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Votubia for treating the benign tumours caused by tuberous sclerosis: subependymal giant cell astrocytoma and renal angiomyolipoma

Votubia is a medicine that contains the active substance Everolimus. It is available as tablets ( 2.5, 5, 10 mg ). Votubia is used to treat the following benign tumours caused by the genetic disease tuberous sclerosis: a) subependymal giant cell astrocytoma ( SEGA ), a benign tumour of the brain, where it is used in adults and children aged three years and above whose brain tumour cannot be surgically removed, b) renal angiomyolipoma, a benign tumour of the kidneys, where it is used in adults who are at risk of complications but who do not require immediate surgery.

Because the number of patients with tuberous sclerosis is low, the disease is considered rare, and Votubia was designated an orphan medicine ( a medicine used in rare diseases ) on 4 August 2010.
Votubia is taken by mouth once a day at the same time every day, consistently either with or without food. For SEGA, the starting dose depends on the body surface area ( calculated using the patient’s height and weight ), but the doctor will adjust the dose based on the patient’s blood levels of the medicine and how well the patient tolerates the medicine. In patients with renal angiomyolipoma, the recommended dose is 10 mg once a day. In case patients experience severe side effects the doctor may need to reduce the dose or interrupt treatment temporarily.
Patients with mild or moderate impairment of liver function should be started at a lower dose. Votubia is not recommended for patients with SEGA and severe impairment of liver function. For patients with renal angiomyolipoma and severe impairment of liver function Votubia is only recommended if the desired benefit outweighs the risk.

The active substance in Votubia, Everolimus, is an anti-tumour medicine that acts by blocking an enzyme called mammalian target of rapamycin ( mTOR ), which has increased activity in tumour cells of patients with SEGA or renal angiomyolipoma. In the body, Everolimus first attaches to a protein called FKBP-12 that is found inside cells to make a complex. This complex then blocks mTOR. Since mTOR is involved in the control of cell division and the growth of blood vessels, Votubia prevents the division of tumour cells and reduces their blood supply.

In SEGA caused by tuberous sclerosis, Votubia has been studied in one main study involving 28 adults and children aged three years and above. The main measure of effectiveness was based on how much the patient’s main brain tumour shrank after six months of treatment.
In renal angiomyolipoma caused by tuberous sclerosis, Votubia has been compared with placebo in one study involving 118 adults. The main measure of effectiveness was the proportion of patients who responded to treatment and whose kidney tumour shrank by at least half.

Votubia was shown to be effective at treating patients with SEGA and renal angiomyolipoma by shrinking the volume of the tumours. In patients with SEGA, the main brain tumour shrank by half in approximately 30% of patients and by about a third in around 70% of patients. In patients with renal angiomyolipoma, the kidney tumour shrank by at least half in 42% of patients ( 33 out of 79 patients ) treated with Votubia, compared with none of the 39 patients who received placebo.

The most common side effects ( seen in more than 1 in 10 patients ) in studies with Votubia are infections, stomatitis and increased blood levels of cholesterol.

Votubia must not be used in people who are hypersensitive ( allergic ) to Everolimus, to related medicines such as Sirolimus and Temsirolimus or to any of the other ingredients.

The CHMP noted that Votubia has been shown to reduce the size of the brain tumours and that this is expected to reduce the signs and symptoms of SEGA such as seizures, hydrocephalus ( accumulation of fluid in the brain ), and increased pressure within the brain. Although surgery remains the standard treatment for this condition, Votubia is expected to benefit patients whose tumour cannot be operated on. Votubia has also been shown to reduce the size of kidney tumours in patients with renal angiomyolipoma. The side effects of the medicine were considered to be manageable and were generally mild or moderate.
The CHMP therefore concluded that the benefits of Votubia outweigh its risks.

Source: European Medicines Agency ( EMA ), 2012