Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2018 Publisher: Pfizer New Zealand Limited, P O Box 3998, Auckland, New Zealand, 1140, Toll Free Number: 0800 736 363
LOETTE is contraindicated in patients with:
The information contained in this document is principally based on studies carried out in women who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.
Cigarette smoking increases the risk of serious cardiovascular side effects (e.g. myocardial infarction, stroke) from oral-contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Use of combined oral contraceptives is associated with an increased risk of venous and arterial thrombotic and thromboembolic events.
For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one, which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient.
New users of combined oral contraceptives should be started on preparations containing less than 50 micrograms of estrogen.
The use of combined oral contraceptives increases the risk of arterial thrombotic and thromboembolic events. Reported events include myocardial infarction and cerebrovascular events (ischaemic and haemorrhagic stroke, transient ischemic attack). The risk of arterial thrombotic and thromboembolic events is further increased in women with underlying risk factors or predisposing conditions such as cigarette smoking, hypertension, hyperlipidaemias, obesity, diabetes, pre-eclamptic toxaemia and increasing age. Caution must be exercised when prescribing LOETTE for women with risk factors or predisposing conditions for arterial thrombotic or thromboembolic events. COC users with migraine (particularly migraine with aura) may be at increased risk of stroke.
The use of combined oral contraceptives increases the risk of venous thrombotic and thromboembolic events. Use of any combined oral contraceptives increases the risk of venous thrombotic and thromboembolic events compared to no use. The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism (VTE) manifesting as deep venous thrombosis and/or pulmonary embolism may occur during the use of all combined oral contraceptives. The approximate incidence of VTE in users of low estrogen dose (< 50 µg ethinylestradiol) oral contraceptives is up to 4 per 10,000 woman- years compared to 0.5-3 per 10,000 woman-years in non-oral contraceptive users. The increased risk of venous thrombotic and thromboembolic events during any combined oral contraceptive use is less than the incidence associated with pregnancy (which is estimated as 6 per 10,000 pregnant womanyears). Venous thromboembolism is fatal in 1-2% of cases.
The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and venous thromboembolism. Examples of predisposing conditions are: obesity, surgery or trauma with increased risk of thrombosis, recent delivery or second-trimester abortion, prolonged immobilisation and increasing age.
A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of combined oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, combined oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery with an increased risk of thrombosis, and during prolonged immobilisation.
Because the immediate post-partum period is associated with an increased risk of thromboembolism, combined oral contraceptive use should begin no sooner than the 28th postpartum day following either delivery in a non-lactating woman or second-trimester abortion.
The most important risk factor for cervical cancer is persistent human papillomavirus infection.
Several epidemiological studies suggest that oral contraceptive use may be associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer. The studies suggest that there is an “ever used” effect in addition to duration of use. These findings must be balanced against evidence of effects attributable to sexual behaviour, smoking and other factors. In cases of undiagnosed abnormal genital bleeding, adequate diagnostic measures are indicated.
A meta-analysis from 54 epidemiological studies showed that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptive use. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in combined oral contraceptive users (due to more regular clinical monitoring), the biological effects of combined oral contraceptives or a combination of both. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combined oral contraceptive users is small in relation to the lifetime risk of breast cancer. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
Established risk factors for the development of breast cancer include increasing age, family history, obesity, nulliparity, and late age for first full-term pregnancy.
Women with a strong family history of breast cancer or who have breast nodules, fibrocystic breast disease or abnormal mammograms should be monitored with particular care.
In very rare cases hepatic adenomas, and in extremely rare cases, hepatocellular carcinoma may be associated with combined oral contraceptives use. The risk appears to increase with duration of combined oral contraceptive use. Hepatic adenomas may rupture and cause death through intraabdominal haemorrhage. Such lesions may present as an abdominal mass or with the signs and symptoms of an acute abdomen and should be considered if the patient has abdominal pain and tenderness or evidence of intra-abdominal bleeding.
Women with a history of COC-related cholestasis and women who develop cholestasis during pregnancy are more likely to develop cholestasis with COC use. Such patients who use COCs should be carefully monitored, and COC use should be discontinued if cholestasis recurs.
Hepatocellular injury has been reported with combined oral contraceptive 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 combined oral contraceptive use, use a non-hormonal form of contraception and consult their doctor.
Acute or chronic disturbances of liver function require the discontinuation of combined oral contraceptive use until liver function has returned to normal (see section 4.3).
Steroid hormones may be poorly metabolised in patients with impaired liver function.
During clinical trials with the combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, transient, asymptomatic elevations of alanine transaminase (ALT) greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medications such as combined oral contraceptives.
LOETTE must be discontinued 2 weeks prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. LOETTE can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen (see section 4.3).
With the use of combined oral contraceptives, there have been case reports of retinal thrombosis, which may lead to partial or complete loss of vision. Oral contraceptives should be discontinued and the cause immediately evaluated if there are signs or symptoms such as visual changes; onset of proptosis or diplopia; papilloedema, or retinal vascular lesions.
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal.
Evidence from clinical trials with LOETTE indicates that there are no clinically significant changes in carbohydrate metabolism parameters.
Glucose intolerance has been reported in oral contraceptives users. In particular, some progestogens are known to increase insulin secretion and create insulin resistance, while estrogens (>75 micrograms) may create a state of hyperinsulinism. However, in the non-diabetic woman, low dose oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, diabetic women and women with impaired glucose tolerance should be carefully observed while taking oral contraceptives. See section 4.3.
A small proportion of women will have adverse lipid changes while taking OCs. Non-hormonal contraception should be considered in women with uncontrolled dyslipidaemias.
A small proportion of women may have persistent hypertriglyceridaemia while taking oral contraceptive tablets. Elevations of plasma triglycerides in combined oral contraceptive users may lead to pancreatitis and other complications.
Estrogens increase serum high-density lipoproteins (HDL cholesterol), whereas a decline in serum HDL cholesterol has been reported with many progestational agents. Some progestogens may elevate low-density lipoprotein (LDL) levels and may render the control of hyperlipidaemias more difficult. The net effect of a combined oral contraceptive depends on the balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.
Women who are being treated for hyperlipidaemias should be followed closely if they elect to use combined oral contraceptives.
An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use.
In women with hypertension, or a history of hypertension or hypertension-related diseases (including certain renal diseases), another method of contraception may be preferable. If combined oral contraceptives are used in such cases, close monitoring is recommended; and if significant elevation of blood pressure occurs, the drug should be discontinued.
For most women, elevated blood pressure will generally return to baseline after stopping combined oral contraceptives, and there appears to be no difference in the occurrence of hypertension among ever- and never- users.
Combined oral contraceptive use is contraindicated in women with uncontrolled hypertension (see section 4.3).
The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent or severe requires discontinuation of combined oral contraceptives and evaluation of the cause.
Women with migraine (particularly migraine with aura) who take combined oral contraceptives may be at increased risk of stroke (see section 4.4, Arterial Thrombosis and Thromboembolism).
Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important. If this bleeding persists or recurs, non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy, infection, pregnancy or other conditions. If pathology has been excluded, continued use of LOETTE or a change to another formulation may solve the problem.
In some women, withdrawal bleeding may not occur during the usual inactive tablet interval. If LOETTE has been taken according to directions, it is unlikely that the woman is pregnant. However, if LOETTE has not been taken according to directions prior to the first missed withdrawal bleed or if two consecutive withdrawal bleeds are missed, tablet taking should be discontinued and a non-hormonal back-up method of contraception should be used until the possibility of pregnancy has been excluded.
Some women may encounter post-pill amenorrhoea possibly with anovulation, or oligomenorrhoea, especially when such a condition was pre-existent.
A complete personal and family medical history and physical examination should be taken prior to the initiation of LOETTE use, and should be repeated at least annually during the use of LOETTE. Special attention should be given to blood pressure, breasts, abdomen and pelvic organs. A Papanicolaou smear and relevant laboratory tests should be carried out.
LOETTE should be used with caution in patients with epilepsy. The deterioration of this condition may indicate that LOETTE should be discontinued (see also section 4.5).
Serum folate levels may be depressed by oral contraceptive use. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
Patients becoming significantly depressed while taking LOETTE should stop the medication and use an alternative method of contraception in an attempt to determine whether the symptom is medicine related. Women with a history of depression should be carefully observed and the medicine discontinued if depression recurs to a serious degree.
LOETTE does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations (see section 4.2).
Interactions between ethinylestradiol and other substances may lead to decreased or increased ethinylestradiol concentrations, respectively. Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see section 4.3 and section 4.4, Hepatitis C).
Therefore, COC users must switch to an alternative method of contraception (e.g., progestogenonly contraception or non-hormonal methods) prior to starting therapy with anti-viral HCV medicinal products such as ombitasvir, paritaprevir, ritonavir, dasabuvir. COCs can be restarted 2 weeks following completion of treatment with an anti-viral HCV medicinal product.
Decreased ethinylestradiol serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the oral contraceptive.
Examples of substances that may decrease serum ethinylestradiol concentrations include any substance that reduces gastrointestinal transit time and, therefore, ethinylestradiol absorption, and substances that induce hepatic microsomal enzymes, such as rifampicin, phenytoin, primidone, rifabutin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil, ritonavir and barbiturates.
St. John’s wort (Hypericum perforatum) may induce hepatic microsomal enzymes, which may result in reduced efficacy of oral contraceptives. This may also result in breakthrough bleeding.
During concomitant use of LOETTE and substances that may lead to decreased ethinylestradiol serum concentrations, it is recommended that a non-hormonal back-up method of contraception (other than the rhythm or temperature methods) be used in addition to the regular intake of LOETTE. In the case of prolonged use of such substances combined oral contraceptives should not be considered the primary contraceptive.
After discontinuation of substances that may lead to decreased ethinylestradiol serum concentrations, use of a non-hormonal back-up method of contraception is recommended for at least 7 days.
Longer use of a back-up method, a minimum of 4 weeks, is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, such as rifampicin, resulting in decreased ethinylestradiol serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing substance.
There have been reports of pregnancy when COCs were co-administered with certain antibiotics (e.g., ampicillin and other penicillins, tetracyclines).
Examples of substances that may increase serum ethinylestradiol concentrations include atorvastatin; competitive inhibitors for sulfation in the gastrointestinal wall, e.g. ascorbic acid (vitamin C) and paracetamol, and substances that inhibit cytochrome P450 3A4 isoenzymes, (e.g. itraconazole, fluconazole, and indinavir).
Ethinylestradiol may inactivate certain CYP450 enzymes and therefore may reduce the metabolism of other drugs. It may also induce hepatic drug conjugation, particularly glucuronidation. Accordingly, plasma and tissue concentration may either be increased (e.g. cyclosporin, theophylline, corticosteroids) or decreased (e.g. lamotrigine).
The prescribing information of concomitant medications should be consulted to identify potential interactions.
The use of oral contraceptives may influence the results of certain laboratory tests including:
Category B3.
Pregnancy must be excluded before starting LOETTE. If pregnancy occurs during use of LOETTE, the preparation must be withdrawn immediately.
Extensive epidemiological studies have revealed no increased risk of birth defects in children born to women who used combined oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect; particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. See also section 4.3.
Estrogen-containing oral contraceptives given in the post-partum period may affect lactation. There may be a decrease in the quantity and a change in the composition of the breast milk. Furthermore, small amounts of contraceptive steroids and/or metabolites have been identified in the milk of mothers receiving them. A few adverse effects on the child have been reported, including jaundice and breast enlargement. The use of estrogen-containing oral contraceptives should be deferred until the infant has been completely weaned.
LOETTE is presumed to be safe or unlikely to produce an effect on the ability to drive or use machines.
Use of combined oral contraceptives has been associated with increased risk of the following:
Arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, venous thrombosis, transient ischemic attack and pulmonary embolism
Cervical intraepithelial neoplasia and cervical cancer
Breast cancer diagnosis
Benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenomas).
Other adverse reactions, per CIOMS frequency categories, are listed below: Very Common: ≥10%, Common: ≥1% and <10%, Uncommon: ≥0.1% and <1%, Rare: ≥0.01% and <0.1%, Very Rare: <0.01%.
Common: Vaginitis, including candidiasis.
Very Rare: Hepatic adenomas, hepatocellular carcinomas.
Very Rare: Aggravation of varicose veins.
Common: Nausea, vomiting, abdominal pain
Uncommon: Abdominal cramps, bloating
Very Rare: Pancreatitis, ischaemic colitis
Not known: Inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
Rare: Cholestatic jaundice
Very Rare: Gallbladder disease, including gallstones*
Not known: Hepatocellular injury (e.g. hepatitis, hepatic function abnormal).
Uncommon: Changes in appetite (increase or decrease)
Rare: Glucose intolerance
Very Rare: Exacerbation of porphyria.
Common: Mood changes, including depression, changes in libido.
Very Common: Headache, including migraines
Common: Nervousness, dizziness
Very Rare: Exacerbation of chorea.
Common: Acne
Uncommon: Rash, chloasma (melasma), which may persist, hirsutism, alopecia
Rare: Erythema nodosum
Very Rare: Erythema multiforme.
Rare: Intolerance to contact lenses
Very Rare: Optic neuritis**, retinal vascular thrombosis.
Very Common: Metrorrhagia (breakthrough bleeding/spotting)
Common: Breast pain, tenderness, enlargement, secretion, dysmenorrhoea, change in menstrual flow, change in cervical ectropion and secretion, amenorrhoea.
Very Rare: Haemolytic uraemic syndrome.
Rare: Anaphylactic/anaphylactoid reactions including cases of urticaria, angioedema and severe reactions with respiratory and circulatory symptoms
Very Rare: Exacerbation of systemic lupus erythematosus.
Common: Fluid retention/oedema.
Common: Changes in weight (increase or decrease)
Uncommon: Increase in blood pressure, changes in serum lipid levels, including hypertriglyceridaemia
Rare: Decrease in serum folate levels***.
* Oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women.
** Optic neuritis may lead to partial or complete loss of vision.
*** Serum folate levels may be depressed by oral contraceptive therapy.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
None stated.
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