Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Approved indication: cutaneous T cell lymphoma
Zolinza (Merck Sharp & Dohme)
capsules containing 100 mg
Australian Medicines Handbook section 14.2.3
Serious adverse events occurred in 14 patients and included dehydration, thrombocytopenia, vomiting, anaemia, hypotension, infection, nausea, pulmonary embolism, fever and sepsis. The INR was increased in some patients on warfarin and decreased in others. Two patients died during the study – one as a consequence of disease progression and the other from untreated sepsis. Overall, the incidence of drug-related serious adverse events and discontinuations was lowest in patients who took vorinostat 400 mg once daily.1
In another non-randomised open-label phase II trial, 74 patients with advanced refractory disease received oral vorinostat 400 mg daily. Average treatment duration was 5.3 months. Overall 30% of patients partially responded to vorinostat. One patient was completely clear of skin disease after 281 days of treatment. Around a third of patients reported they had experienced relief from pruritus. The median time to response was 55 days (28 to 171 days). The median duration of response end point was not reached but was estimated to be at least 185 days (34 to 441 days). The overall time to progression was 148 days. Survival of patients was not reported.2 At study completion, 58 of the 74 patients had discontinued treatment − 49 of these withdrawals were due to lack of efficacy or progressive disease and nine were due to an adverse event.
The most common drug-related adverse events in the trial were diarrhoea (48.6% of patients), fatigue (45.9%), nausea (43.2%), anorexia (25.7%), taste disturbance (24.3%), thrombocytopenia (21.6%), weight decrease (20.3%), alopecia (17.6%), muscle spasms (16.2%), blood creatinine increase (14.9%), anaemia (12.2%), chills (12.2%), vomiting (12.2%), constipation (10.8%) and dry mouth (10.8%). Most of these were mild to moderate, but some such as fatigue, thrombocytopenia, nausea, anorexia and muscle spasms were more severe. Drug-related serious adverse events occurred in eight of the 74 patients. These included pulmonary embolism, deep vein thrombosis, anaemia, blood creatinine increase, dehydration, gastrointestinal haemorrhage, ischaemic stroke, streptococcal bacteraemia, syncope and thrombocytopenia. There were three deaths in the trial – one from disease progression (day 52), one secondary to a stroke (day 227) and one of unknown cause (day 2).2
One of three patients taking warfarin in the trial required a dose reduction to maintain target INR. ECG changes were observed in 15 patients, including three patients with a prolonged QTc interval.2
As thromboembolic events have been reported with vorinostat, doctors should be vigilant for the signs and symptoms, particularly in patients with a history of pulmonary embolism and deep vein thrombosis. Dose-related thrombocytopenia and anaemia can also occur so platelet counts and haemoglobin should be monitored. Dose reduction or discontinuation of treatment may be needed. Prothrombin time and INR were altered in some patients taking warfarin with vorinostat and should be monitored closely.
Increased serum glucose was found in two-thirds of patients taking vorinostat. Transient increases in serum creatinine were also detected in almost half of patients. Occasionally these increases were severe. Fortnightly chemistry tests, including electrolytes, glucose and serum creatinine, are recommended for the first two months of treatment, then monthly after that.
Nausea, vomiting and diarrhoea are not uncommon with vorinostat. These can lead to dehydration and patients should be advised to drink at least 2 L water a day. Treatments for nausea, vomiting and diarrhoea may be required. Vorinostat should not be given with other drugs that inhibit histone deacetylases, for example valproic acid, as adverse effects may be cumulative. Severe thrombocytopenia with gastrointestinal bleeding and anaemia has been reported with concomitant valproic acid use.
Following an oral dose of 400 mg with a high-fat meal, peak serum concentrations of vorinostat were reached after a median of 4 hours (2–10 hours). Absorption is lower in the fasted state so vorinostat should be given with food. Vorinostat is extensively metabolised but only 1% of metabolites are excreted renally. It is contraindicated in severe hepatic impairment and is not recommended for people with moderate hepatic impairment.
Vorinostat seems to have some benefit for up to a third of patients given the 400 mg daily dose, either by reducing the amount of skin affected or relieving symptoms of pruritus. However, vorinostat is associated with serious adverse effects and it is not known if it actually extends the life of patients.1,2
Although vorinostat has been approved in the USA since 2006, an application for its approval in Europe was withdrawn by the sponsor in 2008. This appeared to be in response to queries from the European Medicines Agency (EMA), which was concerned that the trials were non-randomised and that there was no comparator to vorinostat. In the absence of a randomised controlled trial, it is difficult to quantify the risk of thromboembolism with vorinostat, and the EMA concluded that the risks may outweigh the benefits. They were also concerned that there were no survival data from the trials.
The Transparency Score () is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
- Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:31-9 .
- Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109-15.