Composition, form of production and packaging
Capsules 1 caps.
dabrafenib 50 mg
28 pcs. - bottles (1) - packs of cardboard.
120 pcs. - bottles (1) - packs of cardboard.
Capsules 1 caps.
dabrafenib 75 mg
28 pcs. - bottles (1) - packs of cardboard.
120 pcs. - bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Dabrafenib is a potent selective ATP-inhibiting RAF kinase inhibitor with half the maximum inhibitory concentration of IC 50 for the BRAF V600E, BRAF V600K and BRAFV 600D isoenzymes of 0.65 nmol, 0.5 nmol and 1.84 nmol, respectively. Oncogenic mutations of the BRAF gene lead to constitutive activation of the RAS / RAF / MEK / ERK pathway and stimulation of growth of tumor cells. Mutations of the BRAF gene are detected with high frequency with specific neoplasms, including melanoma (approximately in 50% of cases).
The most commonly observed mutation of the BRAF gene is V600E, and the next most common mutation is the V600K, which is 95% of the mutations of the BRAF gene in all cancer patients. In rare cases, other mutations such as V600D, V600G and V600R can be detected.
Dabrafenib also inhibits the wild-type CRAF and BRAF isoenzymes, IC 50 for which are 5.0 nmol and 3.2 nmol, respectively. Dabrafenib inhibits the growth of melanoma cells bearing the mutation of the BRAF V600 gene, both in vitro and in vivo.
The pharmacokinetics of dabrafenib have been studied in patients with a mastastatinizing melanoma with a mutation of the BRAF gene after a single or repeated use of the drug (150 mg twice a day, the interval between doses is 12 hours).
Dabrafenib is absorbed by oral administration, the maximum plasma concentration (C max ) is reached 2 hours after the dose (mean time). The average absolute bioavailability of dabrafenib for oral use is 95% (90% confidence interval: 81-110%). After a single application, the exposure of dabrafenib C max and the area under the pharmacokinetic curve "concentration-time" (AUC) increases dose-dependently (at doses from 12 mg to 300 mg), but after repeated use (2 times a day), the increase in exposure is less dependent on dose. With repeated use, the exposure of dabrafenib is somewhat reduced, possibly due to the induction of its own metabolism. The average cumulation ratio of AUC day 18 / day 1 was 0.73. After taking dabrafenib 150 mg twice daily, the geometric mean C max , AUC 0-t ) and the pre-dose concentration (C t ) were 1478 ng / ml, 4341 ng / hr and 26 ng / ml, respectively.
Dabrafenib intake during food reduces its bioavailability (C max and AUC decrease by 51% and 31%, respectively) and slows down absorption, compared with fasting dabrafenib.
Dabrafenib binds to blood plasma proteins (the degree of binding is 99.7%). The apparent volume of distribution is 70.3 liters.
The first stage of the metabolism of dabrafenib is the formation of hydroxydabrafenib catalyzed by the isoenzymes CYP2C8 and CYP3A4. The hydroxydabrafenib is then oxidized to carboxy dibrafenib using the CYP3A4 isoenzyme. Carboxy-dibrafsib can be subjected to non-enzymatic decarboxylation with the formation of desmethyldabrafenib. Carboxedabrafenib is excreted into bile and urine. Desmethydabrafenib, most likely, is formed and is absorbed in the intestine.Desmethyldabrafenib is oxidized by the isoenzyme CYP3A4. The final half-life of hydroxydabrafenib corresponds to the half-life of the parent compound (10 hours), whereas the carboxy- and desmethyl metabolites of dabrafenib are characterized by a longer half-life (21-22 hours). After repeated doses of the drug, the ratio of the mean AUC of the metabolite and the starting compound, dabrafenib, was 0.9, 11, and 0.7 for the hydroxy, carboxy, and desmethyl dibrafenib, respectively. Judging by the exposure, relative efficacy and pharmacokinetic properties, hydroxy- and desmethyldabrafenib probably play an important role in the clinical effect of dabrafenib;the activity of carboxydabrafenib probably does not play a significant role.
The final half-life period of dabrafenib after oral administration is 8 hours (due to the lengthening of the terminal phase). The clearance of dabrafenib is 17.0 l / h after a single application and 34.4 l / h in 2 weeks when taken twice a day.
The main way of elimination after oral administration is excretion through the intestine (71% of the dose labeled with a radioactive label). When excreted by the kidneys, only 23% of the dose, labeled with a radioactive label, is released.
Special patient groups
Patients with impaired hepatic function
According to the population analysis data, in patients with mild liver function impairment, the clearance of dabrafenib for oral administration did not significantly differ from the clearance of dabrafenib in patients with normal liver function. In addition, a mild degree of impaired liver function had no significant effect on the concentration of dabrafenib metabolites in plasma. Dabrafsnib should be used with caution in patients with moderate to severe hepatic impairment.
Patients with impaired renal function
According to the population analysis, the effect of light (glomerular filtration rate (GFR) 60-89 ml / min / 1.73 m 2 ) and mean (GFR 30-59 ml / min / 1.73 m 2 ) of the degree of renal dysfunction on the clearance of dabrafenib when administered orally was weak and clinically insignificant. Also, mild and moderate renal impairment did not significantly affect the plasma concentrations of hydroxy-, carboxy- and desmethodubrafsib. Data on the use of dabrafenib in patients with severe renal impairment are not available.
According to population pharmacokinetic analysis, age has no significant effect on the pharmacokinetics of dabrafenib. Age 75 years and older is a predictor of higher plasma concentrations of carboxy- and desmethyldabrafenib (40% increase in exposure), compared to those in people under 75 years of age.
Body weight and sex
According to the population pharmacokinetic analysis, body weight and sex have an effect on the clearance of dabrafenib for oral use; body weight also affects the volume of distribution after ingestion and distributional clearance. However, these pharmacokinetic differences are not considered clinically significant.
There is insufficient data to assess the possible influence of the race on the pharmacokinetics of dabrafenib.
Interactions with drugs
Studies of human liver microsomes show that dabrafenib is a substrate of CYP3A4 and CYP2C8 isoenzymes, while hydroxydabrafenib and desmethodabrafenib are substrates of the CYP3A4 isoenzyme. In vitro, dabrafenib is the substrate of the human P-glycoprotein and breast cancer resistance protein (BCRP).
In human hepatocytes, dabrafenib causes a dose-dependent increase in mRNA levels of CYP2B6 and CYP3A4 isoenzymes up to 32 times compared to control levels.Dabrafenib is a moderate inhibitor of the CYP3A4 isoenzyme in vivo. In a clinical study, in 12 patients after combined repeated use of dabrafenib and a single application of midazolam (substrate of the isoenzyme CYP3A4), Cmax and AUC (0-?) Of midazolam decreased by 61 and 74%, respectively. Dabrafenib is a mild inducer of the CYP3A4 isoenzyme and can induce other isoenzymes such as CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP-glucuronosyltransferase, and induce anion carriers. In vitro, dabrafenib and its metabolites: hydroxydabrafenib, carboxydabrafenib and desmethydabrafenib, exhibited properties of inhibitors of human polypeptide carriers of organic anions OATP1B1, OATP1B3, and carriers of organic anions OAT1 and OAT3. In vitro, dabrafenib and desmethyldabrafenib are moderate inhibitors of BCRP.
- treatment of patients with unresectable or metastatic melanoma with a mutation of the gene BRAF V600.
Confirmation of the BRAF V600 gene mutation with an approved or validated test is necessary to select patients for dabrafenib therapy.
The efficacy and safety of the drug Rafinlar in the treatment of melanoma with a mutation of the wild-type BRAF gene has not been established. The drug Rafinlar should not be used in the treatment of melanoma with a mutation of the wild-type BRAF gene.
The recommended dose is 150 mg (2 capsules of 75 mg) 2 times a day (corresponding to a total daily dose of 300 mg).
The drug Rafinlar should be taken no later than one hour before a meal, or not earlier than two hours after a meal, observing a 12-hour interval between doses. The drug Rafinlar should be taken every day at the same time.
Treatment should continue until the disease progresses or signs of unacceptable toxicity develop (see Table 2).
If the next dose was missed, and before taking the next dose remains less than 6 hours, the missed dose should not be taken.
Modification of the dose
If unwanted reactions develop, treatment can be temporarily discontinued, the dose reduced or treatment discontinued (see Tables 1 and 2).
Dose modification or discontinuation of treatment is not recommended for such undesirable reactions as squamous cell carcinoma of the skin or a new case of primary melanoma.
Treatment should be interrupted if the patient's body temperature is? 38.5 В° C. Regular monitoring of the condition of patients for signs and symptoms of infection should be made.
The recommended dose reduction scheme and recommendations for dose modification are presented in Table 1 and Table 2, respectively. It is recommended that after any correction, the dose is not less than 50 mg 2 times a day.
Table 1. Recommended scheme of dose reduction Rapinlar
Dose change / dosage regimen
The first dose reduction of 100 mg orally 2 times a day
The second dose reduction of 75 mg orally 2 times a day
The third dose reduction of 50 mg orally 2 times a day
In case of intolerance, 50 mg 2 times a day cancellation of the drug Rafinlar
Table 2. Recommended scheme for modifying the dose of Rafinlar
Target organ Undesirable reactions 1 Dose modification
Pyretic reaction to the drug вЂў fever from 37.3 to 40 В° C. вЂў Avoid using the Rafinlar drug before resolving an undesirable reaction. Then resume the use of the drug Rafinlar in the same or a smaller dose (see Table 1).
вЂў fever above 40 В° C; вЂў fever, complicated by tremors, lowering blood pressure, dehydration or kidney failure. Or вЂў stop using Rapinlar on an ongoing basis. Or вЂў refrain from using the Rafinlar drug before resolving an undesirable reaction. Then resume the use of the drug Rafinlar in a smaller dose (see Table 1).
Other вЂў intolerable adverse reactions of the 2nd degree; вЂў Any unwanted reactions of the 3rd degree. вЂў Avoid using the drug Rafinlar until an undesirable reaction is resolved to 1 degree or less. Then resume the use of the drug Rafinlar in a smaller dose (see Table 1).
вЂў any first-time adverse reaction of grade 4 Or вЂў stop the use of Rapinlar on an ongoing basis. Or вЂў refrain from using the Rafinlar drug before resolving the undesired reaction to 1 degree or less. Then resume the use of the drug Rafinlar in a smaller dose (see Table 1).
вЂў relapse of the undesired reaction of the 4th degree; вЂў an intolerable undesired 2nd degree reaction or any unwanted reaction of grade 3 or 4 with the use of the drug Rapinlar at a dose of 50 mg 2 times a day. вЂў stop using Rapinlar on an ongoing basis
1 - the severity of unwanted reactions is assessed according to the Standard Criteria for the Evaluation of Unwanted Reactions (STS-AE), version 4.0.
After achieving control over unwanted reactions, an increase in the dose is possible. The increase in dose is carried out according to the same scheme (in reverse order) as the reduction. The dose should not exceed 150 mg 2 times a day.
The effectiveness and safety of the drug Rafinlar in children and adolescents (under the age of 18 years) is not established.
In patients older than 65 years, no dose adjustment is required.
Patients with impaired renal function
In patients with mild to moderate renal impairment, dose adjustment is not required. According to population pharmacokinetic analysis, mild to moderate renal impairment does not affect the clearance of dabrafenib or the concentration of its metabolites when administered orally. Clinical data on the use of the drug Rafinlar with a severe degree of renal dysfunction are absent, and the need for dose adjustment is not established. Use with caution the drug Rafinlar with severe renal impairment.
Patients with impaired hepatic function
In patients with mild impairment of liver function, dose adjustment is not required. According to population pharmacokinetic analysis, the mild degree of impaired liver function does not affect the clearance of dabrafenib or the concentration of its metabolites when administered orally. Clinical data on the use of the drug Rafinlar with an average or severe degree of liver dysfunction are absent; the need for dose adjustment is not established. Dabrafenib and its metabolites are eliminated mainly through the liver (metabolism and excretion with bile), therefore, with an average or severe degree of liver function disorder, an increase in systemic action is possible. Caution is advised to use the drug Rapinlar with moderate or severe degree of impaired liver function.
Consolidated safety data were obtained from five clinical studies (dubrafenib monotherapy), which included 578 patients with melanoma. Approximately 30% of patients received dabrafenib for more than 6 months.
In the general population, the most frequent (> 15%) adverse reactions were hyperkeratosis, headache, fever, arthralgia, fatigue, nausea, dermal papillomas, alopecia, rash and vomiting in the general population to assess dabrafenib safety.
The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1 000 and <1/100), rarely (? 1/10 000 and <1/1 000), very rarely (<1/10 000). Frequency categories were formed on the basis of clinical studies of the drug.
Frequency of occurrence of undesirable reactions
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Very common: papilloma
Often: acrochordon (filiform wart, soft fibroma), squamous cell carcinoma, including squamous cell carcinoma of the skin, cancer in situ (Bowen's disease) and keratoacanthoma, seborrheic keratosis
Infrequently: a new case of primary melanoma.
Immune system disorders
Often: bullous rash
Disorders from the metabolism and nutrition
Very often: decreased appetite
Disturbances from the nervous system
Very often: headache
Disturbances on the part of the organ of sight
Infrequent: uveitis (inflammation of the choroid of the eyeball)
Disturbances from the respiratory system, chest and mediastinal organs
Very often: cough, nasopharyngitis
Disorders from the digestive tract
Very often: nausea, vomiting, diarrhea
Disturbances from the skin and subcutaneous tissues
Very often: skin disorders (rash, hyperkeratosis), alopecia, palmar-plantar erythrodysesthesia syndrome
Often: skin disorders (actinic keratosis, skin damage, dry skin, erythema)
Disturbances from musculoskeletal and connective tissue
Very often: arthralgia, myalgia, pain in the extremities, back pain, joint pain
Disorders from the kidneys and urinary tract
Often: interstitial nephritis
Infrequent: renal failure, acute renal failure
General disorders and disorders at the site of administration
Very often: asthenia, chills, fatigue, hyperthermia
Often: influenza-like syndrome
Laboratory and instrumental data
Very often: hyperglycemia, increased activity of alkaline phosphatase
- Pregnancy and the period of breastfeeding;
- Children under 18 years.
Dabrafenib should be used with caution in patients with moderate to severe hepatic impairment, severe renal impairment.
PREGNANCY AND LACTATION
Data on the effect of dabrafenib on human fertility are not available. The animals observed undesirable phenomena from the male reproductive system. Male patients should be informed of the risk of spermatogenesis, which may be irreversible.
Controlled clinical trials of adequate quality for the use of dabrafenib in pregnant women have not been conducted. Animal studies have demonstrated the reproductive toxicity of dabrafenib. The drug Rapinlar should not be used by pregnant women and women during breastfeeding. If the pregnancy occurs during the period of taking Rapinlar, the patient should be informed of the potential risk to the fetus.
There is no data on excretion of the drug Rapinlar with breast milk in women. However, the risk for a breastfed infant is not excluded, since many drugs are excreted into breast milk. Should decide to discontinue breast-feeding or termination of therapy with Rafinlar, given the importance of the drug to the mother.
APPLICATION FOR FUNCTIONS OF THE LIVER
Dabrafenib should be used with caution in patients with severe renal impairment.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Dabrafenib should be used with caution in patients with moderate and severe hepatic dysfunction
APPLICATION FOR CHILDREN
Is contraindicated in children under 18 years
APPLICATION IN ELDERLY PATIENTS
In patients older than 65 years of dose adjustment is not required.
Women of childbearing age should use effective contraception during treatment and for 4 weeks after discontinuation of therapy.
Rafinlar drug may reduce the effectiveness of oral contraceptives, it is recommended to use alternative methods of contraception (e.g., barrier method).
Hyperthermia and serious episodes of fever, non-communicable diseases
The episodes of fever were observed in clinical studies. In rare cases, fever accompanied by severe chills, dehydration and hypotension, which in some cases lead to acute renal failure. Such serious episodes of fever, non-communicable diseases, usually occurs in the first month of treatment. In clinical studies, serious episodes of fever, non-communicable diseases were observed in 1% of patients; effective measures were interrupt the treatment and / or dose reduction for this unwanted reaction, and symptomatic therapy.
Treatment with Rafinlar should be interrupted in the event that the patient's body temperature> 38,5 В° C. The condition of patients should be regularly monitored for signs and symptoms of infection. Dabrafeniba reception can be resumed after a normalization of body temperature, in combination with adequate prevention nsstsroidnymi antiinflammatory drugs paracetamol fire. If the fever is accompanied by other signs or symptoms of severe, reception dabrafeniba after normalization of temperature should be resumed at a reduced dose and if clinically appropriate.
Squamous skin cancer
There have been reports of cases of squamous cell skin cancer (including keratoakantomu and mixed keratoakantomu) in patients taking dabrafenib. Before starting treatment and during therapy dabrafenibom should regularly monitor the condition of the skin: every 2 months during the first 6 months of treatment, then every 3 months. After discontinuation of the drug is needed check-up after 2 months.
With the development of squamous cell skin cancer is necessary resect an affected area of skin and dabrafenibom therapy should continue without dose adjustment. Patients should be warned that the appearance of new skin lesions, you should immediately inform your doctor.
New cases of primary melanoma
There are reports of new cases of primary melanoma in patients taking dabrafenib. These cases were detected during the first 5 months of treatment and did not require modification treatments except resection of the affected area. Requires regular monitoring skin condition (according to the scheme described for squamous cell skin cancer).
Malignancies of other localization
In in vitro experiments there was a paradoxical activation of MAP kinase signaling cascade in cells carrying the gene mutation BRAF wild type and exposed to BRAF inhibitors. This increases the risk of development of malignant tumors of other localization (including tumors harboring a mutation RAS) in patients receiving dabrafenib.
Uveitis (inflammation of the uvea)
There have been reports of adverse reactions on the part of the organ of vision, such as uveitis and iritis (inflammation of the iris). During treatment requires monitoring of ophthalmologic symptoms such as vision changes, photophobia, pain in the eyes.
In applying the drug Rafinlar may develop hyperglycemia requiring insulin therapy destination or oral hypoglycemic drugs or increasing doses of the aforementioned preparations. In a clinical study in 5 out of 12 patients with a history of diabetes in the application Rafinlar medication became necessary to increase the intensity of hypoglycemic therapy. The incidence of grade 3 hyperglycemia determined on the basis of laboratory parameters, was 6% (12/187) of patients receiving the drug Rafinlar, in contrast to patients treated with dacarbazine in which such cases are not registered.
In treating drug Rafinlar patients previously diagnosed with diabetes or hyperglycemia is necessary to monitor the level of glucose in serum, commonly used in clinical practice. Patients are advised to inform the doctor about the symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination increases.
Deficiency of glucose-6-phosphate dehydrogenase
drug Rafinlar containing sulfoiamidnuyu group increases the potential risk of hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase (G6PD). It is necessary to conduct a thorough medical examination of patients with G6PD deficiency for signs of hemolytic anemia.
Impact on the ability to drive vehicles and manage mechanisms
Studies on the impact of dabrafeniba on the ability to drive or operate machinery have not been undertaken. Pharmacological properties dabrafeniba indicate the absence of any adverse effect on such activity. In assessing the ability to perform actions that require quick decisions, special motor and cognitive skills necessary to take into account the patient's general condition and the profile of adverse reactions dabrafeniba.
On the data on overdose dabrafeniba today is extremely rare. The maximum dose dabrafeniba that patients obtained in clinical trials, was 600 mg (300 mg, 2 times a day).
Specific treatment (antidote) overdose dabrafeniba offline. symptomatic treatment should be carried out during the development of adverse reactions. If you suspect an overdose should be lifted immediately dabrafenib and start supporting therapy. In the future management of patients should be adjusted in accordance with clinical guidelines or toxicological National Center (if possible).
The effect of other drugs on dabrafenib
In preclinical studies in vitro demonstrated that dabrafenib metabolized mainly isoenzymes CYP2C8 and CYP3A4. Co-administration of ketoconazole (an inhibitor of CYP3A4) dabrafeniba AUC increases by 57%. Drugs that are potent inhibitors or inducers CYP2C8 or CYP3A4, can respectively increase or decrease the concentration dabrafeniba. Therefore during therapy dabrafenibom should, wherever possible, the use of alternative medicines. Care must be taken when using powerful inhibitors (for example, ketoconazole, nefazodone, clarithromycin, ritonavir) or inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) CYP2C8 or CYP3A4 together with dabrafenibom.
Drugs that affect the pH of gastric juice
formulations that alter the pH of the upper GI (e.g., proton pump inhibitors, antagonists, H 2 receptor antagonists, antacids) may modify the solubility dabrafeniba and reduce its bioavailability. However, clinical studies evaluating the effect of drugs that alter gastric pH on systemic exposure dabrafeniba not conducted. With the simultaneous application of the drug and Rafinlar proton pump inhibitor, an antagonist of H 2 -receptor or antacid dabrafeniba systemic exposure can be reduced, and influence on the effectiveness of the drug Rafinlar in this case is not established.
Effect dabrafeniba other medicaments
Dabrafenib enhances SYR3A4-mediated metabolism and may increase the activity of other enzymes, including isoenzymes CYP2B6, CYP2C8, CYP2C9 and CYP2C19 and UDP-glucuronosyltransferase. When co-administered midazolam and dabrafeniba AUC of midazolam (substrate of CYP3A4) is reduced. Combined use dabrafeniba and drugs that are sensitive to induction of these enzymes (e.g., hormonal contraceptive, warfarin or dexamethasone) can lead to a reduction in their concentration and loss of efficiency. If the application of such preparations need to be monitored and their efficiency consider using alternative medicines.
TERMS OF RELEASE FROM PHARMACY
TERMS AND CONDITIONS OF STORAGE
Store at a temperature not exceeding 30 В° C. Keep out of the reach of children. Shelf life - 2 years.