Dienogest containg combined oral contarceptives-Pros & cons. The trade/Brand names

My home task is ready:  One junior MD student ( member of this Group)  enquired me about dienogest containg OCP : Here is the answer.Q.1: Who s afraid of VTE induced by COC??  I had no meal for last 5days and my blood sugar is as of now 10 mg% due to starvation to produce these notes!!!!

Dienogest containg OCP-Brand names:-One million dollar Q –Ans: None , So long we prescribe   Oest valerate no chance of VTE “Is   Oest vale are is  less procoagulant than EE as COC” ?  Most of western women who are genetically, Phenotypically more prone to have VTE are scared of taking OCP . They are naturally are worried about oestrogen content of the CC. AS such many of  them are scared about use of Pills . They were demanding some form oestrogen which does not cause  thrombosis, (or  thrombotic by increasing hepatic coagulatory proteins),.

Such women were naturally  worried about risks associated with potent oestrogen(EE)  which is most commonly used in COC .. Now, this apprehension of VTE has been alleviated to a great extent by using another from oestrogen which is not thrombogenic i,.e Valerate prepn. AS such many women nowadays are preferring for  Valerate prepn of oestrogen in COC which  very rarely ever   cause VTE in Indians-.

Q.2:-But is it(Oest valerate)  really safer than Ethinyl oestradiol?? Ans:-In terms of VTE risk there is evidence that the impact on both coagulation and fibrinolyis is less pronounced than with EE formulations , but whether these surrogate studies will translate into a difference in clinical end points is not known.

Q.3 : How E valerate is synthesized?? Few words on Estradiol Valerate

One trick that pharmacologists use in order to ensure reliable blood levels of an orally administered drug is to add a carboxylic acid to form an ester. After the modified drug enters the body the ester is rapidly cleaved away to reveal the native molecule. There is an assumption that cloaking the molecule in this way delays drug degradation at the level of gut and liver. In the case of E2 valeric acid can be added to carbon 17 to form oestradiol valerate. This compound has been widely used both orally and as an injection but until recently had not proven reliable as a COC oestrogen.

Q. 3;-What are Dienogest containg OC  Pills?? For AUB more so if there is an element of endometriosis. Some considers that this  drug may in future be the drug of first choice possibly

When did the dienogest containg OCP came in te market??  Ans:-In 2009 a multiphasic COC containing A) with Oesrtradiol  valerate & Dienogest  :oestradiol valerate together with the progestogen dienogest  was shown to result in acceptable cycle control and contraceptive efficacy. This major development presumably derives from the use of the valerate ester, the choice of partner progestogen and the results of experimentation with new multiphasic dosing schedules. Marketed by Bayer Health Care as Qlaira / Klaira in the European Union and as Natazia in the USA this formulation is claimed to result in better  cycle control than an EE comparator formulation  and indeed may prove useful in the treatment of heavy menstrual bleeding;

Q.4:- What about  four  physic COC containing E2 valerate and dienogest  ?

This has been on the market for a few years. It’s perfect use appears to be associated with an efficacy and acceptability which are comparable to those of low dose pills containing EE. In the opinion of the author the major shortcoming of this new pill is its polyphonic concept as for other non monophasic COCs cycle length cannot be extended to more than 28 days thus precluding delaying or avoidance of withdrawal bleeding . Also women desirous of postponing the occurrence of such bleeds for social, professional or other reasons  will not be able to tailor the length of their pill driven cycle.

Q. 5  : Always to carry out platelate function disorders by hematology Deppt if conventional COC does not help a teen agers with Puberty meno in absence  of PCO  !!! So, as things stand , in peri menarchal DUB : A UK the problem is that out of so many   Studies have reported that up to 20% of suffers of heavy menstrual bleeding peri menarchal DUB have a blood clotting disorder with von Will brand’s  disease and thrombocytopenia or platelet  function disorders being the most common causes . The closer to the menarche that the heavy menstrual bleeding develops the more likely there is an underlying haematological  cause Failure to respond to treatment should prompt investigation of blood clotting. Very  often  the treatment of menorrhagia is the same whether the girl has blood clotting disorder or not but it is essential  that these disorders are diagnosed for future management.

They may be attracted to newer COCs containing oestradiol as opposed to EE- which they may perceive as being more natural  . One such already available is Qlaira a four physic COC containing varying  doses of oestradiol valerate  and dienogest  in a 26/2 regimen i.e. there are only 2 hormone free days . Studies have confirmed that Qlaira is as effective as COCs containing EE . Qlaira has received regulatory  approval for use in the treatment of heavy menstrual bleeding for which it is certainly effective , however it does not lend itself to flexible continuous use elimination of withdrawal bleeds Well, the first choice will be Dienogest containg OCP:--Oestradiol valerate

   Q/. 5: KAP:” Knowledge –Practice –Wisdom”  :-But do we do that in  our day to day practice  ?? I don’t insist on platelate functions tets in Pub meno-Isnt it? How many member insist on this  test if Tx acid & COC fails to control Pub meno. Some gynaecologist are of opinion that like Peri menarchal DUB  this kind of combination i.e. dienogest containg OCP should be  strongly considered before jumping to hysterctomy.

Q.7:- What are the Brand names of dienogest containg COC: Such are :---Qlaira / Klaira / Natazia

1)Day 1-2  Oest valerate 30 mg/day

2)Day 3-7: Oest valerate  20 mg/day + dienogest 2.0 mg /day

3)Day 8-24 E2 V 20 mg /day + dienogest 3.0 mg/day

Day 25-26 E2 V 1.0 mg/day

Day 27 -28 placebo

Q.8. can we use dienogest containg OCP in AUB in perimenoperiod:-Ans:-A recent addition to treatment options is oestradiol valerate with dienogest with a license to treat heavy menstrual bleeding. The authors have found it useful in the treatment of peri menarchal DUB and also useful for  young girls who find it difficult to tolerate oestrogenic side effects including headache and nausea. It is not a first line pill but it has the potential to improve the quality of life of a  young woman  enough to allow her to go to school for example.

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Q. 19=0:Can we have COC with Natural oestrgen (oestradiol  and not Oest valerate)  with LNG as  COC “+:--Another natural oestradiol COC is due to be launched in the UK in 2013. Zoely contains 1.5 mg 17B  oestradiol combined with 2.5 mg of the progestogen nomegestrol acetate . This is a monophasic 24/4 preparation . Unlike Qlaira flexible continued use should be possible with Zoely . Although cycle  control with Zoely was not quite as good as with Yasmin in a comparative trial the bleeds  were shorter and lighter-  possibly due to the shorter hormone  free interval . Efficacy of the two preparation was similar. The other available COC containing a natural oestrogen is a  monophasic preparation combining in each pill 1.5 mg micronized E2 and 2.5 mg nomegestrol acetate . this recently developed highly selective progestin behaves as a complete agonist  at the progesterone receptor site  with absent  or negligible binding to other steroid receptors including the oestrogen androgen and glucocorticoid receptors. It has no effect on carbohydrate and lipid metabolisms Active pills are taken  for 24 days followed by placebo for  4 days .

Q.11. Warning for natural Oest::-- Not to use in acne:--Compared with a pill combining drospirenone and EE, the NOMAC /EE COC  appeared to be associated with more  acne and shorter lighter or absent  withdrawal bleeding .

Q,12:  What is E4 and not E2:---A COC containing a progestin and the natural oestrogen (oestetrol)  is currently being investigated E4 is a natural oestrogen  with remarkable properties whose synthesis from E2  and oestriol  , in the human fetal  liver is regulated by the enzymes 15a and 16a hydroxylase . In the newborn the liver promptly loses its capacity to synthesize E4 because  these enzymes  are no longer  expressed.

Q.13: Few points on E 4—Ans:-E4 is a selective oestrogen receptor   modulator it acts as an agonists on the vaginal wall endometrium bone and the brain but it antagonizes E2 in the breast as potently as tamoxifen does E4  suppresses ovulation  . It binds highly selectively to the oestogen receptor    mainly – unlike EE and E2 – to the alpha receptors.

Also in contrast with EE  and especially  with E2->  E4  does not bind to SHBG and does not stimulate the production of SHBG  in vitro. It causes fewer side effects and its use is associated with less risk than EE; It does not induce      live enzymes to the same extent and should protect

Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin- containing clot to stop bleeding and begin repair of the damaged vessel. Improper coagulation can lead to an increased risk of bleeding (hemorrhage) or obstructive clotting (thrombosis).

Coagulation begins almost instantly after an injury to the blood vessel damages the endothelium lining the vessel. Exposure of the blood to proteins such as tissue factor initiates changes in the blood platelets and the plasma protein fibrinogen, a clotting factor. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneous   Proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which strengthen the platelet plug.

In a recent study of more than 600,000 pregnancies from Norway, Jacobsen and colleagues (2008) reported that DVT alone was more common antepartum whereas PE was more common in the first 6 weeks postpartum.

   INCIDENCE of VTE in Preg & puerperium?

The risk of VTE and PE in otherwise healthy women is the highest during pregnancy and the puerperium. The risk of PE increases about four to six times during pregnancy. Admittedly, The incidence of thromboembolism during pregnancy ranges from I in 500 to I in 2000 pregnancies. DVT and PE occur five times more frequently in the puerperium than during pregnancy. However, in a recent study of more than 600,000 pregnancies from Norway, Jacobsen and colleagues (2008) reported that DVT alone was more common antepartum whereas PE was more common in the first 6 weeks postpartum.