Lenzetto®
Qualitative and Quantitative Composition
Active ingredient(s)
Each actuation delivers
Estradiol Ph. Eur.............................1.53 mg
(Equivalent to 1.58 mg Estradiol hemihydrate)
Ethanol 96% USP.............................0.09 ml
(Octisalate USP and Ethanol 96% use as excipients)
List of Excipients
Octisalate USP, Ethanol 96% USP.
Dosage Form and Strength
Transdermal spray, solution, 1.53 mg/actuation.
The solution is clear, colourless to pale yellow.
Therapeutic Indication
Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in Peri / postmenopausal women (in women at least 6 months since last menses or surgical menopause, with or without a uterus).
The experience in treating women older than 65 years is limited.
Posology
Lenzetto® is administered once daily, either as a monotherapy or as a continuous sequential treatment (when combined with a progestogen).
One metered-dose actuation is administered once daily to the dry and healthy skin of the forearm as a starting dose. The dose may be increased to two metered-dose actuations daily to the forearm based on clinical response. Dose increase should be based on the degree of the woman’s menopausal symptoms and should be made only after at least 4 weeks of continuous treatment with Lenzetto®. The maximum daily dose is 3 metered-dose actuations (4.59 mg/day) to the forearm. Dose increase should be discussed with the physician. For patients who have difficulty applying the prescribed dose to distinct, non-overlapping areas of the same forearm, Lenzetto® may also be applied to sites on the alternate forearm, or to sites on the inner thigh.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration - should be used.
When the degree of the woman’s menopausal symptoms is not reduced after a dose increase, the patient should be back-titrated to the previous dose.
Patients should be re-evaluated periodically as clinically appropriate (e.g. 3-month to 6-month intervals) to determine if treatment is still necessary.
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestogen approved for addition to estrogen treatment should also be initiated to reduce the risk of endometrial cancer. Only progestogens approved for addition to estrogen treatment should be administered.
In women with a uterus
In women with an intact uterus, the product should be combined with a progestogen approved for addition to estrogen treatment in a continuous sequential dosing scheme: the estrogen is dosed continuously. The progestogen is added for at least 12 to 14 days of every 28-day cycle, in a sequential manner.
Advice on how to initiate treatment should be given for treatment naive patients and for patients changing from other HRTs (cyclic, sequential or continuous combined).
In the period in which the estrogen is combined with the progestogen, a withdrawal bleeding can occur. A new 28-day treatment cycle is started without a break.
In women without a uterus
Unless there is a previous diagnosis of endometriosis, it is not recommended to add progestogen for women without a uterus.
Elevated skin temperature
The effect of increased ambient temperature with Lenzetto® has been studied and clinically relevant difference in the extent of absorption of Lenzetto® was not observed. However, Lenzetto® should be used with caution in extreme temperature conditions, such as sun bathing or sauna.
Application of sunscreen
When sunscreen is applied about one hour following Lenzetto®, estradiol absorption may be decreased by 10%. When sunscreen was applied about one hour prior to Lenzetto®, no effect on absorption was observed.
Overweight and obese women
There is some limited data that the rate and extent of absorption of Lenzetto® can be reduced in overweight and obese women. During the treatment, the dose of Lenzetto® may require adjustment.
Dose modification should be discussed with the physician.
Paediatric population
There is no relevant use of Lenzetto® in the paediatric population.
Missed dose
If a dose is missed, the patient should make up for the missed dose as soon as she remembers and take the next dose at the usual time. If it is almost time for the next dose, she should skip the missed dose and take the next dose at the usual time. If one or more doses are missed one primer spraying with the cover on is needed. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.
Method of Administration
The container should be held upright and vertical for spraying. Before a new applicator is used for the first time, the pump should be primed by spraying three times into the cover.
The daily dose is one metered-dose actuation on the inner forearm. If two or three actuation are prescribed as the daily dose, they should be applied to adjacent non-overlapping (side- by-side) 20 cm2 areas on the inner surface of the arm between the elbow and the wrist and allowed to dry for approximately 2 minutes. Women should cover the application site with clothing if another person may come into contact with that area of skin after the spray dries. The site of application should not be washed for 60 minutes. Do not allow another person to touch the site of application within 60 minutes of application.
Do not allow children to come in contact with the area of the arm where Lenzetto® was sprayed. If a child comes in contact with the part of the arm where Lenzetto® was sprayed, wash the child’s skin with soap and water as soon as possible.
Do not allow pets to lick or touch the arm where Lenzetto® was sprayed. Small pets may be especially sensitive to the estrogen in Lenzetto®. Contact a veterinarian if your pet exhibits mammary/ nipple enlargement and/or vulvar swelling, or any other sign of illness.
Studies suggest that compared to applying it to the inner surface of the forearm, absorption of estradiol is similar when Lenzetto® is applied to the skin of the thigh but is lower when applied to the skin of the abdomen.
If the product is used according to the instructions, irrespective of different spray shape or pattern on the skin each puff will deliver the same amount of ingredient on the skin.
Contraindications
- Known, past or suspected breast cancer;
- Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer);
- Undiagnosed genital bleeding;
- Untreated endometrial hyperplasia;
- Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism);
- Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency);
- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);
- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal;
- Porphyria;
- Hypersensitivity to the active substance or to any of the excipients.
Special Warnings and Precautions for Use
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Medical examination/follow-up
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below). Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions, which need supervision
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Lenzetto®, in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- Risk factors for thromboembolic disorders (see below)
- Risk factors for estrogen-dependent tumours, e.g. first-degree heredity for breast cancer
- Hypertension
- Liver disorders (e.g. liver adenoma)
- Diabetes mellitus with or without vascular involvement
- Cholelithiasis
- Migraine or (severe) headache
- Systemic lupus erythematosus
- A history of endometrial hyperplasia (see below)
- Epilepsy
- Asthma
- Otosclerosis
Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
- Jaundice or deterioration in liver function
- Significant increase in blood pressure
- New onset of migraine-type headache
- Pregnancy
Endometrial hyperplasia and carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose. After stopping treatment, risk may remain elevated for at least 10 years.
The addition of a progestogen cyclically for at least 12 days per month/28-day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
For Lenzetto®, the endometrial safety of added progestogens has not been studied.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
Breast cancer
The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HRT, that is dependent on the duration of taking HRT.
Combined estrogen-progestogen therapy
The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 (1 – 4) years.
Estrogen-only therapy
The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen-progestogen combinations.
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images, which may adversely affect the radiological detection of breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial suggest that the use of combined HRTs may be associated with a similar, or slightly smaller, risk.
Venous thromboembolism
HRT is associated with a 1.3-3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.
Generally recognised risk factors for VTE include, use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first-degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit risk of use of HRT.
If VTE develops after initiating therapy, the drug must be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen- progestogen or estrogen-only HRT.
Combined estrogen-progestogen therapy
The relative risk of CAD during use of combined estrogen + progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen + progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Estrogen-only therapy
Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Ischaemic stroke
Combined estrogen-progestogen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.
Visual abnormalities
Retinal vascular thrombosis has been reported in women receiving estrogens. Medication must be discontinued immediately, pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
ALT-elevations
During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section Drug interactions.
Other conditions
Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I- antitrypsin, ceruloplasmin).
HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.
Application of sunscreen
When sunscreen is applied about one hour following Lenzetto®, estradiol absorption may be decreased by 10%. When sunscreen was applied about one hour prior to Lenzetto®, no effect on absorption was observed.
Elevated skin temperature
The effect of increased ambient temperature has been studied and approximately 10% difference was observed in the absorption of Lenzetto®. This effect is not expected to be of clinical relevance for daily administration of Lenzetto®. Nevertheless, Lenzetto® should be used with caution in extreme temperature conditions, such as sunbathing or sauna.
Excipient
This medicine contains 65.47 mg of alcohol (ethanol) in each dose which is equivalent to 72.74%w/v. It may cause burning sensation on damaged skin.
Alcohol-based products are flammable. Keep away from fire. While using the device, open flame, lit cigarette or use of some hot devices (e.g. hairdryers) should be avoided, until the spray has dried on the skin.
Patient Counseling Information
What is Lenzetto® and what it is used for?
Lenzetto® is a Hormone Replacement Therapy (HRT) containing the female hormone estrogen. It is used to alleviate the symptoms of menopause such as hot face, neck and chest (hot flushes), sweating in the whole body, sleeping problems, irritability and dryness of the vagina in postmenopausal women (women with at least 6 months since their last natural period) and in those women who had undergone surgery to remove their ovaries (which causes instant menopause).
Lenzetto® is a spray solution which contains small amounts of a medicine called estradiol. When sprayed onto the skin as directed, it passes through the skin into your bloodstream.
What you need to know before you use Lenzetto®?
Before starting (or restarting) treatment with Lenzetto® your doctor will ask you, about your own and your family’s medical history, if necessary, he may perform physical examination including breast and internal examination. Once you have started on Lenzetto® meet and consult your doctor at least once a year. At these check-ups, discuss with your doctor the benefits and risks of continuing with Lenzetto®. Go for regular breast screening, as recommended by your doctor.
The use of HRT carries risks which need to be considered when deciding whether to start using it, or whether to carry on using it.
The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited. If you have a premature menopause the risks of using HRT may be different. Please talk to your doctor.
Lenzetto® is not a contraceptive.
In what conditions, you should not use Lenzetto®?
You should not use Lenzetto®, if you have or ever had or if you are suspected of having it - breast cancer, cancer which is sensitive to estrogens, such as cancer of the womb lining (endometrium), unexplained vaginal bleeding, excessive thickening of the womb lining (endometrial hyperplasia) and not being treated for it, blood clot in a vein (thrombosis such as deep venous thrombosis or pulmonary embolism), blood clotting disorder (such as protein C, protein S or antithrombin deficiency), blood clots in the arteries (heart attack/stroke/angina), liver disease (and your liver function tests have not returned to normal), rare blood problem called porphyria or if you are allergic to estradiol or any of the other ingredients of this medicine.
How to use Lenzetto®?
When a new applicator is used for the first time, the pump should be primed by spraying three times with the cover on. DO NOT prepare the applicator before each dose; only prepare the applicator once before starting to use a new container.
Make sure that the skin where you want to spray the medicine is healthy, clean and dry (not to be used on broken or damaged skin).
Take off the plastic cover, hold the container upright and rest the plastic cone flat against the skin without keeping any gap between the cone and skin.
Press the actuator button right down once. It should be pushed always fully and held down before releasing.
If another spray is needed, move the cone along your arm so that it is beside the area you have already sprayed. Press the button right down onetime.
If a third spray is needed, move the cone along your arm again and press the button right down one time. If your second or third spray will not fit the same inner forearm, you may also spray onto your other inner forearm.
If you have any difficulty in using Lenzetto® on the forearms, you may also spray onto the inner surface of your thigh. DO NOT apply Lenzetto® to the breasts or any area near the breasts.
When you have finished using Lenzetto®, always put the cover back on the container.
Let the spray dry for at least 2 minutes before getting dressed and at least 60 minutes before bathing or washing. If you get Lenzetto® spray on another area of your skin like your hands, wash that area of your skin with soap and water right away.
Do not massage or rub Lenzetto® into the skin.
Do not allow other people or pets to touch the area of the skin where the spray was applied for at least 60 minutes. If another person (especially a child) accidentally touches the area of your skin where you sprayed Lenzetto®, tell that person to wash the area of their skin with soap and water right away. Therefore, the sprayed area should be covered with clothing 2 minutes after application of the spray.
Avoid using sunscreen on the part of the skin where you intend to spray Lenzetto®. However, if you need to use sunscreen, it should be applied at least one hour prior to using.
If you forget to use Lenzetto® at your normal time, spray the medicine on as soon as you remember, and then use it as you normally would the next day. If it is almost time for your next dose, just wait and apply the next dose as you normally would. If you forget one or more doses one primer spraying with the cover on is needed. Do not use a double dose to make up for a forgotten dose. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.
Do not use each Lenzetto® container for more than the labelled number of sprays even though the bottle may not be completely empty.
In what conditions, you should stop using Lenzetto® and see a doctor immediately?
if you suffer from any condition mentioned in the third question “In what conditions, you should not use Lenzetto®”;
skin or whites of your eyes starts yellowing (jaundice);
a large rise in blood pressure (symptoms may be headache, tiredness, dizziness);
in case of migraine like headaches which happen for the first time;
signs of a blood clot such as - painful swelling, redness of the legs, or sudden chest pain, or difficulty in breathing;
if you become pregnant.
What medicines you should not take along with Lenzetto®?
Some medicines interfere with the effect of Lenzetto® and might lead to irregular bleeding, e.g. medicines for epilepsy (such as phenobarbital, phenytoin and carbamazepine), tuberculosis (such as rifampicin, rifabutin), HIV infection (such as nevirapine, efavirenz, ritonavir, and nelfinavir) and herbal remedies containing St John’s Wort (Hypericum perforatum). You should consult your doctor if you are taking or have recently taken these or any other medicines.
If you need a blood test, tell your doctor or the laboratory staff that you are using Lenzetto® because this medicine can affect the results of some tests.
What are the possible side effects of Lenzetto®?
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects below have been reported with Lenzetto®:
Common side effects (may affect up to 1 in 10 people): Headache, abdominal pain, nausea, rash, itching, irregular uterine bleeding or vaginal bleeding including spotting, breast tenderness, breast pain, weight increase or weight decrease.
Uncommon side effects (may affect up to 1 in 100 people): Hypersensitivity reactions, depressed mood, difficulty in sleeping, dizziness, vertigo (a feeling of dizziness or “spinning”), visual disturbances, palpitations (feeling your heartbeat), diarrhoea, indigestion, increased blood pressure, erythema nodosum (characterized by painful reddish skin nodules), hives (general or localised rash or lumps), skin irritation, swelling due to fluid retention (oedema), muscle pain, breast discolouration, breast discharge, polyps (small growths) in the uterine or cervix, endometrial hyperplasia, ovary cyst, inflammation of genitals (vaginitis), increased liver enzymes and blood cholesterol, underarm pain.
Rare side effects (may affect up to 1 in 1000 people): Anxiety, decrease or increase in sexual drive, migraine, intolerance to contact lenses, bloating, vomiting, increased body hair, acne, muscle cramps, painful menstruation, premenstrual like syndrome, breast enlargement, fatigue.
Other side effects, with frequency “not known” (frequency cannot be estimated from the available data) have been reported with Lenzetto® during post-marketing surveillance: hair loss (alopecia), chloasma (golden brown pigment patches on the face; also called “pregnancy patches”), skin discolouration (for more information see section “Undesirable effects”).
If any adverse event occurred, please report to us via:
Toll Free No: 18001034746
Email: drugsafety@themismedicare.com
Link to download form - https://www.themismedicare.com/adverse-events/