Harmonet

/ Pfizer

Regular daily intake: of tablets for 21 consecutive days is important for the preservation of contraceptive efficacy. Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval during which time a withdrawal bleed occurs. This usually starts on day 2-3 after the last tablet and may not have finished before the next pack is started.
No hormonal: contraceptive use within the preceeding month The user should begin taking “Harmonet” on Day 1 of her natural menstrual cycle (i.e. the first day of her menstrual bleeding). Beginning “Harmonet” use on days 2-7 of the menstrual cycle is allowed, however a nonhormonal back-up method of birth control [such as, condoms and spermicide] is recommended during the first 7 days of “Harmonet” use. Switching from another combined oral contraceptive (COC) Preferably “Harmonet” use should begin on the day after the last active tablet of the previous COC, but no later then the day following the usual tablet-free or inactive tablet interval of the previous COC.
Switching from a progestin: only method of birth control (pill, implant, intrauterine device [IUD] injection)) The user may discontinue use of the progestin only pill on any day; use of “Harmonet”should begin the following day. “HARMONET” use should begin on the same day that a progestin only implant or a progestin only IUD is removed. “Harmonet”use should begin on the day that the next progestin only injection is scheduled
In each of these situations, the user should be advised to additionally use a back-up method of birth control during for the first 7 days of “Harmonet” use.
Following first trimester abortion: The woman may start immediately. When doing so, she need not take additional contraceptive measures.
Postpartum: Because the immediate post-partum period is associated with an increased risk of thromboembolism, “Harmonet” use should begin no sooner than the 28th postpartum day after delivery or second-trimester abortion. The woman should be advised to additionally use a back- up method for the first 7 days of tablet taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of Harmonet use or the woman has to wait for her first menstrual period before beginning Harmonet use.
For full details see prescribing information.

Contraceptive.

· Presence or risk of arterial thromboembolism (ATE):
– Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
– Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
– Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
– History of migraine with focal neurological symptoms.
– A high risk of arterial thromboembolism due to multiple risk factors or to the  presence of one serious risk factor such as:
diabetes mellitus with vascular symptoms (micro or macroangiopathy)
severe hypertension
severe dyslipoproteinaemia
– Coronary disease
· Presence or risk of venous thromboembolism (VTE):
– Venous thromboembolism – current VTE (on anticoagulants) or history of VTE (eg. deep venous thrombosis [DVT] or pulmonary embolism [PE])
– Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
– Major surgery with prolonged immobilisation
– A high risk of venous thromboembolism due to the presence of multiple risk factors
· Thrombogenic valvulopathy;
· Thrombogenic arrhythmias;
· Suspected or confirmed breast cancer;
· Suspected or confirmed oestrogen-sensitive neoplasms (endometrial etc.);
· Hepatic adenoma or carcinoma;
· Severe hepatic disorders – until hepatic function has normalised;
· Abnormal vaginal bleeding of unknown cause;
· Suspected or confirmed pregnancy;
· Hypersensitivity to the active substances or to any of the excipients.
· This medicinal product is contraindicated for concomitant use with the medicinal products containing ombitasvir/ paritaprevir/ritonavir and dasabuvir, or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/ velpatasvir/voxilaprevir.

Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as this medicinal product may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors.
It is estimated  that out of 10,000 women who use a CHC containing gestodene between 9 and 12 women will develop a VTE in one year; this compares with about 62 in women who use a levonorgestrel-containing CHC.
In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period. VTE may be fatal in 1-2% of cases.
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. See prescribing information for list of symptoms of deep vein thrombosis (DVT) or pulmonary embolism (PE).
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (eg transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). This medicinal product is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed.
Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
For list of symptoms of a cerebrovascular accident or MI, see prescribing information.
Gynaecological cancers
Published data do not demonstrate a causal relationship with the use of oral contraceptives whose benefits appear higher than the risks. However, all women who use this type of product should be kept under close medical supervision. If unexpected vaginal bleeding occurs, the necessary diagnostic measures should be taken to exclude a pregnancy, a malignant tumour or other possible causes.
Hepatic tumours and diseases
In very rare cases, benign hepatic tumours such as hepatic adenoma – and in even rarer cases, malignant hepatic tumours such as hepatocellular carcinoma – have been reported in oral CHC users. The risk of developing a tumour increases with the duration of treatment. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhage.
Women with a history of oral CHC-related cholestasis and women who develop cholestasis during pregnancy are more likely to develop cholestasis with oral CHC use. Such patients who use oral CHCs should be carefully monitored, and oral CHC use should be discontinued if cholestasis recurs.
Hepatocellular injury has been reported with oral CHC use. Early identification of drug-related hepatocellular injury can decrease the severity of hepatotoxicity when the drug is discontinued. If hepatocellular injury is diagnosed, patients should stop their oral CHC, use a non-hormonal form of contraception and consult their doctor.
Acute or chronic disturbances of liver function may necessitate the discontinuation of oral CHC use until liver function has returned to normal.
Headaches and migraine
The occurrence or aggravation of a migraine or the development of a new type of recurrent persistent or severe headache requires the immediate discontinuation of treatment and a search for the cause.
Users suffering from migraine (particularly those with aura) under treatment with oral CHCs can present a higher risk of developing a cerebrovascular accident.
Ocular lesions
Cases of retinal vascular thrombosis capable of causing partial or complete blindness have been associated with usage of oral CHCs. The use of oral CHCs must be discontinued immediately if one of the following phenomena occur:
– painless blurred vision
– inexplicable loss of sight, gradual or sudden, partial or complete;
– proptosis or diplopia;
– papillary oedema;
– signs of retinal vascular lesions or optic neuritis.
In these cases, the necessary diagnostic and therapeutic measures must be taken.
Hypertension
A rise in arterial blood pressure has been reported in some users of oral CHCs. Another method of contraception should be used in women with hypertension, a history of hypertension or a hypertension based on a pathology (including certain renal pathologies). If an oral CHC is used in these patients, close medical monitoring is recommended and use of the contraceptive should be stopped if there is a significant increase in blood pressure.
Oral CHCs are contraindicated in patients with uncontrolled hypertension.
Genital bleeding or absence of menstruation
In some women withdrawal bleeding may not occur during the tablet-free interval. If the oral CHC has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, pregnancy should be excluded before continuing the use of oral CHCs and a nonhormonal back-up method of contraception should be used until the possibility of pregnancy is excluded.
Metrorrhagia and/or intercurrent blood loss (spotting) sometimes occurs, especially during the first three months that the tablets are taken. Hence any irregular bleeding does not need require investigation before an adaptation period of about three cycles.
If metrorrhagia and/or spotting are persistent, occur at irregular intervals during several successive cycles, or for the first time after prolonged use, a possible organic cause should be investigated. Suitable diagnostic measures should be taken to exclude a pregnancy or tumour.
Once a pathological cause has been excluded, the problem of metrorrhagia may be solved by the continuation of the use of this drug or a switch to another hormonal contraceptive. However, due to the increased risk of thromboembolic diseases, great caution is necessary when considering a switch to a pill containing a higher dose of oestrogen.
Some women can present with oligomenorrhoea or amenorrhoea (possibly accompanied by anovulation) after ending oral contraceptives, especially if these problems were already present before treatment was started. These phenomena generally stop spontaneously. If they are prolonged, it may be necessary to investigate a possible pineal gland pathology.
Depression
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use. Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Women with a history of depression should be closely monitored. If a serious depression develops during the treatment, it should be stopped and another method of contraceptive should be used to determine the causality.
Immunity
Angio-edema: Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Glucose and lipid metabolism
Glucose intolerance has been reported in users of oral CHCs. Users of oral CHCs who have glucose intolerance or suffer from diabetes mellitus should be closely monitored.
Women under oral contraceptives who are being treated for hyperlipidaemia (hypertriglyceridaemia, hypercholesterolaemia) should be closely monitored. A small portion of women will have adverse lipid changes while taking oral CHCs. Use of an additional non-hormonal, mechanical method of contraception is recommended in women with uncontrolled dyslipidemias. Persistent hypertriglyceridaemia can occur in a low proportion of oral CHC users. Elevations of plasma triglycerides in oral CHC users may lead to pancreatitis and other complications. If the hypertriglyceridaemia cannot be controlled, a non-hormonal method of contraception should be considered.
Other warnings
If one of the following situations occurs, treatment must be stopped immediately:
– acute disorders of hearing or other sensory disorders;
– at the first symptoms of thrombophlebitis or thromboembolic disease;
– at the onset of cholestatic jaundice, anicteric hepatitis or generalised pruritus;
– an increase in number of epileptic seizures.
Particular attention should be paid to users:
– presenting with benign breast tumours;
– presenting with uterine dystrophies (hyperplasia, fibromas);
– presenting with hyperprolactinaemia with or without galactorrhoea;
– with a history or current pathology known to be associated with, or which can worsen during
pregnancy or the usage of oral CHCs: epilepsy, otosclerosis, asthma, varicose veins, gestational herpes, gallstones, systemic lupus erythematosis, hepatic, cardiac or renal dysfunction, chorea, haemolytic uraemic syndrome.
If contraception fails, an ectopic pregnancy can occur just as easily as an intra-uterine pregnancy.
If chloasma/melasma appears during a pregnancy or under oral CHCs, exposure to sunlight should be avoided.
Diarrhoea and vomiting can reduce the intestinal absorption of oral CHCs.
Use of oral contraceptives can affect the normal metabolism of tryptophan, which in turn can cause a relative deficiency of pyridoxine.
Contains lactose and sucrose. Patients with rare hereditary problems of fructose or intolerance, galactose intolerance, the Lapptotal lactase deficiency, or glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Laboratory tests
The use of oral CHCs may cause certain physiologic changes that may be reflected in the results of certain laboratory tests.
See prescribing information for full details.

Nausea, vomiting, headaches, breast tension, changed body weight or libido, depressive moods, chloasma, gastric upsets. Reduction of menstrual flow, missed menstruation, intermenstrual bleeding. May accelerate erythrocyte sedimentation in the absence of any disease.
See prescribing information for full details.

Interactions between ethinyloestradiol and other drugs can cause a decrease or increase in plasma levels of ethinyloestradiol.
The decrease in plasma levels of ethinyloestradiol can increase the incidence of intermenstrual bleeding and menstrual irregularities and may reduce the efficacy of the oral contraceptive. During concomitant use of substances that may lead to decreased ethyniestradiol serum concentrations, it is recommended that an additional non-hormonal, mechanical method of contraception (condoms, spermicides etc.) be used. Another method of contraception should be considered in the case of prolonged usage of these drugs.
After the discontinuation of drugs capable of reducing serum concentrations of ethinyloestradiol, it is recommended that an additional non-hormonal, mechanical method of contraception (condoms, spermicides etc.) be used for at least seven days. In the case of treatment with hepatic enzyme inducers, these measures must be observed for longer. It can actually take several weeks until the induction of enzymes has completely stopped, depending on the dose administered, the duration of treatment and the levels of elimination of the inducer.
Contraindicated association
An interaction has been observed between oral contraceptives and St. John’s Wort (Hypericum perforatum). This interaction is probably due to an induction of certain cytochrome P450 isoenzymes by Hypericum perforatum. St. John’s Wort (Hypericum perforatum) should therefore not be used at the same time as oral contraceptives.
Non-recommended associations
Decrease in plasma levels of ethinylestradiol:
– any drug capable of reducing gastrointestinal transit time.
– enzyme inducers: anticonvulsants (barbiturates, phenytoin, primidone, carbamazepine, topiramate, felbamate), dexamethasone, phenylbutazone, rifabutin, rifampicin, griseofulvin. Reduction in contraceptive efficacy through an increase in hepatic metabolism during treatment and one cycle after ending treatment.
– ritonavir (probably by induction of hepatic enzymes)
– modafinil: risk of reduction in contraceptive efficacy during treatment and one cycle after ending treatment with modafinil.
– Probably also oxcarbazepine and nevirapine.
Increase in plasma levels of ethinylestradiol:
– atorvastatin
– ascorbic acid and paracetamol
– drugs that inhibit cytochrome P450 3A4 isoenzymes such as indinavir, fluconazole, voriconazole, troleandomycin (which can increase the risk of intrahepatic cholestasis during concomitant administration of oral CHCs), ketoconazole and itraconazole.
Others
Oral antidiabetic or insulin requirements can be modified by the effect of oral contraceptives on glucose tolerance.
Oral contraceptives can influence the metabolism of other drugs by inhibiting hepatic microsomal enzymes, or by inducing hepatic drug conjugation, particularly glucuronidation or by other mechanisms. Tissue or plasma concentrations of these drugs may be reduced (e.g. lamotrigine, levothyroxine, valproate) or increased (for example theophylline, ciclosporin, corticosteroids, oral anticoagulants), but the clinical significance is not always clear.
In patients treated with flunarizine: risk of galactorrhoea through the flunarizine-induced increase in sensitivity of breast tissue to prolactin.
The Summary of Product Characteristics (section “Interactions”) should be consulted for all concomitant medication.
Pharmacodynamic interactions
During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin,transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Therefore, users must switch to an alternative method of contraception (e.g., progestagenonly contraception or non-hormonal methods) prior to starting therapy with these combination drug regimens. This medicinal product can be restarted 2 weeks following completion of treatment with these combination drug regimens.

Pregnancy:
Pregnancy must be excluded before starting contraceptive treatment.
If a pregnancy is suspected, use of oral contraceptive must be stopped immediately.
There is no conclusive evidence that the estrogen and progestin contained in the oral CHC will damage the developing child if conception accidentally occurs during oral CHC use.  From a clinical viewpoint, unlike diethylstilbestrol, the currently available results of numerous epidemiological studies enable a risk of malformation with estrogens administered alone or in association at the start of pregnancy to be excluded. As a result, the discovery of a pregnancy under estrogen/progestogen treatment does not justify an abortion.
The increased risk of VTE during the postpartum period should be considered when re-starting this drug.
Lactation:
Use during lactation can cause a reduction in milk production and modify its
composition. Small quantities of hormonal contraceptives and/or their metabolites have been found in breast milk and some undesirable effects have been reported in the baby, notably jaundice and a swelling of the chest. The use of oral CHCs is generally not recommended until the nursing mother has completely weaned her child. If the woman wishes to breast feed, another method of contraception should be suggested.

Symptoms
The symptoms of overdosage in adults and children are as follows: nausea, vomiting, dizziness, abdominal pain, somnolence, fatigue. In the user, withdrawal bleeding and breast tenderness can occur.
Treatment
There is no specific antidote and any treatment should depend on the symptoms.