Diphereline PR Adverse Reactions

General tolerance in men (see Precautions): Since patients suffering from locally advanced or metastatic, hormone-dependent prostate cancer are generally old and have other diseases frequently encountered in this aged population, more than 90% of the patients included in clinical trials reported adverse events, and often the causality is difficult to assess.
As seen with other GnRH agonist therapies or after surgical castration, the most commonly observed adverse events related to triptorelin treatment were due to its expected pharmacological effects. These effects included hot flushes, erectile dysfunction and decreased libido.
With the exception of immuno-allergic (rare) and injection site (<5%) reactions, all adverse events are known to be related to testosterone changes.
The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration.
The frequency of the adverse reactions is classified as follows: 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). No frequency can be determined for the adverse reactions reported after marketing. Consequently, they are reported with "frequency not known".
3.75 mg: (See Table 1.)

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11.25 mg: (See Table 2.)

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Triptorelin causes a transient increase in circulating testosterone levels within the first week after the initial injection of the sustained release formulation. With this initial increase in circulating testosterone levels, a small percentage of patients (≤5%) may experience a temporary worsening of signs and symptoms of their prostate cancer (tumour flare), usually manifested by an increase in urinary symptoms (<2%) and metastatic pain (5%), which can be managed symptomatically. These symptoms are transient and usually disappear in one to two weeks.
Isolated cases of exacerbation of disease symptoms, either urethral obstruction or spinal cord compression by metastasis have occurred. Therefore, patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy (see Precautions).
The use of GnRH agonists, to treat prostate cancer may be associated with increased bone loss and may lead to osteoporosis and increases the risk of bone fracture.
An increase in lymphocytes has been reported in patients treated with GnRH analogues. This secondary lymphocytosis is apparently related to castration induced by GnRH and suggests that gonadal hormones are involved in thymic involution.
Patients receiving long-term treatment by GnRH analogue in combination with radiation may have more side effects especially gastrointestinal, related to radiotherapy.
General tolerance in women (see Precautions): As a consequence of decreased oestrogen levels, the most commonly reported adverse events (expected in 10% of women or more) were headache, libido decreased, sleep disorder, mood changes, dyspareunia, dysmenorrhoea, genital haemorrhage, ovarian hyperstimulation syndrome, ovarian hypertrophy, pelvic pain, abdominal pain, vulvovaginal dryness, hyperhidrosis, hot flushes and asthenia.
The following adverse reactions, considered as at least possibly related to triptorelin treatment, were reported. Most of these are known to be related to biochemical or surgical castration.
The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100). No frequency can be determined for the adverse reactions reported after marketing. Consequently, they are reported with frequency "not known". (See Table 3.)

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At the beginning of treatment, the symptoms of endometriosis including pelvic pain, dysmenorrhoea may be exacerbated very commonly (≥10%) during the initial transient increase in plasma oestradiol levels. These symptoms are transient and usually disappear in one or two weeks.
Genital haemorrhage including menorrhagia, metrorrhagia may occur in the month following the first injection.
Long-term use of GnRH analogues may lead to bone loss which is a risk factor of osteoporosis.
General tolerance in children (see Precautions): The frequency of the adverse reactions is classified as follows: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100). No frequency can be estimated for the adverse reactions reported after marketing. Consequently, they are reported with frequency "not known". (See Table 4.)

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11.25 mg: Vaginal bleeding may occur in the month following the first injection.
Breast Cancer: 3.75 mg: The most commonly observed adverse reactions associated with triptorelin treatment for up to 5 years in combination with either tamoxifen or an aromatase inhibitor in the TEXT and SOFT studies were hot flush, musculoskeletal disorder, fatigue, insomnia, hyperhidrosis, vulvovaginal dryness and depression.
The frequencies of the adverse reactions reported with triptorelin in combination with tamoxifen (N = 2325) or exemestane (N = 2318) are shown in the following table. The classifications are as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000). (See Table 5.)

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The ADRs identified previously should be used in addition to the triptorelin ADRs identified in men and women in the previous tables to fully describe the ADR profile for the use of OFS in combination with either exemestane or tamoxifen.
Osteoporosis has been reported with a higher frequency with the use of triptorelin in combination with exemestane than in the combination with tamoxifen (39% versus 25%) (see Precautions).
Musculoskeletal disorder and fractures were also more commonly reported in the combination with exemestane than in the combination with tamoxifen (89% versus 76% and 6.8% versus 5.2%, respectively).
Hypertension has been reported as a targeted adverse event at a very common frequency with triptorelin in combination with either exemestane or tamoxifen (23% and 22% respectively).
Hyperglycaemia and diabetes have been reported as targeted adverse events at a common frequency with triptorelin in combination with either exemestane or tamoxifen (hyperglycaemia: 2.6% and 3.4% respectively; diabetes: 2.3% and 2.3% respectively).