SPC changes, 3.6mg Zoladex

Section 4.8

Text update in first paragraph, now reads, “The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from Zoladex clinical trials and post-marketing sources. The most commonly observed adverse reactions include hot flushes, sweating and injection site reactions.”

Text update in Table, now reads,

Table: Zoladex 3.6 mg adverse drug reactions presented by MedDRA System Organ Class

a     A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus.

b    These are pharmacological effects which seldom require withdrawal of therapy.

c     These may manifest as hypotension or hypertension, have been occasionally observed in patients administered Zoladex. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with Zoladex. Rarely, such changes have been sufficient to require medical intervention, including withdrawal of treatment from Zoladex.

d    These are generally mild, often regressing without discontinuation of therapy.

e     Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically.

f     Observed in a pharmaco-epidemiology study of LHRH agonists used in the treatment of prostate cancer. The risk appears to be increased when used in combination with anti-androgens. ”

Section 10

SmPC changes - Zoladex 3.6 Implant

Section 4.3

Deletions and additional text added to 1^st and 2^nd paragraphs,

“Known severe hypersensitivity to the active substance or to any of the excipients of this product.

Pregnancy and lactation (see section 4.6).”

Section 4.4

Change to 1^st paragraph,

“Zoladex is not indicated for use in children, as safety and efficacy have not been established in this patient group.”

Sub heading, Males, deletions and additional text throughout,

“Males

The use of Zoladex in men at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully, and the patients monitored closely during the first month of therapy. If spinal cord compression or renal impairment due to ureteric obstruction are present or develop, specific standard treatment of these complications should be instituted.

Consideration should be given to the initial use of an anti-androgen (e.g. cyproterone acetate 300 mg daily for three days before and three weeks after commencement of Zoladex) at the start of LHRH analogue therapy since this has been reported to prevent the possible sequelae of the initial rise in serum testosterone.

The use of LHRH agonists may cause reduction in bone mineral density. In men, preliminary data suggest that the use of a bisphosphonate in combination with an LHRH agonist may reduce bone mineral loss. Particular caution is necessary in patients with additional risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with anticonvulsants or corticosteroids, family history of osteoporosis).Mood changes, including depression have been reported. Patients with known depression and patients with hypertension should be monitored carefully.

Reduction in glucose tolerance has been observed in men receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in patients with pre-existing diabetes mellitus. Thus, monitoring of blood glucose levels should be considered.”

Sub heading, Females, deletions and additional text throughout,

“Females

Breast cancer indication

Reduced bone mineral density:

The use of LHRH agonists may cause reduction in bone mineral density.  Following two years treatment for early breast cancer, the average loss of bone mineral density was 6.2% and 11.5% at the femoral neck and lumbar spine respectively.  This loss has been shown to be partially reversible at the one year off treatment follow-up with recovery to 3.4% and 6.4% relative to baseline at the femoral neck and lumbar spine respectively, although this recovery is based on very limited data. In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy. Preliminary data suggest that the use of Zoladex in combination with tamoxifen in patients with breast cancer may reduce bone mineral loss.

Benign indications

Loss of bone mineral density:

The use of LHRH agonists is likely to cause reduction in bone mineral density averaging 1% per month during a six month treatment period. Every 10% reduction in bone mineral density is linked with about a two to three times increased fracture risk. In the majority of women, currently available data suggest that recovery of bone loss occurs after cessation of therapy.

In patients receiving Zoladex for the treatment of endometriosis, the addition of hormone replacement therapy has been shown to reduce bone mineral density loss and vasomotor symptoms.

No specific data is available for patients with established osteoporosis or with risk factors for osteoporosis (e.g. chronic alcohol abusers, smokers, long-term therapy with drugs that reduce bone mineral density, e.g. anticonvulsants or corticosteroids, family history of osteoporosis, malnutrition, e.g. anorexia nervosa). Since reduction in bone mineral density is likely to be more detrimental in these patients, treatment with Zoladex should be considered on an individual basis and only be initiated if the benefits of treatment outweigh the risks following a very careful appraisal. Consideration should be given to additional measures in order to counteract loss of bone mineral density.

Withdrawal bleeding

During early treatment with Zoladex some women may experience vaginal bleeding of variable duration and intensity. If vaginal bleeding occurs it is usually in the first month after starting treatment. Such bleeding probably represents oestrogen withdrawal bleeding and is expected to stop spontaneously. If bleeding continues, the reason should be investigated.

There are no clinical data on the effects of treating benign gynaecological conditions with Zoladex for periods in excess of six months.

The use of Zoladex may cause an increase in cervical resistance and care should be taken when dilating the cervix.

Zoladex should only be administered as part of a regimen for assisted reproduction under the supervision of a specialist experienced in the area.

As with other LHRH agonists, there have been reports of ovarian hyperstimulation syndrome (OHSS), associated with the use of Zoladex 3.6 mg in combination with gonadotrophin. The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS.  If OHSS risk is present, human chorionic gonadotrophin (hCG) should be withheld, if possible.

It is recommended that Zoladex is used with caution in fertilisation treatment of patients with polycystic ovarian syndrome as follicle recruitment may be increased.

Fertile women should use non-hormonal contraceptive methods during treatment with Zoladex and until reset of menstruation following discontinuation of treatment with Zoladex.

Patients with known depression and patients with hypertension should be monitored carefully.

Treatment with Zoladex may lead to positive reactions in anti-doping tests.”

Section 4.5

Reformatted text,

“Not known.”

Section 4.6

Deletions and additional text to 1^st and 2^nd paragraphs,

“Pregnancy: Zoladex should not be used during pregnancy since concurrent use of LHRH agonists is associated with a theoretical risk of abortion or foetal abnormality. Prior to treatment, potentially fertile women should be examined carefully to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses resume (see also warning concerning the time to return of menses in section 4.4).

Pregnancy should be excluded before Zoladex is used for fertilisation treatment. When Zoladex is used in this setting, there is no clinical evidence to suggest a causal connection between Zoladex and any subsequent abnormalities of oocyte development or pregnancy or outcome.”

Section 4.7

Deletions and additional text to section,

“There is no evidence that Zoladex would result in impairment of ability to drive or operate machinery.”

Section 4.8

Deletion of text and additional new text and table,

“The following frequency categories were based on all adverse reactions from clinical trials, post-marketing studies and spontaneous reports. The most commonly observed adverse reactions include hot flushes, sweating and injection site reactions.

The following convention has been used for classification of frequency: 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) and Not known (cannot be estimated from the available data).

Table: Zoladex adverse drug reactions presented by MedDRA System Organ Class

a           A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus.

b          These are pharmacological effects which seldom require withdrawal of therapy.

c          These may manifest as hypotension or hypertension, have been occasionally observed in patients administered Zoladex. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with Zoladex. Rarely, such changes have been sufficient to require medical intervention, including withdrawal of treatment from Zoladex.

d          These are generally mild, often regressing without discontinuation of therapy.

e          Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically.

   Post-marketing experience

A small number of cases of changes in blood count, hepatic dysfunction, pulmonary embolism and interstitial pneumonia have been reported in connection with Zoladex.

In addition, the following adverse drug reactions have been reported in women treated for benign gynaecological indications:

Acne, change of body hairs, dry skin, weight gain, increase in serum cholesterol, ovarian hyperstimulation syndrome (if concomitantly used with gonadotrophins), vaginitis, vaginal discharge, nervousness, sleep disorder, tiredness, peripheral oedema, myalgias, cramp in the calves, nausea, vomiting, diarrhoea, constipation, abdominal complaints, alterations of voice.

Initially, breast cancer patients may experience a temporary increase in signs and symptoms, which can be managed symptomatically.

Rarely, breast cancer patients with metastases have developed hypercalcaemia on initiation of therapy. In the presence of symptoms indicative of hypercalcaemia (e.g. thirst), hypercalcaemia should be excluded.Rarely, some women may enter the menopause during treatment with LHRH analogues and not resume menses on cessation of therapy. Whether this is an effect of Zoladex treatment or a reflection of their gynaecological condition is not known.”

Section 4.9

Deletions and additional text to section,

“There is not much experience of overdose in humans.  In cases where Zoladex has been given before the planned time of administration, or when a bigger dose of Zoladex than originally planned has been given, no clinically significant undesirable effects have been observed.  Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses of Zoladex.  In case of overdosage, the condition should be managed symptomatically.”

Section 10

23^rd October 2009

New and deleted text in red:
 

4.4 Special warnings and special precautions for use

Zoladex is not indicated for use in children, as safety and efficacy have not been established in this group of patients.

Males

The use of Zoladex in men at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully, and the patients monitored closely during the first month of therapy.  Consideration should be given to the initial use of an anti-androgen (e.g. cyproterone acetate 300 mg daily for three days before and three weeks after commencement of Zoladex) at the start of LHRH analogue therapy since this has been reported to prevent the possible sequelae of the initial rise in serum testosterone.  If spinal cord compression or renal impairment due to ureteric obstruction are present or develop, specific standard treatment of these complications should be instituted.

The use of LHRH agonists in men may cause a reduction in bone mineral density.

A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. Consideration should therefore be given to monitoring blood glucose.

Females

Section 4.1

Reworded to clarify the prostate cancer indication:

(i)       Treatment of prostate cancer in the following settings (see also section 5.1):

§         In the treatment of metastatic prostate cancer

§         In the treatment of locally advanced prostate cancer, as an alternative to surgical castration

§         As adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer

§         As neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer

§         As adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression

Section 5.1

Additional new 3^rd, 4^th and 5^th paragraphs

In the management of patients with metastatic prostate cancer, Zoladex has been shown in comparative clinical trials to give similar survival outcomes to those obtained with surgical castrations. 

In comparative trials, Zoladex has been shown to improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in patients with high‑risk localised (T₁-T₂ and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T₃-T₄) prostate cancer.  The optimum duration of adjuvant therapy has not been established; a comparative trial has shown that 3 years of adjuvant Zoladex gives significant survival improvement compared with  radiotherapy alone.  Neo-adjuvant Zoladex prior to radiotherapy has been shown to improve disease-free survival in patients with high risk localised or locally advanced prostate cancer.

After prostatectomy, in patients found to have extra-prostatic tumour spread, adjuvant Zoladex may improve disease‑free survival periods, but there is no significant survival improvement unless patients have evidence of nodal involvement at time of surgery.  Patients with pathologically staged locally advanced disease should have additional risk factors such as PSA of at least 10 ng/mL or a Gleason score of at least 7 before adjuvant Zoladex should be considered.  There is no evidence of improved clinical outcomes with use of neo-adjuvant Zoladex before radical prostatectomy.

Section 10

New revision date of text: 28 January 2008