VANTAS 50 MG IMPLANT

Active substance: HISTRELIN ACETATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Vantas 50 mg implant

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each implant contains approximately 50 mg histrelin acetate corresponding to
41 mg histrelin.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Implant.
The implant is in the form of a small, thin flexible tube. The histrelin acetate
core is placed in a non-biodegradable 34.5 mm x 3.15 mm cylindrically shaped
hydrogel reservoir.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Palliative treatment of advanced prostate cancer.

4.2

Posology and method of administration

The recommended dose of Vantas is one implant for 12 months. An
average of 50 µg histrelin acetate is delivered daily. The implant is
inserted subcutaneously in the inner aspect of the upper arm.

Response to Vantas therapy should be monitored by clinical parameters
and by measuring prostate-specific antigen (PSA) serum levels. Clinical
studies have shown that serum testosterone concentrations may increase
during the first week of treatment (testosterone flare-up). Testosterone
concentrations then decreased and reached castrate levels (≤ 50 ng/dL) by
Week 4. Once attained, castrate level was maintained as long as Vantas
therapy continued. If a patient's clinical response appears to be suboptimal, then it would be advisable to confirm that patient’s serum
testosterone concentration is at castrate level.
The implant must be removed after 12 months of treatment. At the time
the implant is removed a new implant may be inserted in order to continue
the treatment. Please see insertion and removal procedures below.
Pediatric Population
Vantas is not indicated for use in women and children under 18 years old
as the safety and efficacy of Vantas have not been established in these
populations. No data are available.
Hepatic impairment and Renal impairment
Vantas has not been studied adequately in patients with impaired liver
function.
In patients with mild to moderate renal impairment (CLcr: 15-60 ml/min),
no adjustments in drug dosing are warranted. Vantas has not been studied
in prostate cancer patients with severe renal impairment.

4.3

Contra-indications
Vantas is contraindicated in patients with hypersensitivity to histrelin or to
any of the excipients listed in section 6.1, GnRH, GnRH-agonists/analogues, or stearic acid. Anaphylactic reactions to synthetic LHRH or
LHRH-agonists/-analogues, have also been reported.

4.4

Special warnings and precautions for use
Reactions to the treatment with Vantas should be monitored by regular measurement
of serum concentrations of testosterone and prostate-specific antigen, especially if the
anticipated clinical or biochemical response to treatment has not been achieved. (See
section 4.2.).
Histrelin, causes a transient increase in serum concentrations of testosterone during
the first week of treatment. Patients may experience a worsening of symptoms or
onset of new symptoms, including joint pain, bone pain, neuropathy, haematuria, or
ureteral or bladder outlet obstruction. Cases of ureteral obstruction and spinal cord

compression, which may lead to paralysis with or without fatal complications, have
been reported in connection with LHRH-agonists. Patients with metastatic vertebral
lesions and/or urinary tract obstruction should be closely observed during the first few
weeks of therapy. These patients should be considered for prophylactic treatment with
anti-androgens. If spinal cord compression or renal impairment occurs, the standard
treatment for these complications should be initiated.
The results of the testosterone determinations are dependent on the method of
analysis. It is advisable to be aware of the type and precision of the assay
methodology to ensure the correct clinical and therapeutic decisions.
Long-term androgen deprivation either by bilateral orchiectomy or administration of
GnRH analogues is associated with increased risk of bone loss and may lead to
osteoporosis and increased risk of bone fracture. In addition, patients may experience
metabolic changes (e.g. glucose intolerance or worsening of existing diabetes) or an
increased risk of cardiovascular events. Patients at high risk for metabolic or
cardiovascular diseases should be carefully assessed before commencing treatment
and adequately monitored during androgen deprivation therapy.
Vantas should be used with caution in patients with abnormal hepatic function in
order to ascertain applicability of Vantas in such patients, as Vantas has not been
studied adequately in patients with impaired liver function.
There is an increased risk of incident depression (which may be severe) in patients
undergoing treatment with GnRH agonists, such as histrelin. Patients should be
informed accordingly and treated as appropriate if symptoms occur.
Insertion of an implant is a surgical procedure. Only Vantas implantation device can
be used for insertion of the implant. Careful adherence to the recommended
procedures for insertion and removal is recommended in order to reduce the risk of
complications and implant expulsion (see section 6.6).
In cases where the implant is difficult to locate by palpation, ultrasound or CT scan
may be used.
Children and women have not been studied.
The container of this medicinal product contains latex rubber. May cause severe
allergic reactions.

4.5

Interaction with other medicinal products and other forms of interaction
No pharmacokinetic-based drug-drug interaction studies have been performed
with Vantas.
Treatment with histrelin results in suppression of the pituitary-gonadal system.
Results of diagnostic tests of pituitary/gonadotropic and gonadal functions
conducted during or after histrelin treatment may be affected.

4.6

Fertility, pregnancy and lactation
Preclinical studies have shown that histrelin decreases fertility in animals due
to its pharmacological effect. However, fertility returns to normal after
cessation of treatment (See section 5.3.).
Due to its indication, Vantas has not been studied in pregnant or breast-feeding
women and is not for use in women.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.

4.8

Undesirable effects
The safety of Vantas was evaluated in 171 patients with prostate cancer treated for up
to 36 months in two clinical trials. Vantas, like other LHRH-analogues, caused a
transient increase in serum testosterone concentrations during the first week of
treatment. Therefore, potential exacerbations of the signs and symptoms of the
disease during the first few weeks of treatment are a factor in patients with vertebral
metastases and/or urinary obstruction or hematuria. If these conditions are
aggravated, it may lead to neurological problem such as weakness and/or paraesthesia
of the lower limbs or worsening of urinary tract symptoms (see section 4.4).
In the first 12 months after insertion of the implant(s), an implant extruded through
the incision site in eight out of 171 patients in the clinical trials. In a pivotal study, a
detailed evaluation of implant site reactions was also conducted. Insertion site
reactions were very common and were experienced by 13.8 % of the patients in the
study. All these local site reactions were reported as mild in severity. The majority of
these reactions were associated with initial insertion or removal/insertion of a new
implant and began and resolved within the first two weeks following implant
insertion. Reactions persisted in 2.8 % of the patients, and an additional 2.8 %
developed insertion-site reactions after the first two weeks following implantation.
Of 138 patients in a pivotal study, 2 patients developed a local skin infection and
inflammation. The one instance resolved after treatment with oral antibiotics, and the
other without treatment. Local reactions following insertion of a subsequent implant
were comparable to those seen after initial insertion.
The following possibly or probably related systemic adverse events occurred during
clinical trials after up to 24 months treatment with Vantas. The reported undesirable
effects during Vantas treatment in clinical trials are stated in Table 1 below according
to the organ system and frequence.
Very common ( 1/10)
Common ( 1/100 to <1/10)
Uncommon ( 1/1,000 to <1/100)
Rare ( 1/10,000 to <1/1,000)
Very rare (<1/10,000), not known (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.









Table 1: The incidence of possible or probably related undesirable effects reported by
patients treated with Vantas up to 24 months.

Organ group

Very common

Common

Infections and
infestations
Blood and lymphatic
system disorders
Metabolism and
nutrition disorders

Rare
Skin infection

Anaemia
Fluid retention,
hypercalcemia,
hypercholesterolaemia,
food cravings, increased
appetite

Psychiatric disorders

Mood changes,
depression, decreased
libido, insomnia
Dizziness, headache

Nervous system
disorders
Cardiac disorders

Vascular disorders

Uncommon

Tremor, lethargy
Palpitations, ventricular
extrasystoles

Hot flushes*

Blushing

Haematoma

Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders
Hepatobiliary
disorders

Exercise induced
dyspnoea

Skin and
subcutaneous tissue
disorders
Musculoskelatal and
connective tissue
disorders
Renal and urinary
disorders

Hypertrichosis

Night sweats, pruritus,
hyperhidrosis

Arthralgia, pain in the
extremities

Back pain, muscle
spasm, muscle
infiltration, neck pain
Renal failure,
nephrolithiasis, dysuria,
haematuria

Reproductive system
and breast disorders

Erectile dysfunction*,
testicular atrophy*,
gynecomastia*

Constipation

Abdominal discomfort,
nausea

Hepatic disorder

Pollakisuria, impaired
renal function**,
urinary retention

Sexual dysfunction,
breast pain, breast
tenderness, genital
pruritus (males)

General disorders
and administration
site conditions

Injury at the
application site,
erythema at the
application site,
asthenia, fatigue,
reaction at the
application site, pain,
tenderness

Peripheral edema, pain
(exacerbated), swelling,
pain (non specific),
malaise, feelings of
cold, irritability

Investigations

Weight gain, elevated
blood glucose

Elevated aspartateaminotransferase,
elevated blood lactate
dehydrogenase, elevated
blood testosterone,
lowered creatinine
clearance, elevated acid
phosphatase in the
prostate, weight loss
Ureteral stent occlusion,
bruising

Injury, poisoning
and procedural
complications

*Anticipated pharmacological reaction to inhibition of testosterone
** 5 of 8 patients experienced a single instance of mildly impaired renal function (defined as
creatinine clearance 30 ml/min and < 60 ml/min), which resolved to the normal range by the
next medical consultation.



Long-term androgen deprivation either by bilateral orchiectomy or administration of
GnRH analogues is associated with increased risk of bone loss and may lead to
osteoporosis and increased risk of bone fracture. In addition, patients may experience
metabolic changes (e.g. glucose intolerance or worsening of existing diabetes) or an
increased risk of cardiovascular events.

4.9

Overdose
Not relevant.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Gonadotropin-releasing hormones. ATC code:
H01CA03.
Histrelin is a synthetic analogue of a naturally occurring LHRH. After
implantation of Vantas, histrelin is diffused into the tissue, resulting in
inhibition of pituitary LH secretion leading to a fall in serum testosterone
concentrations in males. The effect is reversible on discontinuation of therapy.

Application
site
inflammation

Initially, Vantas like other LHRH agonists may transiently increase serum
testosterone concentration.
By one month after the implantation, testosterone concentrations have fallen to
within castrate range (≤ 50 ng/dL) and remain suppressed while Vantas is
present. This inhibition leads to prostate tumour regression and symptomatic
improvement in the majority of patients.
The implant is inserted subcutaneously and remains in place for 12 months
whilst the drug is released through the hydrogel reservoir. The mean daily
release over the 12-month period is approximately 50 μg histrelin acetate with
higher histrelin plasma concentration in the beginning of the dosing period and
lower concentration towards the end, but maintaining castration level of
testosterone.
The implant's hydrogel reservoir determines the diffusion rate in the waterbased environment. Hydrogel is not dissolved, but is similar to living tissue in
composition, which contributes to its biocompatibility as it lessens the
mechanical irritation of surrounding cells and tissue. It also displays low
surface tension in vivo, which lessens the tendency for proteins to be absorbed
and gather on the surface. This is important for the prevention of thrombosis
and other biological rejection processes.

5.2

Pharmacokinetic properties
Absorption:
Following subcutaneous insertion of one Vantas 50 mg implant in patients
with advanced prostate cancer (n = 17), peak serum concentrations of 1.10 ±
0.375 ng/ml (mean value ± SD) occurred at a median of 12 hours. Continuous
subcutaneous release was evident as serum levels were sustained throughout
the entire 52-week dosing period. The mean serum histrelin concentration at
the end of the 52-week treatment period was 0.13 ± 0.065 ng/ml. When
histrelin serum concentrations were measured following a second implant
inserted after 52 weeks, the observed serum concentrations over 8 weeks
following insertion of the second implant were comparable to the level in the
same period following the first implant. The average rate of subcutaneous drug
release from 41 implants, assayed for residual drug content, was 56.7 ± 7.71
μg/day over the 52-week dosing period. The relative bioavailability for the
Vantas implant in prostate cancer patients with normal renal- and hepatic
function compared to a subcutaneous bolus dose in healthy male volunteers
was 92 %. Serum histrelin concentrations were proportional to dose after one,
two or four 50 mg Vantas implants (50, 100 or 200 mg as histrelin acetate) in
42 prostate cancer patients.
Distribution:
The apparent volume of distribution of histrelin following a subcutaneous
bolus dose (500 μg) in healthy adult volunteers was 58.4 ± 7.86 L. The
fraction of drug unbound in plasma measured in vitro was 29.5 % ± 8.9 %
(mean value ± SD).

Biotransformation:
An in vitro drug metabolism study using human hepatocytes identified a single
histrelin metabolite resulting from C-terminal dealkylation. Peptide fragments
resulting from hydrolysis are also likely metabolites. Following a
subcutaneous bolus dose in healthy volunteers, the apparent clearance of
histrelin was 179 ± 37.8 ml/min (mean value ± SD), and the terminal half-life
was 3.92 ± 1.01 hr (mean value ± SD). The apparent clearance following
insertion of a 50 mg (as histrelin acetate) Vantas implant in 17 prostate cancer
patients was 174 ± 56.5 ml/min (mean value ± SD).
Elimination:
No drug excretion study has been conducted with Vantas 50 mg implants.
Luteinizing hormone (LH) returned to normal level 1 to 6 weeks after
extraction of the implant. The testosterone level also returned to normal level
within 2 weeks of the
increase in LH-level, which indicated that the inhibition is reversible.
Special populations:
Geriatrics
The majority (89.9 %) of the 138 patients studied in the primary clinical trial
were 65 years or older.
Paediatrics
Safety and efficacy for Vantas in paediatric patients have not been established
(see section 4.2).
Race
When serum histrelin concentrations were compared for 7 Latin-American, 30
Black and 77 Caucasian patients, average histrelin concentrations were
similar.
Renal impairment:
When average serum histrelin concentrations were compared between 42
prostate cancer patients with mild to moderate renal impairment (CLcr: 15-60
ml/min) and 92 patients with no renal or hepatic impairment, the levels were
approximately 50 % higher in those patients with renal impairment (0.392
ng/ml versus 0.264 ng/ml). Greater concentrations were noted in patients with
a greater degree of renal impairment. There is no data in patients with severe
renal impairment. These changes as a result of renal impairment are not
considered to be clinically relevant. Therefore, no adjustments in drug dosing
are warranted for these patient subpopulations.
Hepatic insufficiency
The influence of hepatic insufficiency on the pharmacokinetics of histrelin has
not been adequately studied.

5.3

Preclinical safety data
No signs of overt toxicity were seen in repeated dose toxicity studies and the
effects were related mainly to the pharmacological properties of histrelin.
Carcinogenicity studies in rats at doses up to 30 times and in mice at doses up
to 230 times the human dose revealed, as seen with other LHRH agonists, an
increase in tumours of hormonally responsive tissues (testes, pancreas,
mammary and pituitary glands). In addition, there was an increase in
histiocytic sarcomas in female mice at the highest dose.
Mutagenicity studies performed with saline extracts of implants with and
without histrelin were negative in a battery of genotoxicity studies.
Local tolerance studies showed that Vantas is a mild irritant and becomes
encapsulated over time. Mineralization occurred in rats, rabbits and dogs, but
not in monkeys.
Administration of histrelin in laboratory animals was associated with atrophy
of reproductive organs and reduced fertility. This is due to the
pharmacological effect and full reversibility was demonstrated after cessation
of administration.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
The drug core contains stearic acid.
The acrylic copolymer shell consists of:
• 2-hydroxyethyl methacrylate
• 2-hydroxypropyl methacrylate
• trimethylolpropan trimethacrylate.
The storage solution of the implant consists of:
• sodium chloride
• water for injections

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
Implant
Store in a refrigerator (2 °C-8 °C). Do not freeze.
Store in the original package in order to protect from light.
Implantation device
The implantation device supplied is sterile in its pouch.
Do not store above 25 °C. Do not refrigerate or freeze. Store in the original package
in order to protect from light.

6.5

Nature and contents of container
The implant is contained in a type I glass vial and supplied with a Tefloncoated stopper (chlorobutyl isoprene rubber) and an aluminium seal. The
stopper contains latex rubber. The implant is stored in 2 ml of 1.8 % sterile
sodium chloride solution.
Vantas is supplied in a carton with an amber plastic bag, which contains the
glass vial with the implant.
The sterile implantation device is supplied in a self-sealing Tyvek-bag for
sterilization, which is placed in a carton.

6.6

Special precautions for disposal and other handling
Vantas implantation device is for single use only.
Packaging and any unused product or waste material should be disposed of in
accordance with local requirements.
Insertion procedure
It is important that aseptic technique be used in order to minimize the risk of
infection. Sterile gloves are required for insertion and removal of the implant.
Identification of the insertion site
The patient should lie on his back with the arm that is least used (i.e. the left
arm in a right-handed person) flexed so the physician has ready access to the
inner aspect of the upper arm. Prop the arm with pillows so the patient can
easily hold that position. The optimum site for insertion is approximately half
way between the shoulder and the elbow in the crease between the biceps and
triceps muscle.
Preparation of the implantation device

Prepare the implantation device before preparation of the insertion site and
prior to insertion. Remove the implantation device from its sterile bag. The
device is supplied with the cannula fully extended. Verify this by inspecting
the position of the green retraction button. The button should be all the way
forwards, toward the cannula, and away from the handle.
Remove the metal band from the glass vial, remove the rubber stopper and use
a mosquito clamp to grasp either tip of the implant. Avoid grasping or
clamping the middle of the implant to prevent distortion of the implant.
Insert the implant into the implantation device. The implant will lie in the
cannula in such a way that just the tip is visible at the bottom of the bevel.
Inserting the implant
Swab the insertion site with povidone-iodine and place a fenestrated drape
over the site.
Anesthetic
Ensure that the patient is not allergic to lidocaine/adrenaline. Inject a few ml
of the anesthetic, starting at the planned incision site and then infiltrating up to
the length of the implant, 32 mm, in a fan-like fashion.
Incision
Using a scalpel make a 2-3 mm shallow skin incision on in the inner aspect of
the upper arm perpendicular to length of the biceps.
Insertion
Grasp the implantation device by its handle.
Insert the tip of the device into the incision with the bevel upward, and
advance the device subcutaneously along the path of the anaesthetic up to the
inscribed line on the cannula. To ensure subcutaneous placement, the
implantation device should visibly raise the skin at all times during insertion.
Make sure that the implantation device does not enter muscle tissue.
Hold the device in place at the same time as you move your thumb toward the
green retraction button. Press the button down to release the locking
mechanism, then draw the button back to the back-stop whilst holding the
device in place. The cannula is withdrawn from the incision leaving the
implant in the dermis. Withdraw the implantation device from the incision.
The freed implant can be checked by palpation.
Note: Do not attempt to push the device deeper once the retraction process has
started to avoid severing the implant. If you wish to re-start the procedure,
withdraw the device, grasp the implant by the tip to extract it, reset the
retraction button to the most forward position, reload the implant and start the
procedure again.
Closing the incision

Close the incision using one or two sutures (optional) with the knots facing
inside the incision. Apply a thin layer of antibiotic ointment directly onto the
incision. Close the incision with two surgical steri-strips. Apply a gauze
dressing over the incision and secure it with a bandage.
Removal procedure and insertion of new implant
The Vantas implant must be removed after 12 months of treatment.
Locating the implant
The implant can be located by palpating the area near the incision of the
previous year. The implant is normally readily palpated. Press on the distal
end of the implant to determine the proximal tip location relative to the old
incision.
If the implant is difficult to locate, ultrasound may be used. If the implant
cannot be located by ultrasound, other imaging techniques such as CT or MRI
may be used to locate it.
Preparation of the insertion site
Patient position and preparation of the implantation site are the same as for the
initial implantation. Swab the area above and around the implant with
povidone-iodine. Drape the area with a fenestrated drape.
Anesthetic
First determine that the patient is not allergic to lidocaine/adrenaline then press
down on the tip of the implant furthest from the original incision. Inject a
small amount of lidocaine/adrenaline at the tip near the incision, then advance
the cannula along the length, but beneath the implant, steadily injecting a
small amount of anesthetic into the skin. The anesthetic will raise up the
implant within the dermis. If a new implant is to be inserted, you have the
option of placing the implant in the same "pocket" as the removed one, or of
using the same incision and inserting the implant in the opposite direction. If
you place the implant in the opposite direction, inject the anesthetic along the
length of the new implant prior to explantation.
Incision/explantation
Use a scalpel to make a 2-3 mm incision near the tip and approximately 1-2
mm deep. Generally, the tip of the implant will be visible through a thin
pseudo-capsule of tissue. If the implant is not visible, press down on the distal
tip of the implant and massage it forward towards the incision. Carefully
"nick" the pseudo-capsule to reveal the polymer tip.
Grasp the tip with a mosquito clamp and extract the implant.
If inserting a new implant, proceed as per the initial instructions. The new
implant may be placed through the same incision site. Alternatively, the
opposite arm may be used.
Patient instructions – aftercare

Give the patient the information leaflet. Instruct the patient to avoid wetting
the arm containing the implant for 24 hours. The pressure bandage can be
removed after 24 hours. The patient must not remove the surgical steri-strips.
These strips should be allowed to fall off by themselves after several days.
Patients should avoid lifting heavy objects and participating in strenuous
physical activity involving the treated arm for 7 days to allow the incision to
fully close.

7

MARKETING AUTHORISATION HOLDER
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland

8

MARKETING AUTHORISATION NUMBER(S)
PL 27925/0047

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 01/09/2008
Date of last renewal: 13/02/2011

10

DATE OF REVISION OF THE TEXT
11/07/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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