золинза

Overdose

No specific information is available on the treatment of overdosage of Золинза.

In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known if vorinostat is dialyzable.

Contraindications

None.

Undesirable effects

The following serious adverse reactions have been associated with Золинза in clinical trials and are discussed in greater detail in other sections of the label.

Thromboembolism

Myelosuppression

Gastrointestinal Toxicity

Hyperglycemia

Clinical Chemistry Abnormalities

Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors

The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth). The most common serious drug-related adverse reactions were pulmonary embolism and anemia.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Золинза was evaluated in 107 CTCL patients in two single arm clinical studies in which 86 patients received 400 mg once daily.

The data described below reflect exposure to Золинза 400 mg once daily in the 86 patients for a median number of 97.5 days on therapy (range 2 to 480+ days). Seventeen (19.8%) patients were exposed beyond 24 weeks and 8 (9.3%) patients were exposed beyond 1 year. The population of CTCL patients studied was 37 to 83 years of age, 47.7% female, 52.3% male, and 81.4% white, 16.3% black, and 1.2% Asian or multi-racial.

Table 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0). Â

Table 1: Clinical or Laboratory Adverse Reactions Occurring in CTCL Patients (Incidence ≥ 10% of patients)

The frequencies of more severe thrombocytopenia, anemia and fatigue were increased at doses higher than 400 mg once daily of Золинза.

The most common serious adverse reactions in the 86 CTCL patients in two clinical trials were pulmonary embolism reported in 4.7% (4/86) of patients, squamous cell carcinoma reported in 3.5% (3/86) of patients and anemia reported in 2.3% (2/86) of patients. There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia and ureteric obstruction.

Of the CTCL patients who received the 400-mg once daily dose, 9.3% (8/86) of patients discontinued Золинза due to adverse reactions. These adverse reactions, regardless of causality, included anemia, angioneurotic edema, asthenia, chest pain, exfoliative dermatitis, death, deep vein thrombosis, ischemic stroke, lethargy, pulmonary embolism, and spinal cord injury.

Of the CTCL patients who received the 400-mg once daily dose, 10.5% (9/86) of patients required a dose modification of Золинза due to adverse reactions. These adverse reactions included increased serum creatinine, decreased appetite, hypokalemia, leukopenia, nausea, neutropenia, thrombocytopenia and vomiting. The median time to the first adverse reactions resulting in dose reduction was 42 days (range 17 to 263 days).

Laboratory abnormalities were reported in all of the 86 CTCL patients who received the 400-mg once-daily dose.

Increased serum glucose was reported as a laboratory abnormality in 69% (59/86) of CTCL patients who received the 400-mg once daily dose; only 4 of these abnormalities were severe (Grade 3). Increased serum glucose was reported as an adverse reaction in 8.1% (7/86) of CTCL patients who received the 400-mg once daily dose.

Transient increases in serum creatinine were detected in 46.5% (40/86) of CTCL patients who received the 400-mg once daily dose. Of these laboratory abnormalities, 34 were NCI CTCAE Grade 1, 5 were Grade 2, and 1 was Grade 3.

Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown.

Based on reports of dehydration as a serious drug-related adverse reaction in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration.

The frequencies of individual adverse reactions were substantially higher in the non-CTCL population. Drug-related serious adverse reactions reported in the non-CTCL population which were not observed in the CTCL population included single events of blurred vision, asthenia, hyponatremia, tumor hemorrhage, Guillain-Barré syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension, and vasculitis.

In patients recovering from bowel surgery and treated perioperatively with Золинза, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred.

Therapeutic indications

Золинза® is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.

Pharmacodynamic properties

A randomized, partially-blind, placebo-controlled, 2-period crossover study was performed to assess the effects of a single 800-mg dose of vorinostat on the QTc interval in 24 patients with advanced cancer. This study was conducted to assess the impact of vorinostat on ventricular repolarization. The upper bound of the 90% confidence interval of the placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec at every time point through 24 hours. Based on these study results, administration of a single supratherapeutic 800-mg dose of vorinostat does not appear to prolong the QTc interval in patients with advanced cancer; however the study did not include a positive control to demonstrate assay sensitivity. In the fasted state, oral administration of a single 800-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 8.6±5.7 μM•hr and 1.7±0.67 μM and 2.1 (0.5-6) hours, respectively.

In clinical studies in patients with CTCL, three of 86 CTCL patients exposed to 400 mg once daily had Grade 1 ( > 450-470 msec) or 2 ( > 470-500 msec or increase of > 60 msec above baseline) clinical adverse reactions of QTc prolongation. In a retrospective analysis of three Phase 1 and two Phase 2 studies, 116 patients had a baseline and at least one follow-up ECG. Four patients had Grade 2 ( > 470-500 msec or increase of > 60 msec above baseline) and 1 patient had Grade 3 ( > 500 msec) QTc prolongation. In 49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT interval, 2 had QTc measurements of > 500 msec and 1 had a QTc prolongation of > 60 msec.

Pharmacokinetic properties

The pharmacokinetics of vorinostat were evaluated in 23 patients with relapsed or refractory advanced cancer. After oral administration of a single 400-mg dose of vorinostat with a high-fat meal, the mean ± standard deviation area under the curve (AUC) and peak serum concentration (Cmax) and the median (range) time to maximum concentration (Tmax) were 5.5±1.8 μM•hr, 1.2±0.62 μM and 4 (2-10) hours, respectively.

In the fasted state, oral administration of a single 400-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 4.2±1.9 μM•hr and 1.2±0.35 μM and 1.5 (0.5-10) hours, respectively. Therefore, oral administration of vorinostat with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state. However, these small effects are not expected to be clinically meaningful. In clinical trials of patients with CTCL, vorinostat was taken with food.

At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0±2.0 μM•hr, 1.2±0.53 μM and 4 (0.5-14) hours, respectively.

Vorinostat is approximately 71% bound to human plasma proteins over the range of concentrations of 0.5 to 50 μg/mL.

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively.

In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).

Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was 16±5.8% of vorinostat dose as the O-glucuronide of vorinostat, and 36±8.6% of vorinostat dose as 4-anilino-4-oxobutanoic acid. Total urinary recovery of vorinostat and these two metabolites averaged 52±13.3% of vorinostat dose. The mean terminal half-life (t½) was ~2.0 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Pulmonary embolism occurred in 5% (4/86) of patients receiving Золинза, and deep vein thrombosis has also been reported. Monitor for signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events.

Treatment with Золинза can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with Золинза as clinically appropriate.

Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration. Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with Золинза.

Hyperglycemia has been observed in patients receiving Золинза and was severe in 5% (4/86) of patients. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter.

Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of Золинза. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).

Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of Золинза and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently..

Золинза can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Золинза in pregnant women. Results of animal studies indicate that vorinostat crosses the placenta and is found in fetal plasma at levels up to 50% of maternal concentrations. Doses up to 50 and 150 mg/kg/day were tested in rats and rabbits, respectively (~0.5 times the human exposure based on AUC0-24 hours). Treatment-related, developmental effects including decreased mean live fetal weights, incomplete ossifications of the skull, thoracic vertebra, sternebra, and skeletal variations (cervical ribs, supernumerary ribs, vertebral count and sacral arch variations) in rats at the highest dose of vorinostat tested. Reductions in mean live fetal weight and an elevated incidence of incomplete ossification of the metacarpals were seen in rabbits dosed at 150 mg/kg/day. The no observed effect levels (NOELs) for these findings were 15 and 50 mg/kg/day ( < 0.1 times the human exposure based on AUC) in rats and rabbits, respectively. A dose-related increase in the incidence of malformations of the gall bladder was noted in all drug treatment groups in rabbits versus the concurrent control. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

See FDA-Approved Patient Labeling (PATIENT INFORMATION)

Patients should be instructed to drink at least 2 L/day of fluid to prevent dehydration and should promptly report excessive vomiting or diarrhea to their physician. Patients should be instructed about the signs of deep vein thrombosis and should consult their physician should any evidence of deep vein thrombosis develop. Patients receiving Золинза should seek immediate medical attention if unusual bleeding occurs. Золинза capsules should not be opened or crushed.

Patients should be instructed to read the patient insert carefully.

Carcinogenicity studies have not been performed with vorinostat.

Vorinostat was mutagenic in vitro in the bacterial reverse mutation assays (Ames test), caused chromosomal aberrations in vitro in Chinese hamster ovary (CHO) cells and increased the incidence of micro-nucleated erythrocytes when administered to mice (Mouse Micronucleus Assay).

Effects on the female reproductive system were identified in the oral fertility study when females were dosed for 14 days prior to mating through gestational day 7. Doses of 15, 50 and 150 mg/kg/day to rats resulted in approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC. Dose dependent increases in corpora lutea were noted at ≥ 15 mg/kg/day, which resulted in increased peri-implantation losses were noted at ≥ 50 mg/kg/day. At 150 mg/kg/day, there were increases in the incidences of dead fetuses and in resorptions.

No effects on reproductive performance were observed in male rats dosed (20, 50, 150 mg/kg/day; approximate exposures of 0.15, 0.36 and 0.70 times the expected clinical exposure based on AUC), for 70 days prior to mating with untreated females.

Pregnancy Category D

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Золинза, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of Золинза in pediatric patients have not been established.

Of the total number of patients with CTCL in trials (N=107), 46 % were 65 years of age and over, while 15 % were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals should be considered, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Золинза was studied in 42 patients with non-CTCL cancer and varying degrees of hepatic impairment after single and multiple-dose administration. Compared to patients with normal liver function, AUC increases of 50 to 66% were observed in patients with hepatic impairment. The incidence of Grade 3 or 4 thrombocytopenia increased in patients with mild (bilirubin of 1 to 1.5 x ULN and AST < ULN, or bilirubin ≤ ULN and AST > ULN) and moderate (bilirubin 1.5 to ≤ 3 x ULN) hepatic impairment treated daily at doses of 300 and 200 mg respectively.

Patients with severe hepatic impairment (bilirubin > 3 x ULN) have not been treated at doses greater than 200 mg a day. Reduce the initial dose of Золинза in patients with bilirubin 1 to 3 x ULN or AST > ULN.

Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat. Patients with pre-existing renal impairment should be treated with caution.

Dosage (Posology) and method of administration

The recommended dose is 400 mg orally once daily with food.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Золинза capsules should not be opened or crushed.

If a patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. The dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week, as necessary.

Reduce the starting dose to 300 mg orally once daily with food in patients with mild to moderate hepatic impairment (bilirubin 1 to 3 x ULN or AST > ULN). There is insufficient evidence to recommend a starting dose for patients with severe hepatic impairment (bilirubin > 3 x ULN)..