IRNIZET 100

Indications

• Colorectal cancer
• Small cell lung cancer
• Pancreatic cancer
• Gastric cancer

Dosage

Children: Refer to the BNF for Children for specific dosing information. Dosing in pediatric populations should be carefully calculated based on body surface area and adjusted for individual tolerance.

Adults: Refer to the BNF for specific dosing information. Typical dosing regimens may vary based on the treatment protocol and patient factors.

Mechanism of action

Irinotecan exerts its effects by inhibiting DNA topoisomerase I, an enzyme critical for DNA replication and transcription. It is converted into its active metabolite, SN-38, which binds to the topoisomerase I-DNA complex, preventing the religation of single-strand breaks that are created during DNA replication. This interference leads to replication fork arrest and results in lethal double-stranded breaks in the DNA, causing apoptosis in cancer cells.

Pharmacodynamics

As an antineoplastic agent, irinotecan has demonstrated significant antitumor activity in various preclinical studies involving mouse models and human carcinoma xenografts. Its effectiveness is attributed to its ability to induce DNA damage, leading to cell death in rapidly dividing cancer cells.

Pharmacokinetics

Irinotecan is administered intravenously and is subject to hepatic metabolism. Its conversion to the active metabolite SN-38 occurs via carboxylesterase enzymes primarily in the liver and gastrointestinal tract. The pharmacokinetics of irinotecan can be influenced by factors such as liver function and concomitant medications. The elimination half-life of irinotecan is approximately 9 to 10 hours, while SN-38 has a longer half-life, contributing to its prolonged effects.

Adverse effects

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Fatigue
• Neutropenia
• Anemia
• Alopecia

Interactions

• HIV protease inhibitors: Severe (increases risk of toxicity)
• Fibrates: Severe (increases exposure)
• Macrolides: Severe (increases risk of toxicity)
• Clarithromycin: Severe (increases risk of toxicity)
• Gemfibrozil: Unknown (increases exposure)
• Live vaccines: Unknown (increases risk of generalized infection, possibly life-threatening)
• Mitotane: Unknown (decreases exposure)
• Neuromuscular blocking drugs, non-depolarising: Unknown (decreases effects)
• Pitolisant: Unknown (decreases exposure)
• St John's Wort: Unknown (decreases exposure)

Pregnancy

Use with caution; potential risks to the fetus must be considered.

Breast-feeding

Not recommended due to potential excretion in breast milk and risk to the infant.

Storage

Store at 20-25°C (68-77°F); protect from light.

Formulations

• Injection
• Powder for solution

Indications

• Metastatic colorectal cancer
• Advanced pancreatic cancer
• Small cell lung cancer

Dosage

Children: Refer to the BNF for Children for specific dosing information in paediatric patients, as dosing may vary significantly based on age, weight, and clinical condition.

Adults: The usual dose for adult patients with metastatic colorectal cancer is 180 mg/m2 administered as an intravenous infusion every two weeks, in combination with other agents such as fluorouracil and leucovorin. Dosing regimens may vary based on specific treatment protocols.

Mechanism of action

Irinotecan is converted in the body to its active metabolite, SN-38, which then inhibits topoisomerase I. This enzyme is crucial for DNA unwinding and replication; by inhibiting it, irinotecan causes DNA strand breaks, ultimately leading to apoptosis in cancer cells.

Pharmacodynamics

The pharmacodynamics of irinotecan involve its ability to induce apoptosis in cancer cells by stabilizing the topoisomerase I-DNA complex. This results in the accumulation of DNA damage, particularly in S-phase cells. The drug is known for its dose-dependent toxicity, particularly leading to myelosuppression and gastrointestinal side effects such as diarrhea.

Pharmacokinetics

Irinotecan is administered intravenously and exhibits a complex pharmacokinetic profile. It is subject to extensive hepatic metabolism, primarily by the enzyme UGT1A1. The elimination half-life of irinotecan is approximately 6 to 12 hours, while its active metabolite SN-38 has a longer half-life. The drug's clearance can be affected by variations in UGT1A1 enzyme activity among individuals, influencing both efficacy and toxicity.

Contra-indications

• Acute porphyrias
• Patients aged over 75 years with certain conditions

Adverse effects

• Alopecia
• Anaemia
• Anxiety
• Appetite decreased
• Arrhythmias
• Arthralgia
• Asthenia
• Diarrhoea
• Dizziness
• Drowsiness
• Dry eye
• Dyspnoea
• Gastrointestinal disorders
• Headache
• Hyperpyrexia
• Hypertension
• Increased risk of infection
• Influenza-like illness
• Insomnia
• Limb discomfort
• Muscle weakness
• Nausea
• Vomiting
• Peripheral coldness
• Photosensitivity reaction
• Sepsis
• Sweat changes
• Swelling
• Tinnitus
• Tremor
• Urinary disorders
• Vision disorders
• Weight changes

Interactions

• May interact with other antineoplastic agents
• Caution with prior use of other cytotoxic drugs

Precautions

• Monitor for signs of infection
• Assess performance status
• Careful in patients with respiratory disorders
• Caution in those with cardiac conditions

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Not recommended during breastfeeding due to potential adverse effects on the infant.

Storage

Store in a cool, dry place below 25 degrees Celsius. Protect from light.

Formulations

• Irinotecan Hydrochloride 100 mg powder for suspension for infusion
• Irinotecan Hydrochloride 40 mg/ml solution for infusion

Mechanism of action

DNA topoisomerase I is a nuclear enzyme that ensures proper DNA topology during replication and transcription. It relieves torsional strain in the DNA double helix during replication and transcription by creating reversible single-strand breaks. Upon administration, irinotecan is converted into its active metabolite, SN-38, by carboxylesterase in the liver and gastrointestinal tract. Irinotecan and SN-38 both inhibit DNA topoisomerase I, acting on the S and G2 phases of the cell cycle. Irinotecan and SN-38 bind to the topoisomerase I-DNA complex and prevent the religation of single-strand breaks. The ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38 interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA. Because double-stranded breaks cannot be efficiently repaired by mammalian cells, apoptosis of cancer cells occurs. Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.

Pharmacodynamics

Irinotecan is an antineoplastic agent. The administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.