Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Loss of Bone Mineral Density
Use of depot medroxyprogesterone acetate subcutaneous (DMPA-SC) reduces serum estrogen levels and is associated with significant loss of BMD due to the known effect of estrogen deficiency on the bone remodelling system. Bone loss is greater with increasing duration of use; however, BMD appears to increase after DMPA-SC is discontinued and ovarian estrogen production increases.

This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of DMPA-SC by younger women will reduce peak bone mass and increase the risk for fracture in later life i.e., after menopause.

A study to assess the BMD effects of DMPA- IM (Depo-Provera), in adolescent females showed that its use was associated with a statistically significant decline in BMD from baseline. After discontinuing DMPA-IM in adolescents, return of mean BMD to baseline values required 1.2 years at the lumbar spine, 4.6 years at the total hip and 4.6 years at the femoral neck (see section 5.1).
However, in some participants, BMD did not fully return to baseline during follow-up and the long- term outcome is not known in this group.
In adolescents, SAYANA® may be used but only after other methods of contraception have been discussed with the patients and considered to be unsuitable or unacceptable.

A large observational study of predominantly adult female contraceptive users showed that use of DMPA-IM did not increase risk for bone fractures. Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life (see section 5.1 – Relationship of fracture incidence to use of DMPA-IM by women of reproductive age).

In women of all ages, careful re-evaluation of the risks and benefits of treatment should be carried out in those who wish to continue use for more than 2 years. In particular, in women with significant lifestyle and/or medical risk factors for osteoporosis, other methods of contraception should be considered prior to use of SAYANA®.

Significant risk factors for osteoporosis include:

•       Alcohol abuse and/or tobacco use
•       Chronic use of drugs that can reduce bone mass, e.g., anticonvulsants or corticosteroids
•       Low body mass index or eating disorder, e.g., anorexia nervosa or bulimia
•       Previous low trauma fracture
•       Family history of osteoporosis 
For further information on BMD changes in both adult and adolescent females, refer to section 5.1.
Adequate intake of calcium and vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.

Menstrual Irregularities

Most women using SAYANA® experienced alteration of menstrual bleeding patterns. Patients should be appropriately counseled concerning the likelihood of menstrual disturbance and the potential delay in return to ovulation. As women continued using SAYANA®, fewer experienced irregular bleeding and more experienced amenorrhea. After receiving the fourth dose, 39% of women experienced 
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amenorrhea during month 6. During month twelve, 56.5% of women experienced amenorrhea. The changes in menstrual patterns from the three contraception trials are presented in Figures 1 and 2.
Figure 1 shows the increase in the percentage of women experiencing amenorrhea over the 12-month study. Figure 2 presents the percentage of women experiencing spotting only, bleeding only, and bleeding and spotting over the same time period. In addition to amenorrhea, altered bleeding patterns included intermenstrual bleeding, menorrhagia and metrorrhagia. If abnormal bleeding associated with SAYANA® persists or is severe, appropriate investigation and treatment should be instituted.

Figure 1. Percent of SAYANA®-Treated Women with Amenorrhea per 30-Day Month Contraception Studies (ITT Population, N=2053)


100
90
80
70                                                                                   62.0 58.7     56.5
60                                                           53.2           51.7 50.9
Percent



50
39.1    40.5    39.0
40
26.5
30                22.4
20
10       4.0
0
1        2          3          4      5       6       7       8       9       10     11       12 Ns:1831   1854        1840      1729    1717   1689     1544   1550    1520     1413   1404     1273 Month

Amenorrhea


Figure 2. Percent of SAYANA® -Treated Women with Bleeding and/or Spotting per 30-Day Month Contraception Studies (ITT Population, N=2053)


100
90
80
70
Percent


60
50
40
30
20
10
0
1         2             3         4        5       6        7        8        9        10         11       12 Ns:1831     1854          1840      1729     1717    1689     1544    1550     1520      1413       1404     1273 
Month

Spotting Only      Bleeding Only     Bleeding and Spotting


Cancer Risks
Long-term case-controlled surveillance of DMPA-IM 150 mg users found no overall increased risk of ovarian, liver, or cervical cancer and a prolonged, protective effect of reducing the risk of endometrial cancer in the population of users.

Breast cancer is rare among women under 40 years of age whether or not they use hormonal contraceptives.

Results from some epidemiological studies suggest a small difference in the risk of having the disease in current and recent users compared with never-users. Any excess risk in current and recent DMPA 

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users is small in relation to the overall risk of breast cancer, particularly in young women (see below), and is not apparent after 10 years since last use. Duration of use does not seem to be important.

Possible number of additional cases of breast cancer diagnosed up to 10 years after stopping injectable progestogens*

Age at last use of DMPA             No. of cases per 10,000 women       Possible additional cases per who are never-users                 10,000 DMPA users
20                                  Less than 1                         Much less than 1

30                                  44                                  2-3 40                                  160                                 10


* based on use for 5 years
Thromboembolic Disorders
Although MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, any patient who develops such an event, e.g., pulmonary embolism, cerebrovascular disease , retinal thrombosis or deep venous thrombosis, while undergoing therapy with SAYANA® should not be re-administered the drug. Women with a prior history of thromboembolic disorders have not been studied in clinical trials and no information is available that would support the safety of SAYANA® use in this population.

Anaphylaxis and Anaphylactoid Reaction
If an anaphylactic reaction occurs, appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

Ocular Disorders
Medication should not be re-administered pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should not be re-administered.

Precautions

Weight Changes
Weight changes are common but unpredictable. In the phase 3 studies body weight was followed over 12 months. Half (50%) of women remained within 2.2 kg of their initial body weight. 12% of women lost more than 2.2 kg, and 38% of women gained more than 2.3 kg.

Fluid Retention
There is evidence that progestogens may cause some degree of fluid retention, and as a result, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by fluid retention.

Return of Ovulation
Following a single dose of SAYANA®, the cumulative rate of return to ovulation as measured by plasma progesterone was 97.4% (38/39 patients) by one year after administration. After the 14-week therapeutic window, the earliest return to ovulation was one week, and the median time to ovulation was 30 weeks. Women should be counseled that there is a potential for delay in return to ovulation following use of the method, regardless of the duration of use. It is recognised, however, that amenorrhoea and/or irregular menstruation upon discontinuation of hormonal contraception may be due to an underlying disorder associated with menstrual irregularity, especially polycystic ovarian syndrome.

Psychiatric Disorders
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and 
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suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Protection against Sexually Transmitted Infections
Women should be counselled that SAYANA® does not protect against sexually transmitted infections (STIs) including HIV infection (AIDS) but equally, DMPA is a sterile injection and, used as directed, will not expose them to STIs. Safer sex practices including correct and consistent use of condoms reduce the transmission of STIs through sexual contact, including HIV.
The benefits of contraceptive options and their risks must be evaluated individually for each woman.

Carbohydrate/Metabolism
Some patients receiving progestogens may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.

Liver Function
If jaundice develops in any woman receiving SAYANA®, consideration should be given to not re- administer the medication (see section 4.3).

Hypertension and Lipid Disorders
Limited evidence suggests that there is a small increased risk of cardiovascular events among women with hypertension or with lipid disorders who used progestogen-only injectables. If hypertension occurs under SAYANA® treatment and/or the increase in hypertension cannot adequately be controlled by antihypertensive medication, treatment with SAYANA® should be stopped. Additional risk factors for arterial thrombotic disorders include: hypertension, smoking, age, lipid disorders, migraine, obesity, positive family history, cardiac valve disorders, atrial fibrillation.

SAYANA® should be used cautiously in patients with one or more of these risk factors.

Other Conditions
The following conditions have been reported both during pregnancy and during sex steroid use, but an association with the use of progestagens has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.

If any of the conditions/risk factors mentioned is present, the benefits of SAYANA® use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether SAYANA® use should be discontinued.


Laboratory Tests
The pathologist should be advised of progestogen therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components might be affected by progestogen therapy: a) Plasma/urinary steroids are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).
b) Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH).
c) Sex-hormone-binding-globulin (SHBG) concentrations are decreased.

Excipients
As this product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, it may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm. This medicinal product contains less than 1 mmol sodium (23 mg) per 104 mg/0.65 ml, i.e., essentially 'sodium-free'.

Effects on Driving

4.7    Effects on ability to drive and use machines

SAYANA® has no influence on the ability to drive and use machines.