50 mg + 0.5 mg/ml
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is a combined hormonal contraceptive formulated as a depot preparation. NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION contains two different female
hormones. These are norethisterone enanthate (a progestogen) and estradiol valerate (an estrogen). Chemically, Norethisterone Enanthate is 17alpha-Ethynyl-19-nortestosterone 17-heptanoate. The molecular formula is C27H38O3 and molecular weight is 410.59. Chemically, Estradiol valerate is 3-Hydroxyestra-1,3,5(10)-trien-17β-yl pentanoate. The molecular formula is C23H32O3 and molecular weight is 356.5.
STRUCTURAL FORMULA :
Its structural formula is :
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is a sterile, pale yellow oily solution filled in amber ampoule of suitable size.
Each ml contains :
Norethisterone Enanthate 50 mg
Estradiol Valerate B.P. 0.5 mg
Benzyl Alcohol B.P. 2 % v/v
Oily base q.s.
Each ml contains :
Norethisterone Enanthate 50 mg
Estradiol Valerate B.P. 5 mg
Benzyl Alcohol B.P. 2 % v/v
Oily base q.s.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION prevents pregnancy primarily by inhibiting ovulation and changing the cervical mucus. The effect produced on the endometrium is similar to that observed with the use of combined oral contraceptives (COCs). A pattern of bleeding similar to normal menstruation is obtained with the use of NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION. The contraceptive effectiveness of the monthly injections of NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION compares favourably to the effectiveness of methods which use isolated and progestogens effectiveness of oral contraceptives. As NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION contains an estrogen and a progestogen, the precautions related to its use are similar to those of COCs. Since the estrogen component is a natural estrogen, administration is parenteral and the circulating levels reach peaks that are in the range of those of the normal preovulatory phase of the menstrual cycle. The progestogen component exerts typical progestogens effects in women, such as antigonadotropic effects, secretory transformation of endometrium and thickening of the cervical mucus. NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION presents favourable effect on lipid metabolism. Combined injectable contraceptives as NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION demonstrated having minimal effect on liver function in healthy and users do not have hepatic first-pass effect. However, once the steroids hormones contained in combined injectable contraceptives are metabolized in the liver, they could theoretically cause adverse effects in women whose liver function was already compromised.
Pharmacologically active components, estradiol and norethisterone, are completely bioavailable after intramuscular injection of norethisterone enanthate and estradiol valerate. After intramuscular injection of 50 mg of norethisterone enanthate in combination with estradiol valerate 5 mg, the maximum plasma concentration of estradiol (average between 852 and 1570 pmol/L) is reached in about 2 days and the maximum plasma concentration of norethisterone from 4.7 to 10.1 nmol/L in approximately 4.1 to 4.8 days after intramuscular injection. Since the estradiol terminal half-life is considerably shorter than the norethisterone (which, in turn, is due to the different clearances level of the ester of the drug from the reservoir) the second part of the treatment cycle is dominated by component progestagen.
Both components are completely metabolized. The biotransformation of estradiol follows the same path as the endogenous hormone. Norethisterone and its metabolites are excreted in approximately equal amounts in urine and faeces. The excretion of metabolites of estradiol occurs predominantly in the urine. At least 85 % of the dose of both substances are excreted within the injection interval of 28 days. Repeated administration of NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION at intervals of 28 days cause a slight accumulation of norethisterone enanthate, reaching steady state conditions after the third administration. As the pharmacokinetics and biotransformation, do not expect any interaction between norethisterone enanthate and estradiol valerate, it is not likely to be an overload of metabolism due to the slow release rates and low serum concentrations of the substances consecutive active.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is for deep intramuscular use given very slowly into gluteal muscle. It is advisable to place a plaster over the injection site after the injection to prevent any reflux of the NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION solution.
Note : A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy; however, this does not affect the potency of the material.
INSTRUCTIONS FOR USE OF AMPOULE :
The ampoule used in this product is equipped with O.P.C. (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION should only be administered to women with a history of normal cycles. Before starting the NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION, a thorough general medical and gynaecological examination (including the breasts) should be carried out and pregnancy must be excluded.
When not used any hormonal contraceptive in the previous month :
The first injection should be administered on the first day of the menstrual cycle (first day of bleeding). Can also start on cycle days 2-5, but in this case it is recommended to use an additional barrier method for the first 7 days after injection.
When you have taken a combined pill before :
Preferably a woman should start using NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION immediately after taking active tablets for at least 7 days or directly after the last active tablet from the container. To override a method based on progestogen only (mini-pill, injection, implant) or intrauterine system (IUS) releasing progestogen : A woman can replace the mini-pill any day (in the case of an implant or a IUS, the same day of his retirement, whether it is an injectable when the next injection), but in all such cases should be advised to additionally use a barrier method during the first 7 days after injection.
After an abortion in the first quarter :
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION be administered at any time within one week following an abortion. Following these instructions need not take additional contraceptive measures.
After delivery or abortion of the second quarter :
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION should be administered between 21 and 28 day after delivery or abortion in the second quarter or the first postpartum menstruation. Doing so later, she should be advised to additionally use a barrier method during the first 7 days after NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION. However, if the woman has had sex, be excluded that a pregnancy has occurred before the start of NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION or she should expect to have their first menstrual period.
Subsequent injections management :
The second and subsequent injections are given, regardless of the menstrual cycle pattern, at intervals of 30 ± 3 days, i.e. at least 27 and at most 33 days. If the injection interval beyond the maximum of 33 days is exceeded, you can not run from that date with the necessary degree of contraceptive security and you must use additional contraceptive measures; well, you should consult your doctor what action to take. If within 30 days after injection no withdrawal bleeding arises, must first be evaluated for pregnancy through a reliable test.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is contraindicated in :
- Presence or history of thrombotic / thromboembolic arterial or venous (e.g. deep vein thrombosis, pulmonary embolism, myocardial infarction) or stroke.
- Presence or history of previous symptoms of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
- History of migraine with focal neurological symptoms.
- Diabetes mellitus with vascular involvement.
- The presence of a serious risk factor or multiple risk factors for arterial or venous thrombosis may also constitute a contraindication.
- Presence or history of severe liver disease while the liver function values have not returned to normal.
- Presence or history of liver tumours (benign or malignant).
- Known or suspected neoplasms, influenced by sex steroids (e.g. of the genital organs or the breasts).
- Vaginal bleeding undiagnosed.
- Known or suspected pregnancy.
- Hypersensitivity to the active substances or any of the excipients.
There is epidemiological studies combined injectable contraceptives (CICs) assessing risk factors. In general, experience with the use of combined oral contraceptives (COCs), and warnings concerning the precautions should be taken as a basis for the use of CICs. In the event of any of the conditions or risk factors mentioned below, the benefits of using combined contraceptives should be weighed against the possible risks for each user individually and discussed with the same before opting for early use. In cases of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact your doctor. In such cases, the continued use of the product should be the physician’s discretion.
Circulatory disorders :
Epidemiological studies have suggested an association between the use of COCs and an increased risk of thromboembolic disorders and thrombotic arterial and venous, such as myocardial infarction, deep vein thrombosis, pulmonary embolism and stroke. The occurrence of these events is rare. The risk of VTE is highest during the first year of the hormonal contraceptive use. This increased risk is present after starting for the first time the use of COC or restarting use (after an interval of four weeks or more unused pill) of the same COC or another COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months. Overall the risk for venous thromboembolism (VTE) in users of low oestrogen dose (< 50 µg ethinyloestradiol) CICs is two to threefold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery. VTE may be life-threatening or may have a fatal outcome (in 1-2 % of the cases). Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all CICs. Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.
Symptoms of deep vein thrombosis (DVT) can include : unilateral swelling in leg or along the vein from the leg, pain or tenderness in the leg that can be felt only when you are standing or walking, increased warmth in the affected leg, discoloration or leg skin hyperaemia.
Symptoms of pulmonary embolism (PE) can include : sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may bring up blood; sharp chest pain, which may increase with deep breathing; sense of anxiety; severe light headedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). Symptoms of a cerebrovascular accident can include : sudden numbness or weakness of the face, arm or leg, especially on one side of the body; sudden confusion, trouble speaking or
understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include : sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.
Symptoms of myocardial infarction (MI) may include : pain, discomfort, pressure, weight, tightness or fullness in the chest, arm or below the breastbone; discomfort radiating to the back, jaw, neck, arms, stomach; satiety, indigestion or choking sensation, sweating,
nausea, vomiting or dizziness, extreme weakness, anxiety, or dyspnoea, tachycardia or cardiac arrhythmia. Arterial thromboembolic events may be life-threatening or may have a fatal outcome. The potential for synergistic an increased risk of thrombosis should be considered women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative lifetime risk factors. A CIC should not be prescribed in case of a negative benefit-risk assessment.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism. One must consider the increased risk of thromboembolism in the puerperium. Other clinical conditions that have also been associated with adverse circulatory events in include : diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis). No data are available on the use of CICs in users who have sickle
cell anaemia, however, users who have homozygous sickle cell disease may have an increased risk of thrombosis.
Pregnancy : Category X
In animal studies and pregnant women, the drug caused foetal anomalies, with clear evidence of harm to the foetus that is greater than any possible benefit for the patient. NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION should not be used for pregnant women.
Nursing mothers :
There appear to be no adverse effects on infant growth or development when using NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION after six weeks postpartum. NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION does not appear to affect the quantity or quality of breast milk, however, minute amounts of the active substance are excreted with the milk and although considered harmless to a healthy neonate, might theoretically, like other steroids, impair the degradation of bilirubin, especially during the first week of life. If the mother has received NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION, breast-feeding should therefore be withheld from neonates with severe or persistent jaundice requiring medical treatment.
Paediatric use :
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION are not indicated for children.
The effectiveness of norethisterone enanthate and estradiol valerate may be reduced when it is taken with :
- Rifamycins such as rifabutin and rifampicin.
- Antiepileptics such as carbamazepine, phenytoin phenobarbital, primidone and topiramate.
- Antiviral medicines such as nevirapine.
- Anti-bacterials such as tetracycline, chloramphenicol, metronidazole.
Barrier contraception must be used whilst taking any of these combinations, and should be continued for seven days after stopping the other medicine. Norethisterone enanthate and estradiol valerate may increase the blood levels of cyclosporin and individuals taking this combination should be carefully monitored. Norethisterone enanthate and estradiol valerate may affect the control of diabetes. Individuals taking anti-diabetic medicines together with this contraceptive should monitor their blood sugar levels and the dose of the anti-diabetic adjusted if necessary.
Drug/Laboratory Test Interactions :
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and betathromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum (i.e. corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.
Do not dilute with water.
SIDE EFFECTS :
The following side effects have been reported with estrogen and/or progestin therapy.
1. Genitourinary system :
Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhoea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
2. Breasts :
Tenderness, enlargement, pain, nipple discharge, galactorrhoea; fibrocystic breast changes; breast cancer.
3. Cardiovascular :
Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
4. Gastrointestinal :
Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
5. Skin :
Chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
6. Eyes :
Retinal vascular thrombosis; intolerance to contact lenses.
7. Central Nervous System :
Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
8. Miscellaneous :
Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; oedema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcaemia; exacerbation of asthma; increased triglycerides.
Presentation of a single use injectable and administration by a physician minimize the risk of overdose. There have been no reports of serious deleterious effects from overdose.
TREATMENT OF OVERDOSAGE :
There are no antidotes and further treatment should be symptomatic.
PHARMACEUTICAL PRECAUTIONS :
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Store below 30°C (86°F), protected from light.
Do not refrigerate.
Warming and rotating the ampoule between the palms of the hands will redissolve any crystals that may have formed during storage at low temperatures.
SHELF LIFE :
24 months from the date of manufacture.
NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is supplied as 50 mg of Norethisterone enanthate and 0.5 mg of Estradiol Valerate B.P. in 1 ml oily Solution. Each 1 ampoule is packed in a carton with package insert. NORETHISTERONE ENANTHATE AND ESTRADIOL VALERATE INJECTION is supplied as 50 mg of Norethisterone enanthate and 5 mg of Estradiol Valerate B.P. in 1 ml oily Solution.
Each 1 ampoule is packed in a carton with package insert.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.