Midostaurin

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT. It acts through the parent drug and two active metabolites, CGP62221 and CGP52421. Aberrant, constantly active kinase signalling drives both AML with FLT3 mutations and systemic mastocytosis.

Mechanism of Action

• FLT3 inhibition: midostaurin blocks FLT3 receptor signalling and induces cell-cycle arrest and apoptosis in leukaemic cells that express FLT3 ITD or TKD mutant receptors or over-express wild-type FLT3.
• KIT inhibition: in vitro data indicate that it inhibits the D816V mutant KIT receptor at the exposures reached in patients, and wild-type KIT to a much lesser extent. It interferes with aberrant KIT D816V signalling and inhibits mast cell proliferation, survival and histamine release.
• Other kinases: it also inhibits PDGFR, VEGFR2 and members of the protein kinase C family by binding their catalytic domain, which blocks growth-factor signalling and arrests growth.
• Combination with chemotherapy: with cytarabine, doxorubicin, idarubicin and daunorubicin it gave synergistic growth inhibition in FLT3-ITD AML cell lines.
• Active metabolites: in FLT3-ITD cells CGP62221 was about as potent as midostaurin, while CGP52421 was about 10-fold less potent.

Pharmacokinetics

• Absorption: rapid, with the peak of total radioactivity at 1–3 hours; absolute bioavailability is not known. Absorption is less than dose-proportional above 50 mg twice daily. A standard meal raised midostaurin AUC by about 22% and lowered Cmax by 20%; a high-fat meal raised AUC by about 59%, lowered Cmax by 27% and delayed the peak. The capsules are therefore taken with food.
• Time dependence: with repeated dosing, concentrations of midostaurin and CGP62221 rise in the first week, then decline until steady state on day 28. CGP52421 concentrations fall much less.
• Distribution: volume of distribution about 95.2 L. Midostaurin and its metabolites are distributed mainly in plasma rather than red blood cells and are more than 99.8% protein-bound in vitro, mainly to alpha-1-acid glycoprotein.
• Metabolism: extensive and hepatic, mainly through CYP3A4, to the active metabolites CGP62221 and CGP52421.
• Elimination: half-lives of about 21 hours (midostaurin), 32 hours (CGP62221) and 482 hours (CGP52421). About 95% of the recovered dose is excreted in faeces (91% as metabolites, 4% unchanged) and 5% in urine.
• Special populations: exposure to midostaurin and CGP62221 is substantially lower in severe hepatic impairment than with normal liver function; mild or moderate renal impairment needs no dose adjustment.

• Newly diagnosed AML with FLT3 mutation: in adults, in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and, for patients in complete response, followed by Rydapt single-agent maintenance therapy. A FLT3 mutation (internal tandem duplication or tyrosine kinase domain) must be confirmed with a validated test before treatment.
• Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL): as monotherapy in adults.

• Hypersensitivity to midostaurin or to any of the excipients.
• Concomitant use of strong CYP3A4 inducers, for example rifampicin, St John’s wort (Hypericum perforatum), carbamazepine, enzalutamide and phenytoin.

In AML the most frequent reactions were febrile neutropenia (83.4%), nausea (83.4%), exfoliative dermatitis (61.6%), vomiting (60.7%), headache (45.9%), petechiae (35.8%) and pyrexia (34.5%). In ASM, SM-AHN and MCL they were nausea (82%), vomiting (68%), diarrhoea (51%), peripheral oedema (35%) and fatigue (31%). Frequency categories differ between the two indications and are given separately below (AML data are for Rydapt with chemotherapy).

Very common (≥1/10): in AML device-related infection, febrile neutropenia, petechiae, lymphopenia, hypersensitivity, insomnia, headache, hypotension, epistaxis, laryngeal pain, interstitial lung disease or pneumonitis, dyspnoea, nausea, vomiting, stomatitis, upper abdominal pain, haemorrhoids, exfoliative dermatitis, hyperhidrosis, back pain, arthralgia, pyrexia; laboratory findings of decreased haemoglobin, decreased neutrophil count, raised ALT and AST, hypokalaemia, hyperglycaemia, hypernatraemia, QT prolongation and prolonged activated partial thromboplastin time. In ASM, SM-AHN and MCL urinary tract infection, upper respiratory tract infection, headache, dizziness, dyspnoea, cough, pleural effusion, epistaxis, nausea, vomiting, diarrhoea, constipation, peripheral oedema, fatigue, pyrexia; laboratory findings of non-fasting hyperglycaemia, decreased lymphocyte and neutrophil counts, raised total bilirubin, lipase, AST, ALT and amylase, and QT prolongation.

Common (≥1/100 to <1/10): in AML upper respiratory tract infection, hyperuricaemia, syncope, tremor, eyelid oedema, sinus tachycardia, hypertension, pericardial effusion, pleural effusion, nasopharyngitis, acute respiratory distress syndrome, anorectal and abdominal discomfort, dry skin, keratitis, bone pain, pain in extremity, neck pain, catheter-related thrombosis, hypercalcaemia, weight increased. In ASM, SM-AHN and MCL pneumonia, sepsis, bronchitis, oral herpes, cystitis, sinusitis, erysipelas, herpes zoster, febrile neutropenia, hypersensitivity, disturbance in attention, tremor, vertigo, hypotension, haematoma, oropharyngeal pain, interstitial lung disease or pneumonitis, dyspepsia, gastrointestinal haemorrhage, asthenia, chills, oedema, weight increased, contusion, fall.

Uncommon (≥1/1,000 to <1/100): neutropenic sepsis (AML); anaphylactic shock (ASM, SM-AHN and MCL).

Rare (≥1/10,000 to <1/1,000): none listed.

Not known: acute febrile neutrophilic dermatosis (AML, identified after marketing).

Serious reactions to watch for are febrile neutropenia (the most frequent serious reaction in AML, 16%), infections including sepsis and pneumonia, interstitial lung disease or pneumonitis (some fatal), cardiac dysfunction including heart failure (some fatal) and QT prolongation. In ASM, SM-AHN and MCL, nausea, vomiting and diarrhoea led to dose adjustment or interruption in 26% and to discontinuation in 4.2% of patients, mostly in the first 6 months and managed with supportive medicines. Reactions led to discontinuation in 3.1% of AML patients and 9.2% of those with ASM, SM-AHN or MCL.

Midostaurin is extensively metabolised by CYP3A4, so medicines that induce or inhibit this enzyme change its levels.

• Strong CYP3A4 inducers (contraindicated): carbamazepine, rifampicin, enzalutamide, phenytoin and St John’s wort. Rifampicin 600 mg daily lowered midostaurin Cmax by 73% and AUC by 96% after a single 50 mg dose; CGP62221 behaved similarly and CGP52421 AUC fell by 60%.
• Strong CYP3A4 inhibitors: they may raise midostaurin levels. Ketoconazole at steady state raised the AUC of a single 50 mg dose 10-fold and Cmax 1.8-fold (CGP62221 AUC rose 3.5-fold, while the peak levels of both active metabolites halved). Itraconazole at steady state raised midostaurin trough levels 2.09-fold and CGP52421 trough levels 1.3-fold.
• CYP2B6 substrates: midostaurin is a mild CYP2B6 inducer; bupropion exposure fell by about 48% and its peak by 55%. Narrow-range CYP2B6 substrates such as bupropion or efavirenz should be used with caution and may need dose adjustment.
• CYP1A2 and CYP2E1 substrates: in vitro midostaurin inhibits CYP1A2 and CYP2E1 and induces CYP1A2. Caution with narrow-range substrates such as tizanidine (CYP1A2) and chlorzoxazone (CYP2E1).
• BCRP substrates: rosuvastatin AUC rose by 37% and its peak about doubled, a mild inhibitory effect. Caution with narrow-range BCRP substrates such as rosuvastatin or atorvastatin.
• Hormonal contraceptives: no clinically significant interaction with ethinylestradiol and levonorgestrel, so contraceptive reliability is not expected to be affected.
• QT-prolonging medicines: consider ECG assessment of the QT interval if Rydapt is taken with medicines that can prolong it.
• Food and grapefruit: the capsules are taken with food. DrugBank advises caution with grapefruit products, which inhibit CYP3A4.

Treatment should be started by a physician experienced in anti-cancer therapy. The capsules are taken orally twice daily at about 12-hour intervals, with food, swallowed whole with a glass of water and not opened, crushed or chewed. Prophylactic antiemetics are given according to local practice and patient tolerance.

Acute Myeloid Leukaemia

• Dose: 50 mg twice daily on days 8–21 of each induction and consolidation chemotherapy cycle. Patients in complete response then take it every day as single-agent maintenance until relapse, for up to 12 cycles of 28 days. In patients having a haematopoietic stem cell transplant, it is stopped 48 hours before the conditioning regimen.
• Pulmonary infiltrates grade 3 or 4: interrupt for the rest of the cycle and resume at the same dose when they resolve to grade 1 or lower.
• Other grade 3 or 4 non-haematological toxicity: interrupt until at most grade 2 (if at least possibly related), then resume.
• QTc above 470 ms and up to 500 ms: reduce to 50 mg once daily for the rest of the cycle; return to the initial dose next cycle if QTc is 470 ms or lower at the start, otherwise stay at 50 mg once daily.
• QTc above 500 ms: withhold for the rest of the cycle. If QTc improves to 470 ms or lower before the next cycle, resume the initial dose; if not, withhold that cycle, and as many cycles as needed.
• Maintenance only: for grade 4 neutropenia (ANC below 0.5 × 10⁹/L) interrupt until ANC is 1.0 × 10⁹/L or higher, then resume 50 mg twice daily; discontinue if ANC stays below 1.0 × 10⁹/L for more than 2 weeks and is suspected to be related to Rydapt. Persistent grade 1 or 2 toxicity that the patient finds unacceptable may justify an interruption of up to 28 days.

Aggressive Systemic Mastocytosis, SM-AHN and Mast Cell Leukaemia

• Dose: 100 mg twice daily to start, continued as long as there is clinical benefit or until unacceptable toxicity.
• Neutrophils: for ANC below 1.0 × 10⁹/L attributed to Rydapt (below 0.5 × 10⁹/L in patients with baseline ANC of 0.5–1.5 × 10⁹/L), interrupt until ANC is 1.0 × 10⁹/L or higher, then resume at 50 mg twice daily and, if tolerated, increase to 100 mg twice daily. Discontinue if low ANC persists for more than 21 days.
• Platelets: for platelets below 50 × 10⁹/L attributed to Rydapt (below 25 × 10⁹/L if baseline was 25–75 × 10⁹/L), interrupt until 50 × 10⁹/L or higher, then resume at 50 mg twice daily and increase if tolerated. Discontinue if low counts persist for more than 21 days.
• Haemoglobin: for haemoglobin below 8 g/dL attributed to Rydapt (or life-threatening anaemia if baseline was 8–10 g/dL), interrupt until 8 g/dL or higher, then resume at 50 mg twice daily and increase if tolerated. Discontinue if it persists for more than 21 days.
• Nausea or vomiting grade 3 or 4 despite optimal antiemetics: interrupt for 3 days (6 doses), then resume at 50 mg twice daily and gradually increase if tolerated.
• Other grade 3 or 4 non-haematological toxicity: interrupt until grade 2 or lower, resume at 50 mg twice daily and increase if tolerated. Discontinue if not resolved within 21 days or if severe toxicity returns at the reduced dose.

Special Populations

• Elderly (65 years and over): no dose adjustment. From age 60, use only in patients eligible for intensive induction chemotherapy with adequate performance status and no significant comorbidities.
• Renal impairment: no adjustment for mild or moderate impairment. Experience in severe impairment is limited and there are no data in end-stage renal disease.
• Hepatic impairment: no adjustment for mild or moderate (Child-Pugh A or B) impairment. Exposure is substantially lower in severe impairment, but efficacy data are too limited to suggest a dose change.
• Acute promyelocytic leukaemia: not studied; use is not recommended.
• Children: not to be used with intensive paediatric AML chemotherapy regimens containing anthracyclines, fludarabine and cytarabine, because of prolonged severe neutropenia and thrombocytopenia.

Missed or Vomited Dose

If a dose is missed, take the next dose at the scheduled time. If vomiting occurs, do not take an extra dose; take the next scheduled dose.

Neutropenia and Infections

Neutropenia occurs with Rydapt alone and with chemotherapy. White cell counts should be checked regularly, especially at the start. Treatment is interrupted for unexplained severe neutropenia and stopped for recurrent or prolonged severe neutropenia suspected to be related to Rydapt. Any serious active infection should be controlled before starting monotherapy. Patients are monitored for signs of infection, including device-related infection, and treated promptly, with Rydapt stopped if needed.

Cardiac Dysfunction and QTc Prolongation

Patients with symptomatic congestive heart failure were excluded from the studies. In the studies of ASM, SM-AHN and MCL, heart failure (some fatal) and transient falls in left ventricular ejection fraction occurred; in the AML study heart failure was not more frequent with Rydapt. In patients at risk, use caution and assess ejection fraction when clinically indicated, at baseline and during treatment. QTc prolongation was seen more often with Rydapt, with no mechanism found; take care in patients at risk, for example from other medicines or electrolyte disturbances.

Pulmonary Toxicity

Interstitial lung disease and pneumonitis, some fatal, have occurred with Rydapt alone or with chemotherapy. Patients are monitored for pulmonary symptoms, and Rydapt is stopped when symptoms of grade 3 or higher without an infectious cause appear.

Pregnancy Test, Contraception, Breastfeeding and Fertility

• Pregnancy test and contraception: females of reproductive potential should have a pregnancy test within 7 days before starting and use effective contraception (methods with pregnancy rates below 1%) during treatment and for at least 4 months after stopping.
• Pregnancy: midostaurin can cause foetal harm. Animal studies showed foetotoxicity, and there are no adequate studies in pregnant women. It is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is unknown whether midostaurin passes into human milk, but it does in rats. Breastfeeding should stop during treatment and for at least 4 months afterwards.
• Fertility: no human data; animal studies showed impaired fertility.

Excipients with Known Effect

Each capsule contains about 83 mg of anhydrous ethanol and 415 mg of macrogolglycerol hydroxystearate; see section 4.4 of the SmPC for the advice that goes with them.

Effect on Driving

Rydapt has a minor influence on the ability to drive and use machines. Dizziness and vertigo have been reported and should be considered.

Rydapt needs no special temperature conditions. Store it in the original container (blister) to protect it from moisture. It is supplied in blisters of 4 capsules, in packs of 56 or 112 capsules; not all pack sizes may be marketed.

3 years.

Prescription only (Rx), started by a physician experienced in anti-cancer therapy. Rydapt is taken at home as capsules, so it is supplied to the patient or to the treating clinic on prescription.