SAYANA PRESS 104 mg/0.65 ml suspension for injection
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Company information
- More information about this medicine
AdultsFirst Injection: To provide contraceptive cover in the first cycle of use, an injection of 104 mg SC should be given during the first five days of a normal menstrual cycle. If the injection is carried out according to these instructions, no additional contraceptive measure is required.Further doses: The second and subsequent injections should be given at 13 week intervals, as long as the injection is given no later than seven days after this time, no additional contraceptive measures (e.g. barrier) are required. If the interval from the preceding injection is greater than 14 weeks (13 weeks plus 7 days) for any reason, then pregnancy should be excluded before the next injection is given. The efficacy of SAYANA PRESS depends on adherence to the recommended dosage schedule of administration.Post Partum: If the patient is not breast-feeding, the injection should be given within 5 days post partum (to increase assurance that the patient is not pregnant). If the injection is to be given at another time then the pregnancy should be excluded. If the patient is breast-feeding, the injection should be given no sooner than six weeks post partum, when the infant's enzyme system is more developed (see section 4.6).There is evidence that women prescribed SAYANA PRESS in the immediate puerperium can experience prolonged and heavy bleeding. Because of this, the drug should be used with caution in the puerperium. Women who are considering use of the product immediately following delivery or termination should be advised that the risk of heavy or prolonged bleeding may be increased. Doctors are reminded that in the non breast-feeding, post partum patient, ovulation may occur as early as week 4.Switching from other Methods of Contraception: When switching from other contraception methods, SAYANA PRESS should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g. patients switching from oral contraceptives should have their first injection of SAYANA PRESS within 7 days after their last active pill).Patients with hepatic impairment: The effect of hepatic disease on the pharmacokinetics of SAYANA PRESS is unknown. As SAYANA PRESS largely undergoes hepatic elimination it may be poorly metabolised in patients with severe hepatic insufficiency (see Section 4.3 Contraindications).Patients with renal impairment: The effect of renal disease on the pharmacokinetics of SAYANA PRESS is unknown. No dosage adjustment should be necessary in women with renal insufficiency, since SAYANA PRESS is almost exclusively eliminated by hepatic metabolism.
Paediatric populationSAYANA PRESS is not indicated before menarche (see Section 4.1 Therapeutic Indications). Data in adolescent females (12-18 years) is available for IM administration of MPA (see Section 4.4 Special Warnings and Precautions for Use and Section 5.1 Pharmacodynamic properties). Other than concerns about loss of BMD, the safety and effectiveness of SAYANA PRESS is expected to be the same for adolescents after menarche and adult females.
Loss of Bone Mineral Density:Use of depot MPA subcutaneous injection 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 subcutaneous injection 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 subcutaneous injection by younger women will reduce peak bone mass and increase the risk for fracture in later life. A study to assess the BMD effects of medroxyprogesterone acetate IM (Depo-Provera, DMPA) in adolescent females showed that its use was associated with a significant decline in BMD from baseline. In the small number of women who were followed-up, mean BMD recovered to around baseline values by 1- 3 years after discontinuing treatment. In adolescents, SAYANA PRESS may be used, but only after other methods of contraception have been discussed with the patients and considered to be unsuitable or unacceptable. 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 PRESS.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 osteoporosisA retrospective cohort study using data from the General Practice Research Database (GPRD) reported that women using MPA injections (DMPA), have a higher risk of fracture compared with contraceptive users with no recorded use of DMPA (incident rate ratio 1.41, 95% CI 1.35-1.47 for the five year follow-up period); it is not known if this is due to DMPA, or to other related lifestyle factors which have a bearing on fracture rate. By contrast, in women using DMPA, the fracture risk before and after starting DMPA was not increased (relative risk 1.08, 95% CI 0.92-1.26). Importantly, this study could not determine whether use of DMPA has an effect on fracture rate later in life.For further information on BMD changes in both adult and adolescent females, as reported in recent clinical studies, refer to section 5.1 (Pharmacodynamic Properties). 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 DMPA subcutaneous injection 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 DMPA subcutaneous injection, fewer experienced irregular bleeding and more experienced amenorrhea. After receiving the fourth dose, 39% of women experienced 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 DMPA subcutaneous injection persists or is severe, appropriate investigation and treatment should be instituted.
Figure 1. Percent of DMPA subcutaneous injection -Treated Women with Amenorrhea per 30-Day Month Contraception Studies (ITT Population, N=2053)
Figure 2. Percent of DMPA subcutaneous injection -Treated Women with Bleeding and/or Spotting per 30-Day Month Contraception Studies (ITT Population, N=2053)
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 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 who are never-users||Possible additional cases per 10,000 DMPA users|
|20||Less than 1||Much less than 1|
Thromboembolic DisordersAlthough 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 or retinal thrombosis or deep venous thrombosis, while undergoing therapy with SAYANA PRESS should not be readministered 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 PRESS use in this population.
Anaphylaxis and Anaphylactoid ReactionIf an anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.
Ocular DisordersMedication 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.
Weight ChangesWeight 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 RetentionThere 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 OvulationFollowing a single dose of DMPA subcutaneous injection, 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 DisordersPatients with a history of treatment for clinical depression should be carefully monitored while receiving SAYANA PRESS.
Protection Against Sexually Transmitted DiseasesPatients should be counselled that SAYANA PRESS does not protect against HIV infection (AIDS) or other sexually transmitted diseases.
Carbohydrate/MetabolismSome patients receiving progestogens may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.
Liver FunctionIf jaundice develops in any woman receiving SAYANA PRESS, consideration should be given to not re-administer the medication. (See section 4.3)
Hypertension and Lipid disordersLimited 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 PRESS treatment and/or the increase in hypertension cannot adequately be controlled by antihypertensive medication, treatment with SAYANA PRESS 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 PRESS should be used cautiously in patients with one or more of these risk factors.
Other conditionsThe 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.
Laboratory TestsThe 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.
ExcipientsAs this product contains methylparahydroxbenzoate and propylparahydroxbenzoate, 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'.If any of the conditions/risk factors mentioned is present, the benefits of SAYANA PRESS 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 PRESS use should be discontinued.
No interaction studies have been performed with SAYANA PRESS.Interactions with other medical treatments (including oral anticoagulants) have rarely been reported, but causality has not been determined. The possibility of interactions should be borne in mind in patients receiving concurrent treatment with other drugs.MPA is metabolized in-vitro primarily by hydroxylation via the CYP3A4. Specific drug-drug interaction studies evaluating the clinical effects with CYP3A4 inducers or inhibitors on MPA have not been conducted and therefore the clinical effects of CYP3A4 inducers or inhibitors are unknown.
PregnancySAYANA PRESS is contraindicated in women who are pregnant. Some reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. If SAYANA PRESS is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be warned of the potential hazard to the fetus.One study found that infants from unintentional pregnancies that occurred 1 to 2 months after injection of medroxyprogesterone acetate Injection 150 mg IM were at an increased risk of low birth weight; this, in turn, has been associated with an increased risk of neonatal death. However, the overall risk of this is very low because pregnancies while on medroxyprogesterone acetate Injection 150 mg IM are uncommon.Children exposed to MPA in utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.
LactationLow detectable amounts of drug have been identified in the milk of mothers receiving MPA. In nursing mothers treated with medroxyprogesterone acetate injection 150 mg IM, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to MPA from breast milk have been studied for developmental and behavioural effects through puberty. No adverse effects have been noted. However, due to limitations of the data regarding the effects of MPA in breastfed infants less than six weeks old, SAYANA PRESS should be given no sooner than six weeks post partum when the infant's enzyme system is more developed.
|System organ class||Very Common||Common||Uncommon||Rare||Not known|
|Infections and infestations||Vaginitis|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)||Breast cancer (see Section 4.4)|
|Immune system disorders||Hypersensitivity reactions (e.g. anaphylaxis & anaphylactoid reactions, angioedema (see Section 4.4)|
|Metabolism and nutrition disorders||Weight increase, weight decrease (see Section 4.4)||Fluid retention (see Section 4.4), increased appetite, decreased appetite|
|Pyschiatric disorders||Depression anorgasmia, anxiety, emotional disorder, affective disorder, libido decreased, irritability||Insomnia, nervousness|
|Nervous system disorders||Dizziness, headache||Migraine, somnolence||Convulsions|
|Ear and labyrinth disorders||Vertigo|
|Vascular disorders||Pulmonary embolus, thrombophlebitis, hypertension (see Section 4.4), varicose vein, hot flush||Thromboembolic disorders (see Section 4.4)|
|Gastrointestinal disorders||Abdominal pain, nausea||Abdominal distension|
|Hepatobiliary disorders||Hepatic enzyme abnormal||Jaundice, disturbed liver function (see Section 4.4)|
|Skin and subcutaneous tissue disorders||Acne||Chloasma, dermatitis, ecchymosis, rash, alopecia, hirsutism, pruritus, urticaria||Skin striae|
|Musculoskeletal and connective tissue disorders||Back pain, pain in limbs||Loss of bone mineral density (see Section 4.4),arthralgia, muscle cramps||Osteoporosis including osteoporotic fractures|
|Reproductive System & Breast Disorders||Amenorrhoea, breast pain/tenderness, dysmenorrhoea, metrorrhagia menometrorrhagia, menorrhagia (see Section 4.4)||Ovarian cyst, uterine haemorrhage (irregular, increase, decrease)vaginal discharge, vulvovaginal dryness, breast enlargement, dyspareunia, galactorrhoea, pelvic pain, premenstrual syndrome|
|General disorders and administration site conditions||Injection site reactions,* fatigue||Asthenia||Pyrexia|
|Investigations||Cervical smear abnormal||Decreased glucose tolerance (see Section 4.4)|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard
BMD Changes in Adult WomenA study comparing changes in BMD in women using DMPA subcutaneous injection with women using medroxyprogesterone acetate injection (150 mg IM) showed no significant differences in BMD loss between the two groups after two years of treatment. Mean percent changes in BMD in the DMPA subcutaneous injection group are listed in Table 1.
Table 1. Mean Percent Change from Baseline in BMD in Women Using DMPA subcutaneous injection by Skeletal Site
|Time on Treatment||Lumbar Spine||Total Hip||Femoral Neck|
|N||Mean % Change (95% CI)||N||Mean % Change (95% CI)||N||Mean % Change (95% CI)|
|1 year||166||-2.7 (-3.1 to -2.3)||166||-1.7 (-2.1 to -1.3)||166||-1.9 (-2.5 to -1.4)|
|2 year||106||- 4.1 (-4.6 to -3.5)||106||-3.5 (-4.2 to -2.7)||106||-3.5 (-4.3 to -2.6)|
|Time in Study||Spine||Total Hip||Femoral Neck|
|Medroxyprogesterone acetate||Control||Medroxyprogesterone acetate||Control||Medroxyprogesterone acetate||Control|
|5 years*||n=33 -5.38%||n=105 0.43%||n=21 -5.16%||n=65 0.19%||n=34 -6.12%||n=106 -0.27%|
|7 years**||n=12 -3.13%||n=60 0.53%||n=7 -1.34%||n=39 0.94%||n=13 -5.38%||n=63 -0.11%|
BMD Changes in Adolescent Females (12-18 years)Results from an open-label, non-randomised, clinical study of medroxyprogesterone acetate Injection (150 mg IM every 12 weeks for up to 240 weeks (4.6 years), followed by posttreatment measurements) in adolescent females (12-18 years) also showed that medroxyprogesterone acetate IM use was associated with a significant decline in BMD from baseline. Among subjects who received ≥ 4 injections/60-week period, the mean decrease in lumbar spine BMD was - 2.1 % after 240 weeks (4.6 years); mean decreases for the total hip and femoral neck were -6.4 % and -5.4 %, respectively. Post-treatment follow-up showed that, based on mean values, lumbar spine BMD recovered to baseline levels approximately 1 year after treatment was discontinued and that hip BMD recovered to baseline levels approximately 3 years after treatment was discontinued. However, it is important to note that a large number of subjects discontinued from the study, therefore these results are based on a small number of subjects (n=71 at 60 weeks and n=25 at 240 weeks after treatment discontinuation). In contrast, a non-comparable cohort of unmatched, untreated subjects, with different baseline bone parameters from the DMPA users, showed mean BMD increases at 240 weeks of 6.4%, 1.7% and 1.9% for lumbar spine, total hip and femoral neck, respectively.
|Table 1. Pharmacokinetic Parameters of MPA After a Single SC Injection of DMPA in Healthy Women (n = 42)|
|Cmax(ng/mL)||Tmax(day)||C91 (min) (ng/mL)||AUC0-91(ng·day/mL)||AUC0- ∞(ng·day/mL)||t½(day)|
AbsorptionMPA absorption from the SC injection site to achieve therapeutic levels is relatively prompt. The mean Tmax attained approximately one week after injection. The peak MPA concentrations (Cmax) generally range from 0.5 to 3.0 ng/mL with a mean Cmax of 1.5 ng/mL after a single SC injection.
Effect of Injection SiteDMPA was administered subcutaneously into the anterior thigh or the abdomen to evaluate effects on MPA concentration-time profile. MPA trough concentrations (Cmin; Day 91) were similar for the two injection locations, suggesting that injection site does not negatively affect the contraceptive efficacy.
DistributionPlasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin; no binding of MPA occurs with SHBG.
BiotransformationMPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites.
EliminationResidual MPA concentrations at the end of the dosing interval (3 months) of DMPA subcutaneous injection are generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after SC administration. Most MPA metabolites are excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates.
Linearity/non-linearityBased on single-dose data, there was no evidence of non-linearity over the dose range of 50 to 150 mg after SC administration. The relationship between the AUC or the Cmin and the SC dose of MPA appeared to be linear. The mean Cmax did not change substantially with increasing dose
RaceThere were no apparent differences in the pharmacokinetics and/or dynamics of MPA after SC administration of DMPA among women of all ethnic backgrounds studied. The pharmacokinetics/dynamics of MPA has been evaluated in Asian women in a separate study.
Effect of Body WeightNo dosage adjustment of SAYANA PRESS is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA was assessed in a subset of women (n = 42, body mass index [BMI] ranged from 18.2 to 46.0 kg/m2). The AUC0-91 values for MPA were 68.5, 74.8, and 61.8 ng -day/mL in women with BMI categories of ≤ 25 kg/m2, >25 to ≤30 kg/m2, and >30 kg/m2, respectively. The mean MPA Cmax was 1.65 ng/mL in women with BMI ≤ 25 kg/m2, 1.76 ng/mL in women with BMI >25 to ≤30 kg/m2, and 1.40 ng/mL in women with BMI > 30 kg/m2, respectively. The range of MPA trough (Cmin) concentrations and the half-lives were comparable for the 3 BMI groups.
Pharmacokinetic/Pharmacodynamic Relationship(s)From a pharmacodynamic perspective, the duration of ovulation suppression depends upon maintaining therapeutic MPA concentrations throughout the 13 week dosing interval.
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- medroxyprogesterone acetate