Consumer medicine information

Zolinza

Vorinostat

BRAND INFORMATION

Brand name

Zolinza

Active ingredient

Vorinostat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zolinza.

What is in this leaflet

This leaflet answers some common questions about ZOLINZA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ZOLINZA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ZOLINZA is used for

ZOLINZA contains an active ingredient called vorinostat.

ZOLINZA is a new type of anti-neoplastic (anti-cancer) medicine known as a histone deacetylase (HDAC) inhibitor.

ZOLINZA is a medicine used for the treatment of a type of cancer called cutaneous T-cell lymphoma, also called CTCL.

CTCL is a disease in which certain cells of the lymph system develop into cancer cells and affect your skin. The cells are called T-cells. They are the white blood cells which help to fight infection. CTCL usually develops slowly. Patches can first form on the skin and may develop into tumours in the skin. The cancer can continue to spread to large areas of the skin and to other organs of the body.

ZOLINZA works by slowing or stopping the growth of these cancer cells. ZOLINZA has also been shown to cause the death of cancer cells.

There are many different types of medicines used to treat CTCL.

Your doctor may have prescribed ZOLINZA for another purpose.

Ask your doctor if you have any questions about why ZOLINZA has been prescribed for you.

ZOLINZA is not addictive.

Safety and effectiveness in children and adolescents has not been established.

This medicine is available only with a doctor's prescription.

Before you take ZOLINZA

When you must not take it

Do not take ZOLINZA if:

  • you have an allergy to ZOLINZA or any of the ingredients listed at the end of this leaflet
  • you have severe liver disease
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking ZOLINZA, talk to your doctor.

Before you start to take ZOLINZA

Tell your doctor if:

  1. you have or have had any medical conditions, especially the following:
  • a blood clot in your lung (pulmonary embolus)
  • a blood clot in a vein (blood vessel) anywhere in your body (deep vein thrombosis)
  • diabetes
  • liver disease
  1. you currently have nausea, diarrhoea or vomiting
  2. you are pregnant or plan to become pregnant
    ZOLINZA may harm your unborn baby. Your doctor will discuss the possible risks and benefits of using ZOLINZA during pregnancy.
  3. you are breast feeding or plan to breast feed
    It is not known if ZOLINZA passes into breast milk. You should stop breast feeding once you start treatment with ZOLINZA.
  4. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell him/her before you start taking ZOLINZA.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and ZOLINZA may interfere with each other. These include:

  • Warfarin, or any other blood thinner, used to prevent blood clots
  • Other HDAC inhibitors, including sodium valproate

These medicines may be affected by ZOLINZA, may affect how well it works, or may increase the risk of side effects ZOLINZA. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ZOLINZA.

How to take ZOLINZA

How much to take

Take ZOLINZA only when prescribed by your doctor.

The recommended dose 400 mg once each day. Take all 4 capsules (100 mg each) by mouth once a day.

Your doctor may lower your dose, depending on your response

How to take it

Swallow each ZOLINZA capsule whole with a glass of water. Do not chew or break open the capsules.

Take ZOLINZA with food or immediately after food.

Follow directions given to you by your doctor carefully. They may differ from the information contained in the leaflet.

Ask your doctor or pharmacist for help if you do not understand the instructions on the bottle label.

If you forget to take it

If you miss a dose, take it as soon as you remember.

If it is almost time to your next dose, skip the dose you missed and take your next dose when you are meant to. Do not take a double dose of ZOLINZA.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

If you have trouble remembering to take your capsules, ask your pharmacist for some hints.

How long to take it

Continue to take ZOLINZA as long as your doctor prescribes it.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, if you think that you or anyone else may have taken too much ZOLINZA. Do this even if there are no signs of discomfort or poisoning.

While you are using ZOLINZA

Things you must do

Drink plenty of fluids while taking ZOLINZA. You should drink at least eight (8) full glasses of liquids every day (2 litres). Having enough fluids may help to reduce the chances of dehydration.

Tell all, doctors, dentists, and pharmacists who are treating you that you are taking ZOLINZA.

Tell your doctor immediately if you develop the following:

  • Leg swelling, chest pain, or shortness of breath, which are signs of possible serious side effects
  • excessive vomiting or diarrhoea

If you are diabetic, tell your doctor immediately if your blood sugar level is high. ZOLINZA may increase blood sugar levels in some diabetics. Your doctor may need to adjust your diet and/or the dose of your diabetes medicine.

Tell your doctor if you feel that ZOLINZA is not helping your condition.

Be sure to keep all of your appointments with your doctor so that your progress can be checked. Your doctor may need to perform regular tests.

Things you must not do

  • Do not give ZOLINZA to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how ZOLINZA affects you. There is no information to suggest that ZOLINZA affects your ability to drive a car or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ZOLINZA. ZOLINZA helps most people with CTCL, but it may have unwanted side effects. All medicines can have side effects. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Stomach problems including diarrhoea, nausea, vomiting, loss of appetite, constipation, and weight loss
  • tiredness
  • low blood cell counts (symptoms include; pale appearance, shortness of breath, unusual bleeding, bruising or bleeding under the skin)
  • dehydration
  • changes in the way things taste, dry mouth
  • muscle aches
  • chills
  • high sugar levels in the blood (symptoms include; passing urine more often than is normal for you, excessive thirst, blurred vision)
  • hair loss

These are the more common side effects of ZOLINZA. Mostly these are mild.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • stroke (symptoms include: numbness or weakness of the arms or legs, headache, dizziness, confusion, difficulty swallowing, slurred or loss of speech)
  • fainting
  • infections of the blood
  • chest pain
  • low blood pressure
  • blood clots in the legs, arms or lungs
  • fever

These are serious side effects. You may need urgent medical attention. Serious side effects have been reported less frequently.

This is not a complete list of all possible side effects. Others side effects may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even it is not on this list.

Tell your doctor if you notice anything else that is making you feel unwell, even it is not on this list.

Ask your doctor or pharmacist if you do not understand anything on this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using ZOLINZA

Storage

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep ZOLINZA in a cool dry place where the temperature stays below 30°C. Do not store ZOLINZA or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not touch ZOLINZA capsules if they are broken or crushed, do not touch the contents of the capsule. If the contents of a broken capsule get on the skin or in the eyes, wash thoroughly.

Disposal

If your doctor tells you to stop taking the capsules, or the capsules have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ZOLINZA comes as a white capsule with "568" over "100 mg" printed black ink on the capsule body.

Ingredients

Active ingredient:

  • vorinostat 100 mg per capsule

Inactive ingredients:

  • microcrystalline cellulose
  • croscarmellose sodium
  • magnesium stearate
  • Empty Hard Gelatin Capsules Part #G3ICSRR0591 Size 3 White Opaque
  • OPACODE monogramming ink S-1-17822 BLACK
  • OPACODE monogramming ink S-1-17823 BLACK.

ZOLINZA does not contain sucrose, tartrazine or any other azo dyes.

Supplier

ZOLINZA is supplied in Australia by:

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A
26 Talavera Road
Macquarie NSW 2113

This leaflet was prepared in 23 December 2020.

Australian Register Number:

AUST R 156430

RCN: 000018965-AU

Published by MIMS February 2021

BRAND INFORMATION

Brand name

Zolinza

Active ingredient

Vorinostat

Schedule

S4

 

1 Name of Medicine

Vorinostat.

2 Qualitative and Quantitative Composition

Each 100 mg Zolinza capsule for oral administration contains 100 mg vorinostat.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zolinza (vorinostat) capsules, 100 mg, are white, opaque hard gelatin capsules with "568" over "100 mg" printed within the radial bar in black ink on the capsule body.

4 Clinical Particulars

4.1 Therapeutic Indications

Zolinza is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease subsequent to prior systemic therapies.

4.2 Dose and Method of Administration

Dosage.

The recommended dose is 400 mg orally once daily with food.
If patients are intolerant to therapy, subsequent doses may be reduced to 300 mg orally once daily with food. The dose schedule may be further reduced to 300 mg once daily with food for 5 consecutive days each week, as necessary.
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
No dosage adjustment is necessary for the elderly (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).
In a phase I study to evaluate tolerability in non-CTCL cancer patients with hepatic impairment, the tolerated dose of Zolinza for those patients with mild and moderate hepatic dysfunction was 300 and 200 mg orally daily, respectively (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

4.3 Contraindications

Zolinza is contraindicated in patients who:
are hypersensitive to any component of this product;
have severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

Thromboembolism.

As pulmonary embolism and deep vein thrombosis have been reported as adverse experiences, physicians should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events (see Section 4.8 Adverse Effects (Undesirable Effects), Serious adverse experiences). Patients should be instructed about the signs of deep vein thrombosis and should consult their physician should any evidence of deep vein thrombosis develop.

Gastrointestinal.

Patients should be instructed to drink at least 2 L/day of fluid to prevent dehydration and should promptly report excessive vomiting or diarrhoea to their physician. Gastrointestinal disturbances, including nausea, vomiting and diarrhoea have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)) which may require the use of antiemetic and antidiarrhoeal medications. Fluid and electrolyte replacement should be administered to prevent dehydration (see Section 4.8 Adverse Effects (Undesirable Effects)). Pre-existing nausea, vomiting, and diarrhoea should be adequately controlled before beginning therapy with Zolinza.

Haematologic.

Treatment with Zolinza is associated with dose related thrombocytopenia and anaemia. If platelet counts and/or haemoglobin are severely reduced during treatment with Zolinza, the dose should be modified or therapy discontinued. (See Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration.) Patients receiving Zolinza should seek immediate medical attention if unusual bleeding occurs.

Hyperglycaemia.

Hyperglycaemia has been observed in patients receiving Zolinza (see Section 4.8 Adverse Effects (Undesirable Effects), Laboratory tests). Serum glucose should be monitored, especially in diabetic or potentially diabetic patients. Adjustment of diet and/or antihyperglycaemic therapy may be necessary.

Use in hepatic impairment.

Zolinza was studied in 42 non-CTCL cancer patients with hepatic impairment. Based on these results, Zolinza should be used with caution in patients with mild and moderate hepatic impairment, and is contraindicated in severe hepatic impairment (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic insufficiency).

Use in the elderly.

In clinical studies, the efficacy and safety of Zolinza in the elderly (≥ 65 years) were comparable to those seen in younger patients (< 65 years). No dosage adjustment is necessary in elderly patients.

Paediatric use.

The safety and effectiveness of Zolinza in paediatric patients have not been studied.

Effects on laboratory tests.

Careful monitoring of blood cell counts and chemistry tests, including electrolytes, glucose and serum creatinine should be performed every 2 weeks during the first 2 months of therapy and monthly thereafter.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vorinostat inhibits CYP drug metabolizing enzymes in human liver microsomes only at high concentrations (IC50 > 75 microM). Gene expression and enzyme activity studies in human hepatocytes detected some potential for suppression of CYP2C9 and CYP3A4 activities by vorinostat at concentrations higher (≥ 10 microM) than clinically relevant concentrations. Thus, vorinostat is not expected to affect the pharmacokinetics of other agents. As vorinostat is not eliminated via the CYP pathways, it is anticipated that vorinostat will not be subject to drug-drug interactions when coadministered with drugs that are known CYP inhibitors or inducers. However, no formal clinical studies have been conducted to evaluate drug interactions with vorinostat.
In vitro studies indicate that vorinostat is not a substrate of human P-glycoprotein (P-gp). In addition, vorinostat has no inhibitory effect on human P-gp mediated transport of vinblastine (a marker P-gp substrate) at concentrations of up to 100 microM. Thus, vorinostat is not likely to inhibit P-gp at the pharmacologically relevant serum concentration of 2 microM (Cmax) in humans.

Coumarin derivative anticoagulants.

Prolongation of prothrombin time (PT) and international normalized ratio (INR) were observed infrequently in patients receiving Zolinza concomitantly with coumarin derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered Zolinza and coumarin derivatives.

Other HDAC inhibitors.

Zolinza should not be administered concomitantly with other HDAC inhibitors (e.g. valproic acid) as class specific adverse reactions may be additive. Severe (grade 4) thrombocytopenia with associated gastrointestinal bleeding and anaemia has been reported with the concomitant use of Zolinza and valproic acid.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects on the female reproductive system were observed in rats, and included dose dependent increases in the number of corpora lutea at all doses (15, 50 or 150 mg/kg/day) and increased resorptions and dead fetuses at 150 mg/kg/day. Serum vorinostat AUC at 15 and 150 mg/kg/day in rats, based on the free fraction of vorinostat, was 0.3 and 2 times the mean clinical AUC at 400 mg/day, respectively.
Male fertility was unaffected at oral doses up to 150 mg/kg/day in rats. Sperm count and motility, testicular weight or testicular and epididymal histomorphology were unaffected. Testicular degeneration was observed in dogs at 100 mg/kg/day PO for 4 weeks, with plasma AUC 0.6 times the clinical AUC. No testicular findings were seen in the 6 month repeat dose study in dogs at plasma AUC 0.5 times the clinical AUC or repeat dose studies in rats for 6 months at plasma AUC approximately 2 times the clinical AUC.
(Category D)
There are no adequate and well controlled studies in pregnant women using Zolinza. Women of childbearing potential should be advised to avoid pregnancy while on Zolinza. If Zolinza 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 foetus.
Vorinostat crossed the placenta in rats and rabbits. No foetal malformations were observed in rats at oral doses at up to 50 mg/kg/day (≤ 1 times the human exposure based on AUC). There were, however, treatment related developmental effects including decreased mean live foetal weights, incomplete ossifications (skull, thoracic vertebra and sternebra) and skeletal variations (cervical ribs, supernumerary ribs, 20 vertebrae and sacral arch variations) at 50 mg/kg/day. In rabbits, the incidence of gallbladder malformations was increased at all doses tested (20-150 mg/kg/day; < 0.1 to 0.6 times the human exposure). Additional findings in rabbits were reduced mean live foetal weights and an increased incidence of incomplete ossification of metacarpals at 150 mg/kg/day.
 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 Zolinza, women should be advised against breastfeeding while taking Zolinza.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The safety of Zolinza was evaluated in 111 CTCL patients in two clinical studies in which 86 patients received 400 mg once daily.
The most common drug related adverse experiences in patients on 400 mg once daily could be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhoea, nausea, anorexia, weight decreased, vomiting, constipation, decreased appetite), constitutional symptoms (fatigue, chills), haematologic abnormalities (thrombocytopenia, anaemia), and taste disorders (dysgeusia, dry mouth).
Table 1 summarizes the specific drug related adverse experiences by frequency and National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0) grade in the CTCL patients who received 400 mg once daily.
The adverse experience profile was generally similar in the remaining CTCL patients who received other doses. The frequencies of more severe thrombocytopenia, anaemia (see Section 4.4 Special Warnings and Precautions for Use, Haematologic) and fatigue were increased at doses higher than 400 mg once daily of Zolinza.

Serious adverse experiences.

The most common serious drug related adverse experiences in the 107 CTCL patients in two clinical studies (including all doses) were pulmonary embolism, reported in 4.7% (5/107) of patients, dehydration and thrombocytopenia each reported in 3.7% (4/107) and anaemia reported in 1.9% (2/107) of patients. There were single experiences of chest pain, death (of unknown cause), deep vein thrombosis, diarrhoea, gastrointestinal haemorrhage, hepatic ischaemia, hypotension, ischaemic stroke, nausea, pyrexia, streptococcal bacteraemia, syncope or vomiting.

Discontinuations.

Of the CTCL patients who received the 400 mg once daily dose, 10.5% (9/86) of patients discontinued Zolinza due to drug related adverse experiences. These adverse experiences included anaemia, angioneurotic oedema, asthenia, chest pain, death, deep vein thrombosis, ischaemic stroke, lethargy, pulmonary embolism and skin lesion.

Dose modifications.

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

Laboratory tests.

Laboratory abnormalities were reported in the 86 patients who received the 400 mg dose and one patient who received a 350 mg dose.
Increased serum glucose was detected by laboratory safety tests in 69% (60/87) of CTCL patients, but was severe (grade 3) in only 5 of these. Hyperglycaemia was reported as a drug related adverse experience in 4.7% (4/86) of CTCL patients who received the 400 mg once daily dose (see Section 4.4 Special Warnings and Precautions for Use, Hyperglycaemia).
Transient increases in serum creatinine were detected in 47.1% (41/87) of CTCL patients; in most cases these increases were nonsevere, however, grade III (severe) cases have been observed.
Proteinuria was detected as a laboratory abnormality (51.4%) in 38 of 74 patients tested. The clinical significance of this finding is unknown.

Dehydration.

Based on reports of dehydration as a serious drug related adverse experience in clinical trials, patients were instructed to drink at least 2 L/day of fluids for adequate hydration. After these precautions were implemented, the incidence of dehydration decreased (see Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal, Effects on laboratory tests).

Adverse experiences in non-CTCL patients.

In addition to the 111 CTCL patients, 312 patients received Zolinza for solid tumors or non-CTCL haematologic malignancies as monotherapy or in combination with other anticancer therapies. Drug related adverse experiences reported in non-CTCL patients were generally similar to those reported in CTCL patients. However, the frequencies of individual adverse experiences were higher in the non-CTCL population. Drug related serious adverse experiences reported in the non-CTCL population which were not observed in the CTCL population included single experiences of blurred vision, deafness, dysphagia, asthenia, abdominal pain, diverticulitis, hyponatraemia, nonsmall cell lung cancer, tumor hemorrhage, Guillain-Barre syndrome, renal failure, urinary retention, cough, hemoptysis, hypertension and vasculitis.
In some patients recovering from surgery of the bowel, anastomotic healing adverse experiences have been reported. Therefore, caution should be exercised in the use of Zolinza in the perioperative period when patients require bowel surgery.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific information is available on the treatment of overdosage of Zolinza.
In clinical studies, the highest total daily doses tested were 600 mg (once daily), 800 mg (400 mg twice daily) and 900 mg (300 mg three times daily). In four patients who took more than the recommended study dose (without exceeding the highest doses tested), no adverse experiences were reported.
The pharmacological effects may be prolonged after serum levels of active vorinostat are no longer present. It is not known if vorinostat is dialyzable.
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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacology and pharmacological actions.

Mechanism of action.

Vorinostat is an inhibitor of histone deacetylases HDAC1, HDAC2 and HDAC3 (class I) and HDAC6 (class II) (IC50 < 86 nanoM). These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. The antineoplastic effect of vorinostat is attributed to the inhibition of HDAC activity and subsequent accumulation of acetylated proteins, including histones. Vorinostat induces cell cycle arrest, differentiation or apoptosis of some transformed cells in vitro. The mechanisms of action for the antineoplastic effect of vorinostat have not been fully characterized.
In vivo, vorinostat demonstrates antineoplastic activity in a variety of rodent tumor models including xenograft models of human prostate, breast and colon carcinoma.

Cardiac electrophysiology.

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 microM.hr and 1.7 ± 0.67 microM 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 events 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.

Clinical trials.

In two open label clinical studies, patients with refractory CTCL have been evaluated to determine their response rate to oral Zolinza. One study assessed several dosing regimens, and the other was a single arm clinical study. In both studies, patients were treated until disease progression or intolerable toxicity.

Advanced cutaneous T-cell lymphoma.

In an open label, single arm, multicenter phase IIb nonrandomized study, 74 patients with advanced stage CTCL were treated with 400 mg once daily Zolinza. The primary endpoint was response rate of oral Zolinza in the treatment of skin disease in patients with advanced CTCL (stage IIB and higher) who have progressive, persistent, or recurrent disease on or following at least two systemic therapies. One of these therapies must have contained bexarotene unless the patient was intolerant of or not a candidate for bexarotene therapy. The population had been exposed to a median of three prior therapies (range 1 to 12). Extent of skin disease was quantitatively assessed by investigators using a modified Severity Weighted Assessment Tool (SWAT). The investigator measured the percentage total body surface area (% TBSA) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm as a "ruler". The total % TBSA for each lesion type was multiplied by a severity weighting factor (1 = patch, 2 = plaque and 4 = tumor) and summed to derive the SWAT score. Efficacy was measured as either a complete clinical response (CCR) defined as no evidence of disease, or partial response (PR) defined as a ≥ 50% decrease in SWAT skin assessment score compared to baseline. Response had to be maintained for at least 4 weeks to be considered either CCR or PR.
Secondary endpoints included relief of pruritus; response duration; time to progression; time to objective response; and safety and tolerability.
The overall objective response was 29.7% (22/74, 95% CI [19.7 to 41.5%]) in all patients treated with Zolinza. In patients with stage IIB and higher CTCL, the overall objective response was 29.5% (18/61). One patient with stage IIB CTCL achieved a CCR. Median time to response was 55 and 56 days (range 28 to 171 days), respectively, in the overall population and in patients with stage IIB and higher CTCL. Overall, the median time to response was less than 2 months; however, in rare cases it took up to 6 months for patients to achieve an objective response to Zolinza (see Table 2).
The median response duration was not reached since the majority of responses continued at the time of analysis, but was estimated to exceed 6 months for both the overall population and in patients with stage IIB and higher CTCL (see Table 2).
The median time to progression approached 5 months (148 days) for the overall population of 74 patients and exceeded 5 months (169 days) for patients with stage IIB and higher CTCL. However the median time to progression was not reached in patients who responded to Zolinza and is estimated to exceed 7.5 months (see Table 2).
In addition to the 22 patients who had demonstrated an objective response, 10 patients with stage IIB or higher CTCL and one patient with stage IB had experienced stable disease, defined as absence of disease progression or absence of response, for 24 weeks. Therefore, 44.6% (33/74) of all patients and 45.9% (28/61) of patients with stage IIB or higher CTCL demonstrated either objective response or 24 weeks of stable disease.
Improvement in skin disease, as measured by some (> 0%) reduction in SWAT at any time point during treatment with Zolinza, was attained in 81.1% (60/74) of all patients treated with Zolinza.
The degree of improvement over time for patients over the course of the study is summarized in Figure 1.
Additional clinical benefit from Zolinza included a ≥ 25% reduction in Sezary cells in 51.9% (14/27) of patients with Sezary syndrome. For patients with palpable clinically abnormal lymph nodes, 41.7% (10/24) patients had a ≥ 50% reduction in the sum of the products of the greatest diameters of their index lymph nodes. In addition, 56.3% (9/16) of the patients with T3 tumor disease had a ≥ 50% reduction in body surface area covered by tumor.
The response to Zolinza was similar whether or not patients responded to previous bexarotene therapy or other last systemic therapy. The treatment just prior to Zolinza, either bexarotene or other therapies, had no obvious impact on the subsequent efficacy of Zolinza. Response to any previous systemic therapy does not appear to be predictive of response to Zolinza. This suggests that CTCL is not cross resistant to Zolinza or to other available marketed and investigational therapies for CTCL.

Cutaneous T-cell lymphoma.

In an open label, nonrandomized phase II study, Zolinza was evaluated to determine the response rate of patients with CTCL who were refractory to or intolerant of at least one conventional treatment. In this study, 33 patients were assigned to one of 3 cohorts: cohort 1,400 mg once daily; cohort 2,300 mg twice daily 3 days/week; or cohort 3,300 mg twice daily for 14 days followed by a 7 day rest (induction). In cohort 3, if at least a partial response was not observed then patients were dosed with a maintenance regimen of 200 mg twice daily. The primary efficacy endpoint, objective response, was measured by the 7 point Physician's Global Assessment (PGA) scale. The investigator assessed improvement or worsening in overall disease compared to baseline based on overall clinical impression. Index and nonindex cutaneous lesions as well as cutaneous tumors, lymph nodes and all other disease manifestations were also assessed and included in the overall clinical impression. CCR required 100% clearing of all findings, and PR required at least 50% improvement in disease findings.
In all patients treated, the objective response was 24.2% (8/33) in the overall population, 25% (7/28) in patients with stage IIB or higher disease and 36.4% (4/11) in patients with Sezary syndrome. The overall response rates were 30.8%, 9.1% and 33.3% in cohort 1, cohort 2 and cohort 3, respectively. No CCR was observed.
Among the 8 patients who responded to study treatment, the median time to response was 83.5 days (range 25 to 153 days). The median response duration was 106 days (range 66 to 136 days). Median time to progression was 211.5 days (range 94 to 255 days).

5.2 Pharmacokinetic Properties

Absorption.

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 microM.hr, 1.2 ± 0.62 microM 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 microM.hr, 1.2 ± 0.35 microM 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 microM.hr, 1.2 ± 0.53 microM and 4 (0.5-14) hours, respectively.

Distribution.

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

Metabolism.

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 are approximately 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).

Excretion.

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 (t1/2) 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.

Special populations.

Based upon an exploratory analysis of limited data, gender, race, and age do not appear to have meaningful effects on the pharmacokinetics of vorinostat.

Paediatric.

Vorinostat was not evaluated in patients < 18 years of age.

Hepatic insufficiency.

Vorinostat is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild (total bilirubin > 1.0 x to 1.5 x ULN or total bilirubin ≤ ULN and AST > ULN) and moderate (total bilirubin 1.5 - ≤ 3 x ULN) degrees of hepatic impairment. In a phase I study of non-CTCL patients with mild and moderate hepatic impairment, the tolerated daily dose, for patients is 300 and 200 mg orally daily respectively, due to dose limiting toxicity of vorinostat.
In general, studies of vorinostat excluded patients with severe hepatic dysfunction. However, a limited number of patients with moderate hepatic dysfunction were enrolled in these studies. In a retrospective analysis of these clinical studies, a total of 48 out of 345 patients (13.9%) were identified as having potential liver function abnormality at enrollment. No clinically meaningful differences in hepatic adverse experiences were observed in patients with a history of hepatic abnormality compared to patients without a reported history of hepatic abnormality.

Renal insufficiency.

Vorinostat was not evaluated in patients with renal impairment. However, renal excretion does not play a role in the elimination of vorinostat.

5.3 Preclinical Safety Data

Genotoxicity.

Vorinostat induced gene mutations in the bacterial reverse mutation assays (Ames test), chromosome aberrations in vitro in Chinese hamster ovary (CHO) cells and chromosome damage in an in vivo micronucleus assay in mice. Vorinostat did not cause chromosome aberrations in human peripheral blood lymphocytes in vitro. Weight of evidence indicates vorinostat is a weakly genotoxic compound, except for chromosome damaging effects in CHO cells.

Carcinogenicity.

Carcinogenicity studies have not been performed with vorinostat.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 100 mg capsule contains microcrystalline cellulose, croscarmellose sodium and magnesium stearate. The capsule shell include Empty Hard Gelatin Capsules Part #G3ICSRR0591 Size 3 White Opaque, Opacode monogramming ink S-1-17822 Black and Opacode monogramming ink S-1-17823 Black.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store below 30°C (86°F).
Direct contact of the powder in Zolinza capsules with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Zolinza capsules should not be opened or crushed (see Section 5.3 Preclinical Safety Data, Genotoxicity).

6.5 Nature and Contents of Container

Zolinza (vorinostat) is available in bottles of 120 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zolinza (vorinostat) is a member of a new class of anti-neoplastic agents called histone deacetylase (HDAC) inhibitors. HDACs catalyze the removal of acetyl groups from the lysine residues of proteins, including histones.
Zolinza contains vorinostat, which is described chemically as N-hydroxy-N'-phenyloctanediamide.
Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride.
The empirical formula is C14H20N2O3. The molecular weight is 264.32.

Chemical structure.

The structural formula of vorinostat is:

CAS number.

The CAS Registry number is 149647-78-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes