Tafinlar - instructions for use, dose, side effects, contraindications

Active substanceDabrafenibDabrafenib

Similar drugsTo uncover

capsules inwards

Dosage form: & nbspcapsules

Composition:

Each capsule contains:
Name of components		Amount, mg
		50 mg		75 mg
Active substance
Dabrafenoba microsylate mesylate¹(in terms of dubrafenib)		59,25 50,00		88,88 75,00
Excipients
Microcrystalline cellulose		118,50		177,70
Magnesium stearate		1,80		2,70
Silica colloidal dioxide		0,45		0,68
Total weight of capsule contents		180,00		270,00
The composition of capsules for the dosage of 50 mg of hypromellose, size No. 2, Swedish Orange (Swedish orange):
Colour	Name of components		Quantity, (% w / w)
Dark red	Iron Oxide Red Dye Oxide		1,29
	Titanium dioxide		0,53
	Hypromellose		q.s. up to 100
The composition of capsules for the dosage of 75 mg of hypromellose, size No. 1, Opaque Pink (Opaque pink):
Colour	Name of components		Quantity, (% w / w)
Dark pink	Iron Oxide Red Dye Oxide		0,56
	Titanium dioxide		1,78
	Hypromellose		q.s. up to 100

Composition of ink (S-1-17822 and S-1-17823)²:

Colour	Name of components	Quantity, (% w / w)
Colour	Name of components	S-1-17822	S-1-17823
The black	Shellac	44,5	44,5
	Iron Oxide Dye Oxide	23,4	23,4
	Propylene glycol	2,0	2,0
	Ammonia water	1,0	1,0
	Butanol	16,64	2,24
	Isopropanol	12,48	26,88

Note:

1. Dabrafenib mesylate is a form of the free-base mesylate salt of dabrafenib. Based on the molecular weight (MM) data, 1.185 mg of the salt (MM = 615.68) is equivalent to 1.00 mg of the free base (MM = 519.57).

2. Ink S-1-17822 and S-1-17823 can be used for both 50 mg dosage and 75 mg dosage.

Description:

Capsules, 50 mg:

Opaque capsules made of hypromellose, size No. 2, with a dark red case and lid with printed identification codes "GS TEW"on the lid and" 50 mg"on the body.

Capsules, 75 mg:

Opaque capsules made of hypromellose, size No. 1, with a case and a lid of dark pink color with printed identification codes "GS LHF"on the lid and" 75 mg"on the body.

Pharmacotherapeutic group:Antitumor agent, protein kinase inhibitor.

ATX: & nbsp

L.01.X.E.23 Dabrafenib

Pharmacodynamics:

Mechanism of action

Dabrafenib is a potent selective ATP-inhibiting RAF kinase inhibitor with half the maximum inhibitory concentration of IC50 for the BRAF V600E, BRAF V600K and BRAF V600D isoenzymes of 0.65 nmol /l, 0.5 nmol /l and 1.84 nmol /l, 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 in specific neoplasms, including melanoma (in about 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, the IC50 for which is 5.0 nmol /l and 3.2 nmol /l, respectively. Dabrafenib inhibits the growth of melanoma cells bearing the mutation of the BRAF V600 gene as in vitro, and in vivo.

Pharmacokinetics:

Suction

Dabrafenib is absorbed when taken orally, the maximum concentration in the plasma (C_m_Oh) is achieved 2 hours after the dose (average 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_m_Oh and the area under the pharmacokinetic curve "concentration-time" (AUC) increases dose-dependently (at doses of 12 mg to 300 mg), but after repeated use (2 times a day), the increase in exposure is less dose-dependent. With repeated use, the exposure of dabrafenib is somewhat reduced, possibly due to the induction of its own metabolism. The average cumulation ratio AUC day 18 / day 1 was 0.73. After taking dabrafenib in a dose of 150 mg twice a day, the geometric mean C_m_Oh, AUQ_(0-τ) and concentration before taking a dose (C_τ) were 1478 ng / ml, 4341 ng x hour / ml and 26 ng / ml, respectively. Taking dabrafenib while eating reduces its bioavailability (FROM_m_Oh and AUC decrease by 51% and 31%, respectively) and slows down absorption compared with fasting dabrafenib.

Distribution

Dabrafenib binds to blood plasma proteins (the degree of binding is 99.7%). The apparent volume of distribution is 70.3 liters.

Metabolism

The first stage of dabrafenib metabolism is the formation of hydroxydabrafenib catalyzed by isoenzymes CYP2C8 and CYP3A4. The hydroxydabrafenib is then oxidized to carboxy dibrafenib by isoenzyme CYP3A4. Carboxydabrafenib may undergo non-enzymatic decarboxylation with the formation of desmethyldabrafenib. Carboxedabrafenib is excreted in bile and urine. Desmethydabrafenib may also form and reabsorbed in the intestine. Desmethyldabrafenib is oxidized by 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 admission the ratio of the mean AUC metabolite and parent compound, dabrafenib, were 0.9, 11, and 0.7 for hydroxy, carboxy, and desmethyl dibrafenib, respectively. Judging by the exposure, the relative activity and pharmacokinetic properties, hydroxy- and desmethyldabrafenib, probably, important in the implementation clinical effectiveness of dabrafenib; the activity of carboxydabrafenib probably does not play a significant role.

Excretion

The final half-life 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 with 2 times 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 did not have a significant effect on the concentration of dabrafenib metabolites in plasma. Dabrafenib 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 m²) and medium (GFR 30-59 ml / min / 1.73 m²) the degree of renal dysfunction in the clearance of dabrafenib while ingestion was weak and clinically insignificant. Also, mild to moderate renal impairment did not significantly affect the plasma concentrations of hydroxy-, carboxy- and desmethyldabrafenib. Data on the use of dabrafenib in patients with severe renal impairment are not available.

Age

According to population pharmacokinetic analysis, age has no significant effect on the pharmacokinetics of dabrafenib. Age 75 years and older is a prognostic parameter of higher plasma concentrations of carboxy- and desmethyldabrafenib (an increase in exposure by 40%), compared with similar indicators in individuals is younger 75 years.

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 regarded as clinically significant.

Race

There is insufficient data to assess the possible influence of the race on the pharmacokinetics of dabrafenib.

Interactions from other medicinal products

Studies of human liver microsome show, what basic enzymes CYP, involved in the oxidative metabolism of dabrafenib in vitro - CYP2C8 and CYP3A4, whereas hydroxydabrafenib and Desmethydabrafenib are substrates CYP3A4. With repeated use of dabrafenib together with ketoconazole, there is a moderate increase FROM_m_Oh (33%) and AUC (71%), as well as AUC hydroxy- and desmethyl dibrafeniba (82% and 68%, respectively). AUC carboxydabrafenib decreased in this case by 16%. When joint the use of dabrafenib and gemfibrozil (inhibitor CYP2C8) there was an increase AUC applied repeatedly dabrafenib (47%), there were no corresponding changes in the concentrations of metabolites.

In vitro dabrafenib is the substrate of human P-glycoprotein and breast cancer resistance protein (BCRP1). However, these vectors have little effect on the bioavailability and excretion of dabrafenib in oral use, so the risk of drug interactions is minimal. Dabrafenib is the inducer of isoenzymes CYP3A4 and CYP2C9, and can induce other isoenzymes, such as CYP2B6, CYP2C8, CYP2C19 and UDP-glucuronosyltransferase (CGT), and may also increase the activity of the vectors. In human hepatocytes dubrafenib causes a dose-dependent increase in mRNA levels of isoenzymes CYP2B6 and CYP3A4 to 32 times compared with control levels. Dabrafenib is an activator isozymes CYP3A4 and CYP2C9 in vivo. In a clinical study in 12 patients after combined repeated use of dabrafenib and a single application of midazolam (substrate isoenzyme CYP3A4) С_m_Oh and AUQ_(0-∞) midazolam decreased by 61% and 74%, respectively. In a separate clinical study In 14 patients with repeated use of dabrafenib, a decrease was observed AUC applied once S-warfarin (substrate CYP2C9) and R-warfarin (substrate CYP3A4/CYP1A2) by 37% and 33%, respectively, and a slight increase in C_max (18% and 19%, respectively). Although in vitro dabrafenib and its metabolites (hydroxydabrafenib, carboxydabrafenib and desmethydabrafenib) showed the properties of inhibitors of human polypeptide carriers of organic anions OATP1B1, OATP1B3, as well as carriers of organic anions OAT1 and OATS, based on the data obtained during clinical trials, the risk of drug interactions is minimal. In vitro Dabrafenib and desmethyldabrafenib are mild inhibitors BCRP, However, based on the data obtained in clinical trials, the risk of interactions with medications is minimal. Neither dubrafenib, nor its three metabolites have an inhibitory effect on P-glycoprotein in vitro.

Indications:Treatment of patients with unresectable or metastatic melanoma with a gene mutation BRAF V600.

Contraindications:

Pregnancy and the period of breastfeeding;
children's age till 18 years.

Carefully:

Dabrafenib should be used with caution in patients with moderate to severe hepatic impairment,severe degree of impaired renal function.

Pregnancy and lactation:

Fertility

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.

Pregnancy

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 occurred during the period of taking the drug Rapinlar, the patient should be informed of the potential risk to the fetus.

Breastfeeding period

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. It should be decided whether to stop breastfeeding or stop the therapy with the drugRafinlar, taking into account the importance of taking the drug for the mother.

Dosing and Administration:

Inside.

Confirmation of gene mutation BRAF V600 with an approved or validated test is necessary for the selection of patients for dabrafenib therapy. Efficacy and safety of Tafinlar in the treatment of melanoma with a gene mutation BRAF wild type not established. The drug Tafinlar should not be used in the treatment of melanoma with wild type BRAF.

Adults

The recommended dose is 150 mg twice a day (corresponding to a total daily dose of 300 mg). The drug Tafinlar should be taken not later than 1 hour before meals, or not earlier than 2 hours after eating, observing a 12-hour interval between doses. The drug Tafinlar should be taken every day at the same time. 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, interruption in treatment, a reduction in dose, or discontinuation of treatment may be required (see Tables 1 and 2). Modification of the dose or interruption of treatment is not recommended at such adverse reactions as squamous cell carcinoma of the skin or a new case of primary melanoma. Treatment should be discontinued if the patient's body temperature increases > 38.5 ° 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. The recommended dose reduction scheme for Tafinlar

Dose change	Dose / intake schedule
First dose reduction	100 mg orally 2 times a day
Second dose reduction	75 mg orally 2 times a day
Third dose reduction	50 mg orally 2 times a day
In case of intolerance 50 mg 2 times a day	cancellation of the drug Tafinlar

Table 2. Recommended scheme for modifying the dose of Tafinlar

Severity of unwanted reaction¹	Modification of the dose²
PYRETIC REACTIONS
- Fever from 37.3 to 40 ° C	Pause
- Fever from 37.3 to 40 ° C	the use of Tafinlar drug before resolving the undesirable reaction, then resume the use of the drug Tafinlar in the same or reduced dosage.
- Fever over 40 ° С - Fever complicated by tremors, lowering of arterial pressure, dehydration or renal insufficiency	- Pause drug administration before resolving the undesirable reaction, then resume the use of the drug Tafinlar in a reduced dose. Or - Completely stop application of Tafinlar.
*Skin Reactions*
- Intolerable skin toxicity 2 degrees - Skin Toxicity 3 or 4	Suspend the drug Tafinlar for up to 3 weeks. - In case of improvement, resumption of Tafinlar drug in a smaller dose. If there is no improvement, stop using Tafinlar completely.
*Reactions from the heart*
- Asymptomatic, absolute reduction of the left ventricular ejection fraction by 10% or more in comparison with the baseline level determined before the start of treatment, and below the established lower limit of the norm (NGN)	Do not modify the dose of Tafinlar.
- Congestive heart failure, accompanied by characteristic symptoms - Absolute reduction of the left ventricular ejection fraction by more than 20% of the baseline level, which is lower than that established in the institution of NGV	Suspend the use of the drug Tafinlar.In case of improvement, resumption of the drug Tafinlar in the same dose.
*Thromboembolism of veins*
- Uncomplicated deep vein thrombosis or pulmonary embolism	Do not modify the dose of Tafinlar.
- Life-threatening pulmonary embolism	Completely stop the use of the drug Tafinlar.
*Reactions from the side of the organ of vision*
- Detachment of retinal pigment epithelium of 2-3 degree	Do not modify the dose of Tafinlar.
- Retinal vein occlusion	Do not modify the dose of Tafinlar.
- Uveitis or iritis	Suspend Tafinlar for up to 6 weeks. - In case of resolving the undesirable reaction to 0-1 degree - resume the use of the drug Tafinlar in the same dose. - If there is no improvement, stop using Tafinlar completely.
*Reactions from the side of the lungs*
- Interstitial lung disease / pneumonitis	Do not modify the dose of Tafinlar.
*Other reactions*
- Intolerable adverse reactions of the 2nd degree - Any undesirable reactions of the 3rd degree	Suspend the use of the drug Tafinlar. - In case of resolving the undesirable reaction to 0-1 degree - resume the use of the drug Tafinlar in a smaller dose. - If there is no improvement, stop using Tafinlar completely.
- The first occurrence of any unwanted reactions of the 4th degree	- Suspend the use of the drug Tafinlar before resolving the undesirable reaction to 0-1 degree, then resume the use of the drug Tafinlar in a smaller dose. Or - Completely stop the use of the drug Tafinlar.
- Repeated adverse reactions of the 4th degree	Completely stop the use of the drug Tafinlar.

¹ - severity of unwanted reactions is assessed according to the Standard Criteria for the Evaluation of Unwanted Reactions (STS-AE), version 4.0.

²- see Table 1. Recommended scheme for dose reduction of the drug Tafinlar.

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 as the reduction, but in the reverse order. Dose drug Tafinlar should not exceed 150 mg 2 times a day.

Hyperthermia

Treatment should be discontinued if the patient's body temperature> 38.5 ° C, and start using antipyretic drugs, such as ibuprofen (preferably) or acetaminophen / paracetamol.Patients should be evaluated for signs and symptoms of infection. The administration of Tafinlar can be resumed after the normalization of body temperature in conjunction with appropriate prevention of antipyretic drugs:

- in the same dose;

- or in a reduced dose if hyperthermia recurs and / or is accompanied by other severe symptoms, such as dehydration, hypotension or kidney failure.

In case of insufficient effect when using antipyretic drugs, the possibility of using oral glucocorticosteroids should be considered.

Special patient groups

Children

The effectiveness and safety of the drug Tafinlar in children and adolescents (under the age of 18 years) is not established.

Elderly patients

In patients older than 65 years, no dose adjustment is required.

Patients with impaired renal function

In patients with mild to moderate dysfunction of kidney correction dose not required. According to population pharmacokinetic analysis, light and medium degree 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 Tafinlar with a severe degree of renal dysfunction are absent, and the need for dose adjustment is not established. Caution should be used drug Tafinlar with a severe degree of impaired renal function.

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 Tafinlar 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. Use with caution the drug Tafinlar with moderate or severe degree of dysfunction.

Side effects:

Combined security data dabrafenaba were obtained on the basis of five clinical studies (monotherapy with dabrafenib), which included 578 patients with melanoma.

Approximately 30% of patients received dubrafenib more than 6 months. AT of the general population for evaluating the safety of dabrafenib, the most frequent (> 15%) adverse reactions were hyperkeratosis, headache, fever, arthralgia, fatigue, nausea, dermal papillomas, alopecia, rash and vomiting. 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: Often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), 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)

Often:	papilloma.
Often:	acrochordon (papilloma), 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
Infrequently:	hypersensitivity, panniculitis.
Infectious and parasitic diseases
Often:	nasopharyngitis.
Disorders from the metabolism and nutrition
Often: Often:	decreased appetite. hypophosphatemia, hyperglycemia.
Disturbances from the nervous system
Often:	headache.
Disturbances on the part of the organ of sight
Often:	irit.
Infrequently:	uveitis (inflammation of the choroid of the eyeball).
Disturbances from the respiratory system, chest and mediastinal organs
Often:	cough.
Disorders from the gastrointestinal tract
Often: Often:	nausea, vomiting, diarrhea. constipation.
Infrequently:	pancreatitis.
Disturbances from the skin and subcutaneous tissues
Often:	disorders of the skin (rash, hyperkeratosis), alopecia, syndrome of palmar-plantar erythrodysesthesia.
Often:	disorders of the skin (actinic keratosis, skin damage, dry skin, erythema, pruritus).
Disturbances from musculoskeletal and connective tissue
Often:	arthralgia, myalgia, pain in the extremities, back pain.
Disorders from the kidneys and urinary tract
Infrequently:	renal failure, acute renal failure.
Rarely:	tubulointerstitial nephritis.
General disorders and disorders at the site of administration
Often:	asthenia, chills, fatigue, hyperthermia.
Often:	influenza-like syndrome.
Laboratory and instrumental data
Often:	increased activity of alkaline phosphatase.
Often:	hyponatremia.

Description of individual adverse reactions

Interval lengthening QT In the combined population, in assessing safety, one patient had an interval length QTcB > 500 msec, and only 3% of patients the maximum recorded elongation of the interval QTc exceeded 60 msec.

Decreased LVEF

Reduction of the left ventricular ejection fraction (LVEF) was registered in 1% of patients, with the majority of cases being asymptomatic and reversible. Patients with LVEF below the lower limit of the standard accepted in the institution were not included in clinical studies using dabrafenib.

Overdose:

Symptoms

To date, data on the overdose of dabrafenib are extremely few. The maximum dose of dabrafenib administered to patients in clinical trials was 600 mg (300 mg twice daily).

Treatment

Specific treatment (antidote) with an overdose of dabrafenib is absent. If unwanted reactions develop, symptomatic therapy should be given. If you suspect an overdose, immediately cancel dubrafenib and begin supporting therapy. In the future, management of patients should be adjusted in accordance with the clinical picture or recommendations of the national toxicology center (if possible).

Interaction:

The effect of other drugs on dubrafenib

In preclinical studies in vitro it was demonstrated that dubrafenib is metabolized predominantly by isoenzymes CYP2C8 and CYP3A4. Joint administration of ketoconazole (inhibitor CYP3A4) and gemfibrozil (inhibitor CYP2C8) increases AUC dubrafeniba on 71% and 47%, respectively. Medicinal products drugs, which are potent inhibitors or inducers CYP2C8 or CYP3A4, are capable of increasing or decreasing the concentrations of dabrafenib, respectively. Therefore, during therapy with dabrafenib, alternative drugs should be used, if possible. Care should be taken when using powerful inhibitors (for example, ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil, saquinavir, itraconazole, voriconazole, posaconazole, atazanavir, telithromycin) or inductors (for example: rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted) CYP2C8 or CYP3A4 together with dabrafenib.

Drugs that affect the pH of gastric juice

Drugs that alter the pH of the upper gastrointestinal tract (eg proton pump inhibitors, H2 receptor antagonists, antacids) can alter the solubility of dabrafenib and reduce its bioavailability. However, clinical studies to evaluate the effect of drugs that change the pH of gastric juice, on the systemic exposure of dabrafenib was not conducted. With simultaneous application dabrafeniba and proton pump inhibitor, H2 receptor antagonist, or antacid, the systemic exposure of dabrafenib may be reduced, and the effect on efficacy dabrafeniba in this case is not established.

Effect of dabrafenib on transport system substances

In vitro dabrafenib is an inhibitor human polypeptide carriers of organic anions OATP1B1 and OATP1B3, and the clinical significance of this phenomenon can not be ruled out.For this reason, caution should be exercised while the use dabrafeniba and substrates or OATV1V1 OATR1VZ such as statins. Although in vitro dabrafenib and its metabolites (gidroksidabrafenib, and karboksidabrafenib dezmetildabrafenib) exhibit properties of human organic anion transporter OAT1 inhibitors and OATZ based on data obtained in clinical studies, the risk of drug interaction is minimal. It was also shown that dubrafenib and dezmetildabrafenib are moderate inhibitors of human protein resistant breast cancer; However, given the clinical exposure, the risk of drug interactions is minimal.

Effect of dabrafenib on other drugs

Dabrafenib strengthens CYP3A4 and CYP2C9-mediated metabolism and may increase the activity of other enzymes, including isozymes CYP2B6, CYP2C8 and CYP2C19 and UDP-glucuronosyltransferase, and can also increase the activity of transporters (e.g., P-glycoprotein (P-gp)). When sharing from dubrafenib AUC midazolam (substrate CYP3A4) and S-warfarin (substrate CYP2C9) decreases. Combined use of dabrafenib and drug drugs, sensitive to induction of these enzymes (eg, hormonal contraceptives, warfarin or dexamethasone), can lead to a decrease in their concentration and loss of efficacy. If the use of such drugs is necessary, one should monitor their effectiveness or consider the use of alternative medicinal products. preparations. It is expected that the number of affected medicines will be large; However, the intensity of the interaction can be different. Groups of affected medications may include, but are not limited to, the following:

- analgesics (for example, fentanyl, methadone);

- antibiotics (for example, clarithromycin, doxycycline);

- antineoplastic agents (eg, cabazitaxel);

- anticoagulants (for example, acenocoumarol, warfarin);

- antiepileptic drugs (for example, carbamazepine, phenytoin, primidon, valproic acid);

- antipsychotics (eg, haloperidol);

- calcium channel blockers (eg, diltiazem, felodipine, nicardipine, verapamil);

- cardiac glycosides (for example, digoxin);

- glucocorticosteroids (for example, dexamethasone, methylprednisolone);

- antiviral drugs for the treatment of HIV infection (for example, amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir);

- hormonal contraceptives;

- hypnotics (for example, diazepam, midazolam, zolpidem);

- immunosuppressants (eg, ciclosporin, tacrolimus, sirolimus).

- statins metabolized CYP3A4 (e.g., atorvastatin, simvastatin).

Special instructions:

Women of reproductive age should use highly effective nonhormonal methods of contraception during treatment and within 2 weeks after the abolition of therapy, as dubrafenib can reduce the effectiveness of hormonal contraceptives. Patients should be notified to the treating doctor about a pregnancy or pregnancy suspected during treatment with dabrafenib.

Hyperthermia

Episodes of fever were noted in clinical studies when dabrafenib is used. Hyperthermia can be accompanied by severe chills, dehydration and hypotension, which in some cases may cause to acute renal failure. During and after severe episodes of hyperthermia, serum creatinine concentration and other renal function should be monitored. There were severe cases fever not associated with infectious diseases, which usually developed during the first month of treatment. In clinical trials effective interventions for this adverse reaction were interruption in treatment and / or dose reduction dabrafenib, and supportive therapy.

Squamous cell carcinoma of the skin (PRK)

There are reports of cases of squamous cell carcinoma of the skin (including keratoacantham and mixed keratoacanthoma) in patients taking dubrafenib. With the use of dabrafenib, about 70% of the phenomena developed during the first 12 weeks of treatment, with a median time before the onset of the phenomenon was 8 weeks. More than 90% of patients who received dubrafenib, in whom PRK developed, continued treatment without modifying the dose. Before starting treatment and during therapy with dabrafenib, the skin should be monitored regularly: every 2 months throughout the course of treatment.Follow-up examinations should be performed every 2-3 months for 6 months after stopping treatment with dabrafenib or before starting another antitumor therapy. When squamous cell carcinoma develops, resection of the affected area of the skin should be performed and dabrafenib therapy should be continued without dose adjustment. Patients should be warned that when new skin lesions appear on the skin, immediately inform your doctor about this.

New cases of primary melanoma

There are reports of new cases of primary melanoma in patients taking dubrafenib. These cases were detected during the first 5 months of therapy and did not require modification of treatment, except resection of the affected area. Regular monitoring of skin condition is necessary (according to the scheme described for squamous cell carcinoma of the skin).

Secondary / recurrent malignant lesions of other sites

In experiments in vitro Paradoxical activation of the MAP kinase signaling cascade in cells was observed with a wild type BRAF, from RAS a mutation and exposed to inhibitors BRAF, which can lead to an increase risk of development of malignant tumors of other localization in patients receiving dubrafenib. When using inhibitors BRAF cases of development of malignant tumors carrying a mutation RAS. It is necessary to ensure that patients are monitored in accordance with clinical indications. After cessation of treatment with dabrafenib, it is necessary to continue monitoring for the development of secondary / recurrent malignant neoplasms of other location up to 6 months or until the beginning of other antitumor therapy.

Pancreatitis

There have been reports of pancreatitis in less than 1% of patients receiving dubrafenib. One case of development of pancreatitis on the first day of treatment with dabrafenib and recurrence of an episode of pancreatitis after resumption of dabrafenib in a reduced dose is described. It is necessary to urgently examine patients with unexplained abdominal pain; The examination should include the determination of the activity of amylase and lipase in the serum. Patients should be closely monitored when resuming dabrafenib treatment after an episode of pancreatitis.

Uveitis (inflammation of the choroid of the eyeball)

In the treatment with dabrafenib, there was a development of uveitis, including iritis (inflammation of the iris of the eye). During therapy, control of ophthalmic symptoms, such as vision changes, photophobia, pain in the eye area, is necessary.

Interval lengthening QT

The maximum recorded elongation interval QTc, exceeding 60 msec, was observed in 3% of patients treated with dabrafenib (in the generalized population, according to the safety assessment, in one patient the length QTc was> 500 msec). Treatment with dabrafenib is not recommended for patients with uncorrectable violations of the balance of electrolytes (including magnesium), the syndrome of lengthening the interval QT, as well as patients taking medications that can lengthen the interval QT.

Monitoring parameters of the electrocardiogram (ECG) and electrolytes (including magnesium) should be performed in all patients before treatment with dabrafenib, one month after the start of treatment and after a dose change. Further develop hyperglycemia. In a clinical study, 5 out of 12 patients with a history of diabetes mellitus dabrafeniba there was a need to increase the intensity of hypoglycemic therapy. The frequency of development of hyperglycemia of grade 3, based on laboratory research, was 6% (12/187) in patients who received dubrafenib, in contrast to patients who received dacarbazine, in which such cases are not registered. In the treatment dubrafenib patients with previously diagnosed diabetes mellitus or hyperglycemia should be monitored concentrations glucose in serum, usually used in clinical practice. Patients are advised to inform the treating physician of symptoms of severe hyperglycemia, such as excessive thirst or increased volume and frequency of urination.

Deficiency of glucose-6-phosphate dehydrogenase

Dabrafenib, containing sulfonamide group, increases the potential risk of hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase (G6PDG).

It is necessary to conduct careful medical control of patients with G6PDH deficiency for signs of hemolytic anemia.

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of dabrafenib on the ability to drive vehicles or work with mechanisms have not been carried out. The pharmacological properties of dabrafenib indicate that there is no adverse effect on this type of activity. Assessing the ability to perform actions that require rapid decision making, special motor and cognitive skills, it is necessary to take into account the general condition of the patient and the profile of undesirable reactions of dabrafenib.

Form release / dosage:

Capsules 50 mg, 75 mg.

Packaging:For 28, 120 capsules in a bottle of high-density opaque white polyethylene with a desiccant, closed with a polypropylene lid with a device for opening against children and equipped with a membrane. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002274

Date of registration:11.10.2013

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

GlaxoSmithKline Trading, ZAO Russia

Representation: & nbspGlaxoSmithKline group of companies GlaxoSmithKline group of companies Unknown

Information update date: & nbsp09.01.2015

Illustrated instructions

Instructions

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