Alvotinib

Imatinib.

Each film-coated tablet contains 100 mg and 400 mg imatinib (as mesilate).
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, low substituted hydroxypropyl cellulose, povidone, crospovidone (Type A), silica colloidal anhydrous, magnesium stearate.
Tablet coat: Hypromellose, polyethylene glycol, talc, red iron oxide (E172), yellow iron oxide (E172).

Pharmacotherapeutic Group: BCR-ABL tyrosine kinase inhibitor. ATC Code: L01EA01.
Pharmacology: Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML patients.
In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl positive tumour cells.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.
Pharmacokinetics: Pharmacokinetics of imatinib: The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg.
Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state.
Absorption: Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in C_max and prolongation of t_max by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated.
Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.
Metabolism: The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.
Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC_(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites.
Elimination: Based on the recovery of compound(s) after an oral ¹⁴C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose).
Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.
Plasma pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily.
Pharmacokinetics in children: As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m²/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC_(0-24) on day 8 and day 1 at the 340 mg/m²/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.
Toxicology: Preclinical safety data: The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits.
Multiple dose toxicity studies revealed mild to moderate haematological changes in animals, accompanied by bone marrow changes in animals.
Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.
Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment.
In a 39-week monkey study, no NOAEL (no observed adverse effect level). Treatment resulted in worsening of normally suppressed malarial infections in these animals.
Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay.
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg.
In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation.
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones.
In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach.
Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m²/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m²/day. The no observed effect level (NOEL) was 30 mg/kg/day.
The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified.

Alvotinib is indicated for the treatment of: Paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment; paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase; adult and paediatric patients with Ph+ CML in blast crisis in the accelerated phase or in the chronic phase of the disease after failure of interferon alfa therapy.
Treatment of adult with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
Adjuvant treatment of adult patient following resection of GIST with a tumor size ≥ 3 cm.

Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies as appropriate.
For doses of 400 mg and above (see dosage recommendation as follows) a 400 mg tablet (not divisible) is available.
The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of mineral water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
Posology for CML in adult patients: The recommended dose of Alvotinib is 600 mg/day for patients in blast crisis. Blast crisis is defined as blasts ≥30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Treatment duration: The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.
Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.
Posology for CML in children: Dosing in children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations - one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients.
There is no experience with the use of Alvotinib in children below 2 years of age.
Dosage in GIST: The recommended dose of Alvotinib is 400 mg/day for patients with unresectable and/or metastatic, malignant GIST.
A dose increase from 400 mg to 600 mg or 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Treatment with Alvotinib in GIST patients should be continued until disease progression.
The recommended dose of Alvotinib is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. In the adjuvant setting the optimal treatment duration with Alvotinib is not known.
Dose adjustment for adverse reactions: Non-haematological adverse reactions: If a severe non-haematological adverse reaction develops with Alvotinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, Alvotinib should be withheld until bilirubin levels have returned to <1.5 x IULN and transaminase levels to <2.5 x IULN. Treatment with Alvotinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m²/day.
Haematological adverse reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.
Dose adjustments for neutropenia and thrombocytopenia: See Table 1.

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Paediatric use: There is no experience in children with CML below 2 years of age (see Pharmacology: Pharmacodynamics under Actions).
Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see Precautions, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Liver dysfunction classification: See Table 2.

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Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

When imatinib is co-administered with other medicinal products, there is a potential for drug interactions (see Interactions).
Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see Interactions).
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib (see Interactions). TSH levels should be closely monitored in such patients.
Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see Dosage & Administration, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 1-12% of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.
Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness or blurred vision during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.

Use in Pregnancy: There are no adequate data on the use of imatinib in pregnant women. Studies in animals have however shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions) and the potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus. Women of childbearing potential must be advised to use effective contraception during treatment and for at least 15 days after stopping treatment with imatinib.
Use in Lactation: There is limited information on imatinib distribution on human milk. Since the effects of low-dose exposure of the infant to imatinib are unknown, woman should not breast-feed during treatment for at least 15 days after stopping treatment with imatinib.

Adverse reactions reported as more than an isolated case are listed as follows, by system organ class and by frequency. Frequency categories are defined using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100),
Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.
Adverse reactions and their frequencies reported in Table 3 are based on the main registration studies. (See Table 3.)

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Active substances that may increase imatinib plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering Alvotinib with inhibitors of the CYP3A4 family.
Active substances that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity could increase metabolism and decrease imatinib plasma concentrations. Co-medications which induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in C_max and AUC_(0-∞) by at least 54% and 70%, of the respective values without rifampicin treatment.
Active substances that may have their plasma concentration altered by imatinib: Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Alvotinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).
Because warfarin is metabolised by CYP2C9, patients who require anticoagulation should receive low-molecular-weight or standard heparin.
Caution should therefore be exercised when using high doses of Alvotinib and paracetamol concomitantly.
In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be increased when imatinib is co-administered (see Precautions). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown.

Incompatibilities: Not applicable.
Special Precautions for Disposal: No special requirements.

Special Precautions for Storage: This medicinal product does not require any special storage conditions.
Store below 30°C.
Shelf-Life: 3 years.

Targeted Cancer Therapy

L01EA01 - imatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

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