I, the target of irinotecan, can make it harder for the drug to bind to this enzyme. Although the enzyme can continue functioning, it becomes resistant to blockade by irinotecan, allowing the tumor cell to continue proliferating unaffected.
• Increased DNA Repair Capacity: Irinotecan treatment causes breaks in DNA. Some tumor cells can rapidly repair this damage by strengthening DNA repair mechanisms, particularly pathways such as homologous recombination. This reduces irinotecan's ability to kill the cell.
• Disruption of Apoptosis (Cell Death) Mechanisms: Normally, when irinotecan damages DNA, the cell detects the damage and destroys itself through apoptosis. However, apoptotic pathways may be disrupted in some tumor cells, for example through p53 mutations. In this situation, the cell continues to survive despite the damage.

Absorption

Because irinotecan is usually administered intravenously, it bypasses gastrointestinal absorption and enters the systemic circulation directly. This results in high bioavailability. Plasma concentrations rise rapidly shortly after administration.

Distribution

Irinotecan can spread throughout body tissues and has a large volume of distribution. It binds moderately to plasma proteins. Its active metabolite, SN-38, also distributes into tissues, exerting its antitumor effect particularly by causing DNA damage in tumor cells. Both irinotecan and SN-38 can remain in plasma and tissues for certain periods.

Metabolism

• Irinotecan is metabolized by several different enzyme systems in the liver and other tissues. The main metabolic pathways are:
• Via esterases: Carboxylesterase enzymes convert irinotecan into the active metabolite SN-38. SN-38 exerts its cytotoxic effect by inhibiting topoisomerase I.
• Glucuronidation: In the liver, SN-38 is glucuronidated by UGT1A1 and converted into the inactive metabolite SN-38 glucuronide. Genetic variations in this process, particularly alleles such as UGT1A1*28 and *6, may cause differences in metabolism between individuals.
• Oxidative metabolism: Irinotecan is also converted into certain inactive metabolites by CYP3A4. One of these metabolites has the potential to be converted back into active SN-38 by esterases. This may indirectly prolong the drug's pharmacological effect.

Dose Range 

• Metastatic Colorectal Cancer (Usually in combination with 5-FU and folinic acid or as monotherapy), weekly regimen: 125 mg/m² IV, 1 time per week, infused over 90 minutes for 4 weeks, followed by a 2-week break. Every two weeks (FOLFIRI regimen): 180 mg/m² IV, every 14 days, in combination with folinic acid and 5-FU (one of the most widely used dosing regimens). Monotherapy: 350 mg/m² IV, every 3 weeks.
• Non-Small Cell Lung Cancer (NSCLC): In combination with platinum-based chemotherapy: 60–65 mg/m² IV, on days 1 and 8, in cycles every 3 weeks (for example, with cisplatin).
• Cervical Cancer (In combination with platinum): 60 mg/m² IV, on days 1 and 8, in 3-week cycles (used in clinical trials).
• Pancreatic Cancer (Investigational or 2nd-Line): Nanoparticle albumin-coated irinotecan (liposomal form): 70–80 mg/m² IV, every 2 weeks (usually with 5-FU/LV).
• Pediatric Tumors (Various doses have been tested in clinical trials): Oral form or IV: 20–50 mg/m²/day for 5 days, at 2–3-week intervals (in conditions such as neuroblastoma and rhabdomyosarcoma).

Drug Interactions

• CYP3A4 Inhibitors and Inducers: Irinotecan is metabolized in the liver by CYP3A4. Drugs that affect this enzyme can therefore alter irinotecan levels and consequently levels of SN-38 (the active metabolite). CYP3A4 inhibitors (toxicity risk increases with higher SN-38 levels): Ketoconazole, itraconazole, clarithromycin, ritonavir / atazanavir / indinavir (HIV protease inhibitors), grapefruit juice.
• CYP3A4 Inducers (SN-38 decreases and effectiveness may decline): Phenytoin, carbamazepine, rifampicin, dexamethasone (high doses), St. John's wort.
• Interactions Through UGT1A1: SN-38 is inactivated by UGT1A1. Drugs that affect UGT1A1 can alter SN-38 metabolism and cause toxicity. Atazanavir (a UGT1A1 inhibitor) can increase SN-38 levels, leading to severe neutropenia.
• Combinations With Antineoplastic Agents: 5-Fluorouracil (5-FU) and folinic acid: Usually used in combination therapy, such as the FOLFIRI protocol. Toxicities may increase, and gastrointestinal adverse effects in particular should be monitored carefully. Bevacizumab: Combining it with irinotecan may increase effectiveness, but risks of serious complications such as gastrointestinal perforation should be monitored.
• Loperamide: Used to treat late-onset diarrhea. There is no interaction, but careful dosing is required.
• Anticoagulants (such as warfarin): Careful monitoring is required because changes in liver enzymes may occur.
• Cholinergic drugs: Acute cholinergic syndrome may occur with irinotecan infusion (sweating, abdominal cramps, increased salivation). Atropine is generally used prophylactically.

Precautions

• Watch for late-onset diarrhea. Diarrhea beginning after 24 hours can be life-threatening. Adequate fluid intake and appropriate treatment for diarrhea, such as loperamide, are required.
• Monitor for sudden diarrhea and cholinergic symptoms during infusion. Symptoms may include sweating, abdominal cramps, and increased salivation. Atropine may be administered before treatment if necessary.
• Bone marrow suppression may develop. A decrease in white blood cells (neutropenia) is particularly common. Regular blood counts should be monitored. Supportive treatment is provided if needed.
• Liver function should be monitored carefully. The drug is metabolized in the liver; liver enzymes and bilirubin levels should be checked.
• Genetic makeup can affect toxicity risk. Patients with certain variations in UGT1A1 may have an increased risk of adverse effects. Dose reduction may be necessary in these patients.
• Fever, chills, or signs of infection require urgent intervention. The risk of infection is high because the drug suppresses the immune system.
• Severe gastrointestinal problems may occur. Mouth sores, abdominal pain, or inflammation of the digestive system may develop. Serious conditions such as intestinal perforation can occur rarely.
• It should not be used during pregnancy. It may harm the unborn baby. Its use is also not recommended during breastfeeding.
• Older patients may be more sensitive. Older individuals may have lower tolerance of the drug; dosing and adverse effects should be monitored closely.
• Concomitant medications should be considered. The effectiveness and adverse effects of irinotecan may change, particularly when it is used with drugs that affect liver enzymes.
• Caution is advised when driving or operating machinery. Effects such as dizziness and fatigue may affect daily activities.

Adverse Effects

• Neutropenia (low white blood cell count): up to 80%
• Nausea / vomiting: 50–70%
• Late-onset diarrhea: 60%
• Fatigue / weakness (asthenia): 40–50%
• Anemia (low red blood cell count): 30–40%
• Mouth sores (stomatitis / mucositis): 20–30%
• Alopecia (hair loss): 10–30%
• Loss of appetite (anorexia): 10–20%
• Early-onset diarrhea (with cholinergic syndrome): 10–20%
• Elevated liver enzymes (AST, ALT, bilirubin): 10–20%
• Febrile neutropenia: 5–10%
• Infection: 5–10%
• Skin rash, itching: 1–5%
• Electrolyte imbalances (hyponatremia, hypokalemia): 1–5%
• Low blood pressure, dizziness: 1–3%
• Interstitial lung disease / pulmonary complications: <1%
• Intestinal perforation / severe colitis: <1%
• Renal failure (secondary to dehydration/sepsis): <1%
• Anaphylactic reactions: <1%