Adoxa CK Kit

Pronunciation: DOX-i-SYE-kleen
Generic Name: Doxycycline with Cleanser
Brand Name: Adoxa CK Kit and Adoxa TT Kit

Adoxa CK Kit is used for:

Treating acne.

Adoxa CK Kit is a tetracycline antibiotic and cleansing pad kit. The antibiotic works by slowing the growth of bacteria, which helps the body's immune system to kill the bacteria. The cleansing pad helps to keep the skin clean. Using both together helps to reduce acne.

Do NOT use Adoxa CK Kit if:

• you are allergic to any ingredient in Adoxa CK Kit or to any other tetracycline (eg, minocycline)


• you are taking acitretin, isotretinoin, or a penicillin antibiotic (eg, amoxicillin)


• you have recently received or will be receiving a live oral typhoid vaccine

Contact your doctor or health care provider right away if any of these apply to you.

Before using Adoxa CK Kit:

Some medical conditions may interact with Adoxa CK Kit. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have diarrhea or a history of lupus or the blood disease porphyria

Some MEDICINES MAY INTERACT with Adoxa CK Kit. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Antacids, barbiturates (eg, phenobarbital), carbamazepine, hydantoins (eg, phenytoin), iron, or urinary alkalinizers (eg, sodium bicarbonate) because they may decrease Adoxa CK Kit's effectiveness


• Acitretin, anticoagulants (eg, warfarin), digoxin, insulin, isotretinoin, or methotrexate because the risk of their side effects may be increased by Adoxa CK Kit


• Live oral typhoid vaccine, hormonal birth control (eg, birth control pills), or penicillins (eg, amoxicillin) because their effectiveness may be decreased by Adoxa CK Kit

This may not be a complete list of all interactions that may occur. Ask your health care provider if Adoxa CK Kit may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Adoxa CK Kit:

Use Adoxa CK Kit as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Adoxa CK Kit kit contains antibiotic capsules or tablets and facial cleansing pads.


• To use the facial cleansing pad, smooth the pad over your face. Avoid getting the cleanser into your eyes, nose, or mouth. Discard after use.


• Take the capsule or tablet by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Take Adoxa CK Kit with a full glass of water (8 oz/240 mL) to prevent ulcers and reduce throat irritation.


• Do not take an antacid that has aluminum, calcium, magnesium, or iron in it within 1 hour before or 2 hours after you take Adoxa CK Kit.


• Use Adoxa CK Kit on a regular schedule to get the most benefit from it. It may take several days to weeks to see the full effect of Adoxa CK Kit.


• Do not use Adoxa CK Kit if it is past the expiration date on the bottle.


• If you miss a dose of Adoxa CK Kit, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Adoxa CK Kit.

Important safety information:

• The cleansing pad is for external use only. Do not get it in your eyes, nose, or mouth. If you get it in your eyes, rinse at once with cool water.


• Long-term or repeated use of Adoxa CK Kit may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Do not receive a live vaccine (eg, typhoid) while you are taking Adoxa CK Kit. Talk with your doctor before you receive any vaccine.


• Hormonal birth control (eg, birth control pills) may not work as well while you are using Adoxa CK Kit. To prevent pregnancy, use an extra form of birth control (eg, condoms).


• Adoxa CK Kit may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Adoxa CK Kit. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Mild diarrhea is common with antibiotic use. However, a more serious form of diarrhea (pseudomembranous colitis) may rarely occur. This may develop while you use the antibiotic or within several months after you stop using it. Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.


• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Talk with your doctor before you use any other medicines or cleansers on your skin.


• Tell your doctor or dentist that you take Adoxa CK Kit before you receive any medical or dental care, emergency care, or surgery.


• Adoxa CK Kit may interfere with certain lab tests. Be sure your doctor and lab personnel know you are taking Adoxa CK Kit.


• Lab tests, including liver function, kidney function, and complete blood cell counts, may be performed while you use Adoxa CK Kit. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Adoxa CK Kit should not be used in CHILDREN younger than 8 years old; permanent yellow-gray-brown tooth discoloration may occur.


• PREGNANCY and BREAST-FEEDING: Adoxa CK Kit has been shown to cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Adoxa CK Kit while you are pregnant. Adoxa CK Kit is found in breast milk. Do not breast-feed while taking Adoxa CK Kit.

Possible side effects of Adoxa CK Kit:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Loss of appetite; nausea; sensitivity to sunlight; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody stools; chest pain; dark urine; decreased urination; fever, chills, or sore throat; moderate to severe sunburn; severe diarrhea; severe irritation, redness, or peeling of the skin; severe or persistent headache; stomach pain or cramps; throat irritation or pain; trouble swallowing; unusual bruising or bleeding; unusual joint pain; unusual tiredness; vaginal irritation or discharge; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Adoxa CK side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Adoxa CK Kit:

Store Adoxa CK Kit at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Adoxa CK Kit out of the reach of children and away from pets.

General information:

• If you have any questions about Adoxa CK Kit, please talk with your doctor, pharmacist, or other health care provider.


• Adoxa CK Kit is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Adoxa CK Kit. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Adoxa CK Kit resources

• Adoxa CK Kit Side Effects (in more detail)
• Adoxa CK Kit Use in Pregnancy & Breastfeeding
• Adoxa CK Kit Drug Interactions
• Adoxa CK Kit Support Group
• 0 Reviews for Adoxa CK - Add your own review/rating

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• Acne

Loestrin 30.

1. Name Of The Medicinal Product

Loestrin 30.

2. Qualitative And Quantitative Composition

Each Loestrin 30 tablet contains:

Norethisterone acetate Ph Eur	1.5mg
Ethinylestradiol Ph Eur	0.03mg

3. Pharmaceutical Form

Pale green convex film coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prevention of pregnancy in women who elect to use oral contraceptives. The efficacy of any contraceptive method, except sterilisation, depends upon the reliability with which it is used. Correct and consistent use of methods can result in lower failure rates.

4.2 Posology And Method Of Administration

For oral use.

One Loestrin 30 tablet should be taken daily at approximately the same time of day for three weeks and then an interval of one week allowed before commencing the second course of tablets. Second and subsequent courses should be taken for three weeks with one week without tablets between courses. Thus each new course of tablets is always started on the same day of the week. It is important that the tablets are taken as directed and should be taken without regard to menstrual bleeding except in the initial cycle.

Pill initiation

Provided that it is reasonably certain that a woman is not pregnant:

• COCs can be started at any time within 5 days of the start of menstrual bleeding without additional contraceptive precautions;

• COCs can be started at any other time in the cycle, or by women who are not menstruating, with additional contraceptive precautions for the first 7 days;

• a switch can be made from other methods of contraception, whether hormonal or not, at any time in the cycle. Additional contraceptive precautions are required for the first 7 days if changing from a non-hormonal method outside the first 5 days of the menstrual cycle.

Post-partum and post-abortum use

After pregnancy combined oral contraception can be started in non-lactating women 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications.

If the pill is started later than 21 days after delivery, then barriers and spermicides should be used until oral contraception is started and for the first 7 days of pill-taking. If unprotected intercourse has taken place after 21 days post-partum, then oral contraception should not be started until the first menstrual bleed after childbirth.

After a miscarriage or abortion, oral contraceptives may be started immediately.

Missed pills

• If one pill is missed during weeks 1, 2 or 3, or if a pack is started 1 day late, the pill should be taken as soon as possible and no additional contraceptive precautions need be taken.

• If more than one pill is missed during weeks 1, 2 or 3, or if a pack is started more than 1 day late, a pill should be taken immediately, daily pills should be continued and additional contraceptive precautions should be taken for the next 7 days;

• if the pills are missed in the first week and unprotected sex has taken place, the woman should discuss with a healthcare professional the use of emergency contraception;

• if the pills are missed in the third week, the current course of pills should be completed and the next pack should be started immediately.

Gastrointestinal upset

Vomiting or diarrhoea may reduce efficacy by preventing full absorption. Barriers and spermicides should therefore be used during and for 7 days after recovery and if these 7 days overrun the end of a pack, the next pack should be started without a break. In this case, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack, she must return to the doctor to exclude the possibility of pregnancy.

4.3 Contraindications

1) Known or suspected pregnancy and lactation.

2) History of confirmed venous thromboembolism (VTE), family history of idiopathic VTE and other known risk factors for VTE.

3) Ischaemic heart disease, severe hypertension or coagulation abnormalities.

4) Liver disease including disorders of hepatic excretion e.g. Dubin-Johnson or Rotor syndromes, infective hepatitis (until liver function returns to normal), known or suspected disorders of lipid metabolism, porphyria, liver adenoma or carcinoma, gallstones or jaundice with prior pill use.

5) Sickle cell anaemia.

6) Known or suspected carcinoma of the breast or estrogen dependent neoplasms.

7) Undiagnosed abnormal vaginal bleeding.

8) History during pregnancy of idiopathic jaundice, severe pruritus, chorea, herpes or deterioration of otosclerosis.

9) Focal, severe or crescendo migraine or transient cerebral ischaemic attacks without headaches.

4.4 Special Warnings And Precautions For Use

The following information is principally based on studies in patients who used oral contraceptives with higher concentrations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower concentrations of both estrogens and progestogens remains to be determined. The efficacy of any contraceptive method, except sterilisation, depends upon the reliability with which it is used. Correct and consistent use of such methods can result in lower failure rates.

Thrombo-embolism

An increased risk of thromboembolic disease (VTE) associated with the use of oral contraceptives is well established but is smaller than that associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called 'third generation' pills) than for women using pills containing levonorgestrel or norethisterone (the so-called 'second generation' pills).

The spontaneous incidence of VTE in healthy, non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 per year. The incidence in users of second generation pills is about 15 per 100,000 women per year of use. The incidence in third generation pills is about 25 cases per 100,000 women per year of use; this excess incidence has not been satisfactorily explained by bias or confounding. The risk of venous thromboembolism is highest during the first year a combined oral contraceptive is taken. This increased risk applies to the first time ever combined oral contraceptive use is begun rather than each time a woman starts a new type of combined oral contraceptive. The level of all these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE such as obesity. The suitability of combined oral contraceptives for patients with any of these risk factors should be discussed with the patient before a final decision is taken.

The physician should be alert to the earliest manifestations of these disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism and retinal thrombosis). Should any of these occur or be suspected, Loestrin should be discontinued immediately.

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes a day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

Hepatic tumours

Benign hepatic tumours have been associated with oral contraceptive usage. Malignant hepatic tumours have also been reported on rare occasions in long term users of oral contraceptives. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur.

Ovarian, endometrial, cervical and breast cancer

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

A meta-analysis from 54 epidemiological studies reported 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 (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or, a combination of both. The additional breast cancers diagnosed in current users of COCs, or in women who have used COCs in the last ten years, are more likely to be localised to the breast than in those women who have never used COCs.

Breast cancer is rare among women under 40 years of age, whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart).

The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the ten years after stopping COC use, such that by 10 years there appears to be no excess.

The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

Estimated cumulative numbers of breast cancers per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs

Reasons for stopping Loestrin immediately

1) Occurrence of migraine in patients who have never previously suffered from it. Any unusually frequent or severe headaches.

2) Any kind of visual disturbance e.g. proptosis or diplopia and migraine.

3) Suspicion of thrombosis or infarction.

4) Combined oral contraceptives should be stopped at least six weeks before elective surgery and during and following prolonged immobilisation e.g. after accidents, etc.

5) Loestrin should be discontinued if the patient becomes jaundiced or has a significant rise in blood pressure.

6) Patients with a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

7) Since the safety of Loestrin in pregnancy has not been demonstrated, it is recommended that for any patient who has missed a period, the absence of pregnancy should be established before continuing the contraceptive regimen.

8) Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy.

Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

Estrogen-progestogen preparations should be used with caution in patients with a history of hypertension and some women experience an increase in blood pressure following the administration of contraceptive steroids. Pregnancy should be excluded before starting treatment. Because these agents may cause some degree of fluid retention, patients with conditions which might be influenced by this such as epilepsy, migraine, asthma, and cardiac or renal dysfunction should be carefully monitored.

A decrease in glucose tolerance has been observed in a significant percentage of patients on oral contraceptives. The mechanism of this decrease is obscure. For this reason, pre-diabetic and diabetic patients should be carefully observed whilst receiving Loestrin.

Under the influence of estrogen-progestogen preparations, pre-existing uterine fibroleiomyomata may increase in size. Loestrin may mask the onset of the climacteric.

The following conditions also require careful consideration: multiple sclerosis, porphyria, tetany, disturbed liver function, gallstones, cardiovascular disease, renal disease, chloasma or any disease that is prone to worsen during pregnancy. The deterioration or first appearance of any of these conditions may indicate that the oral contraceptive should be stopped. Contact lens wearers who develop visual changes or changes to lens tolerance should be assessed by an optometrist.

Interference with laboratory tests

The following laboratory results may be altered by the use of oral contraceptives: hepatic function (increased sulpho-bromophthalein retention and other tests); thyroid function (increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 concentration is unaltered); haematological tests (increased prothrombin and factors VII, VIII, IX and X, decreased antithrombin 3 and increased adrenaline induced platelet aggregation); measurement of pregnanediol excretion (reduced). Other binding proteins may be elevated in the serum, sex-binding globulins are increased, triglycerides may be increased and serum folate levels may be depressed. Therefore, if such tests are abnormal in a patient taking Loestrin, it is recommended that they be repeated after Loestrin has been withdrawn for two months. The pathologist should be advised of the administration of Loestrin when relevant specimens are submitted. Any influence of prolonged administration of Loestrin on pituitary, ovarian, adrenal, hepatic and uterine functions is unknown at present.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other drugs on oral contraceptives

The effectiveness of combined oral contraceptives may be considerably reduced by interaction with drugs that induce hepatic enzyme activity e.g. carbamazepine, griseofulvin, phenytoin, phenobarbital, primidone and rifampicin. Other drugs suspected of having the capacity to reduce the efficacy of oral contraceptives include ampicillin and other broad-spectrum antibiotics.

Additional contraceptive precautions should be taken whilst taking enzyme inducing drugs and some antibiotics and for at least seven days after stopping them. If these seven days run beyond the end of the packet, the new packet should be started immediately without a break. Rifampicin is such a potent inducer that even if the course lasts for less than 7 days, the additional contraceptive precautions should be continued for at least 4 weeks after stopping it.

The herbal remedy St. John's Wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect.

Ascorbic acid and paracetamol may increase plasma ethinylestradiol concentrations, possibly by inhibition of conjugation.

Administration of atorvastatin concomitantly with oral contraceptives containing ethinylestradiol and norethisterone acetate increased AUC values for norethisterone and ethinylestradiol by approximately 30% and 20% respectively.

Effects of oral contraceptives on other drugs:

Oral contraceptive combinations containing ethinylestradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of ciclosporin, prednisolone and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce conjugation of other compounds. Decreased plasma concentrations of paracetamol have been noted when administered with oral contraceptives.

4.6 Pregnancy And Lactation

Loestrin is not recommended for use during pregnancy, suspected pregnancy and in lactating mothers. Studies do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The following adverse effects which have been reported in patients receiving oral contraceptives are believed to be drug-related:

Nausea, vomiting, gastro-intestinal symptoms (such as abdominal cramps and bloating), breakthrough bleeding, spotting, change in menstrual flow, amenorrhoea during and after treatment, oedema, chloasma or melasma, breast changes (tenderness, enlargement and secretion), change in weight, cervical erosion and changes in cervical secretion, suppression of lactation when given immediately post-partum, cholestastic jaundice, migraine, rash (allergic), rise in blood pressure, depression, thrombo-embolic disorders, temporary infertility after discontinuation of treatment, reduced tolerance to carbohydrates, vaginal candidiasis, change in corneal curvature (steepening) and intolerance to contact lenses.

Although the following adverse effects have been reported in women taking oral contraceptives, an association has been neither confirmed nor refuted: prolonged amenorrhoea after discontinuing oral contraceptives, pre-menstrual like syndrome, headache, nervousness, dizziness, fatigue, cataract, backache, hirsutism, loss of scalp hair, erythema multiforme, erythema nodusum, haemorrhagic eruption, itching, changes in appetite, cystitis-like syndrome, vaginitis, porphyria, impaired renal function, haemolytic uraemic syndrome, Budd-Chiari syndrome, acne, changes in libido and colitis.

Menstrual changes

Breakthrough bleeding and spotting are sometimes encountered, especially during the first three months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem.

4.9 Overdose

The usual effects in children are nausea and drowsiness. Slight vaginal bleeding occasionally occurs in girls. In view of the low toxicity following overdosage with oral contraceptives, it is suggested that treatment should be conservative.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Loestrin achieves its contraceptive effect primarily by inhibition of ovulation through gonadotrophin suppression. It is possible that other sites of action such as changes in cervical mucus and in the endometrium may contribute to the efficacy of combined oral contraceptives.

5.2 Pharmacokinetic Properties

Ethinylestradiol is rapidly and almost completely absorbed and peak serum levels are usually attained within an hour of oral administration. At this time, the majority of drug is already conjugated, largely as the sulphate. These conjugates have a primary serum half-life of approximately 7 hours and a terminal half-life of 48 hours and are excreted in urine and faeces.

Norethisterone acetate undergoes rapid absorption with peak serum concentrations occurring at one hour after oral administration. Less than 5% is cleared as unchanged norethisterone; glucuronide and sulphate conjugates are excreted in urine and faeces. The terminal half-life for norethisterone conjugates has been estimated at 70 hours (range: 42 - 84 hours).

5.3 Preclinical Safety Data

The results of the preclinical tests do not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, sucrose, maize starch, talc, powdered acacia, magnesium stearate, industrial methylated spirit*, purified water*, dichloromethane*, propylene glycol*, hypromellose 15, carnauba wax, hydroxypropylcellulose and E104, E110, E131, E132, E133, E171.

* Not present in final product

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 30°C. Store in the outer carton.

6.5 Nature And Contents Of Container

Printed aluminium foil blister strip contained in a cardboard carton together with a product leaflet. Supplied in packs of 21 and 63 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special instructions needed.

7. Marketing Authorisation Holder

Galen Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK.

8. Marketing Authorisation Number(S)

PL 27827/0024.

9. Date Of First Authorisation/Renewal Of The Authorisation

03 April 1974/11 February 2009.

10. Date Of Revision Of The Text

26 October 2011

V-Hist

Generic Name: brompheniramine and phenylephrine (BROM fen IR a meen and FEN il EFF rin)

Brand Names: Alacol, Alenaze-D, Alenaze-D NR, B-Vex D, BPM PE, Brom Tann PE, Bromfed, Bromfed-PD Capsules, BroveX ADT, BroveX PEB, Brovex-D, Children's Cold & Allergy, Dimaphen Elixir, Dimetapp Cold & Allergy, Entre-B, J-Tan D, J-Tan D SR, Phenyl 15/12mg, Phenyl 7.5/6mg, RespaHist II, Rhinabid, Rhinabid PD, Seradex-LA, Tanabid SR, V-Hist, VazoBid, VaZol-D, Vazotab, Zotex-PE

What is V-Hist (brompheniramine and phenylephrine)?

Brompheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of brompheniramine and phenylephrine is used to treat nasal congestion, sneezing, itching, watery eyes, and runny nose caused by allergies, hay fever, and the common cold.

Brompheniramine and phenylephrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about V-Hist (brompheniramine and phenylephrine)?

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. You should not use this medication if you are allergic to brompheniramine or phenylephrine, or to other decongestants, diet pills, stimulants, or ADHD medications. Do not use brompheniramine and phenylephrine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Ask a doctor or pharmacist about taking brompheniramine and phenylephrine if you have heart disease or high blood pressure, diabetes, a thyroid disorder, glaucoma, kidney disease, an enlarged prostate, or problems with urination.

What should I discuss with my healthcare provider before taking V-Hist (brompheniramine and phenylephrine)?

You should not use this medication if you are allergic to brompheniramine or phenylephrine, or to other decongestants, diet pills, stimulants, or ADHD medications. Do not use brompheniramine and phenylephrine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Ask a doctor or pharmacist if it is safe for you to take brompheniramine and phenylephrine if you have:

• 
  

  heart disease or high blood pressure;

  
  


• 
  

  diabetes;

  
  


• 
  

  a thyroid disorder;

  
  


• 
  

  glaucoma;

  
  


• 
  

  kidney disease;

  
  


• 
  

  an enlarged prostate; or

  
  


• 
  

  problems with urination.

  
  

FDA pregnancy category C. It is not known whether brompheniramine and phenylephrine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Brompheniramine and phenylephrine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take V-Hist (brompheniramine and phenylephrine)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Take the medicine with a full glass of water. Do not crush, chew, break, or open an extended-release capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

The chewable tablet must be chewed before you swallow it.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose. Do not take brompheniramine and phenylephrine for longer than 7 days in a row. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include feeling restless or nervous, nausea, vomiting, stomach pain, dizziness, drowsiness, dry mouth, warmth or tingly feeling, or seizure (convulsions).

What should I avoid while taking V-Hist (brompheniramine and phenylephrine)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid becoming overheated or dehydrated during exercise and in hot weather.

Drinking alcohol can increase certain side effects of brompheniramine and phenylephrine. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

V-Hist (brompheniramine and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  fast, pounding, or uneven heartbeat;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  
  


• 
  

  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

• 
  

  drowsiness or dizziness;

  
  


• 
  

  blurred vision;

  
  


• 
  

  dry mouth, nose, or throat;

  
  


• 
  

  mild stomach pain, constipation;

  
  


• 
  

  problems with memory or concentration;

  
  


• 
  

  feeling restless or excited (especially in children);

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  warmth, redness, or tingly feeling under your skin.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect V-Hist (brompheniramine and phenylephrine)?

Before using brompheniramine and phenylephrine, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by brompheniramine and phenylephrine.

Tell your doctor about all other medications you are using, especially:

• 
  

  medicines to treat high blood pressure;

  
  


• 
  

  a beta blocker such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Dutoprol, Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others; or

  
  


• 
  

  antidepressants such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

This list is not complete and other drugs may interact with brompheniramine and phenylephrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More V-Hist resources

• V-Hist Side Effects (in more detail)
• V-Hist Use in Pregnancy & Breastfeeding
• V-Hist Drug Interactions
• V-Hist Support Group
• 0 Reviews for V-Hist - Add your own review/rating

• Alenaze-D Elixir MedFacts Consumer Leaflet (Wolters Kluwer)


• Bromfed MedFacts Consumer Leaflet (Wolters Kluwer)


• BroveX-D Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Entre-B Prescribing Information (FDA)


• J-Tan D Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Rhinabid Sustained-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Compare V-Hist with other medications

• Hay Fever
• Nasal Congestion
• Rhinitis

Where can I get more information?

• Your pharmacist can provide more information about brompheniramine and phenylephrine.

See also: V-Hist side effects (in more detail)

Islotin

Islotin may be available in the countries listed below.

Ingredient matches for Islotin

Metformin

Metformin is reported as an ingredient of Islotin in the following countries:

• Argentina

International Drug Name Search

Diovan 160mg Capsules

1. Name Of The Medicinal Product

Diovan®

Valsartan

* Intensive monitoring is requested only when used for the recently licensed indication in heart failure.

2. Qualitative And Quantitative Composition

One capsule contains 160 mg valsartan.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Capsules.

Appearance: Dark grey cap and flesh opaque body, marked CG GOG in white ink on the cap.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension

Treatment of essential hypertension

Recent myocardial infarction

Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours – 10 days) myocardial infarction (see sections 4.4 and 5.1).

Heart Failure

Treatment of symptomatic heart failure when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta blockers cannot be used (see sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

Posology

Hypertension

The recommended dose of Diovan is 80 mg once daily. The antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg and to a maximum of 320 mg.

Diovan may also be administered with other antihypertensive agents. The addition of a diuretic such as hydrochlorothiazide will decrease blood pressure even further in these patients.

Recent myocardial infarction

In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg twice daily, valsartan should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next few weeks. The starting dose is provided by the 40 mg divisible tablet.

The target maximum dose is 160 mg twice daily. In general, it is recommended that patients achieve a dose level of 80 mg twice daily by two weeks after treatment initiation and that the target maximum dose, 160 mg twice daily, be achieved by three months, based on the patient's tolerability. If symptomatic hypotension or renal dysfunction occur, consideration should be given to a dosage reduction.

Valsartan may be used in patients treated with other post-myocardial infarction therapies, e.g. thrombolytics, acetylsalicylic acid, beta blockers, statins and diuretics. The combination with ACE inhibitors is not recommended (see sections 4.4 and 5.1).

Evaluation of post-myocardial infarction patients should always include assessment of renal function.

Heart failure

The recommended starting dose of Diovan is 40 mg twice daily. Uptitration to 80 mg and 160 mg twice daily should be done at intervals of at least two weeks to the highest dose, as tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.

Valsartan may be administered with other heart failure therapies. However, the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended (see sections 4.4 and 5.1).

Evaluation of patients with heart failure should always include assessment of renal function.

Method of administration

Diovan may be taken independently of a meal and should be administered with water.

Additional information on special populations

Elderly

No dose adjustment is required in elderly patients.

Renal impairment

No dosage adjustment is required for patients with a creatinine clearance >10 ml/min (see sections 4.4 and 5.2).

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80mg. Diovan is contraindicated in patients with severe hepatic impairment and in patients with cholestasis (see sections 4.3, 4.4 and 5.2).

Paediatric patients

Diovan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Severe hepatic impairment, biliary cirrhosis and cholestasis.

- Second and third trimester of pregnancy (see sections 4.4 and 4.6)

4.4 Special Warnings And Precautions For Use

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.

Sodium- and/or volume- depleted patients

In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Diovan. Sodium and/or volume depletion should be corrected before starting treatment with Diovan, for example by reducing the diuretic dose.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of Diovan has not been established.

Short-term administration of Diovan to twelve patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal haemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, other agents that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, therefore monitoring of renal function is recommended when patients are treated with valsartan.

Kidney transplantation

There is currently no experience on the safe use of Diovan in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Diovan as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Impaired renal function

No dosage adjustment is required for patients with a creatinine clearance >10 ml/min. There is currently no experience on the safe use in patients with a creatinine clearance <10 ml/min and patients undergoing dialysis, therefore valsartan should be used with caution in these patients (see sections 4.2 and 5.2).

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Diovan should be used with caution (see sections 4.2 and 5.2).

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Recent myocardial infarction

The combination of captopril and valsartan has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies (see sections 4.2 and 5.1). Therefore, the combination of valsartan with an ACE inhibitor is not recommended.

Caution should be observed when initiating therapy in post-myocardial infarction patients. Evaluation of post-myocardial infarction patients should always include assessment of renal function (see section 4.2).

Use of Diovan in post-myocardial infarction patients commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2).

Heart Failure

In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and Diovan has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended.

Caution should be observed when initiating therapy in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function (see section 4.2).

Use of Diovan in patients with heart failure commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2).

In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of Diovan may be associated with impairment of the renal function.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. Due to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels

If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.

Caution required with concomitant use

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day), and non-selective NSAIDs

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Others

In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.

4.6 Pregnancy And Lactation

Pregnancy

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

AIIRAs therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia); see also section 5.3 “Preclinical safety data”.

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of valsartan during breastfeeding, Diovan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

4.8 Undesirable Effects

In controlled clinical studies in patients with hypertension, the overall incidence of adverse reactions (ADRs) was comparable with placebo and is consistent with the pharmacology of valsartan. The incidence of ADRs did not appear to be related to dose or treatment duration and also showed no association with gender, age or race.

The ADRs reported from clinical studies, post-marketing experience and laboratory findings are listed below according to system organ class.

Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (

For all the ADRs reported from post-marketing experience and laboratory findings, it is not possible to apply any ADR frequency and therefore they are mentioned with a "not known" frequency.

• Hypertension

Blood and lymphatic system disorders
Not known	Decrease in haemoglobin, Decrease in haematocrit, Neutropenia, Thrombocytopenia
Immune system disorders
Not known	Hypersensitivity including serum sickness
Metabolism and nutrition disorders
Not known	Increase of serum potassium, hyponatraemia
Ear and labyrinth system disorders
Uncommon	Vertigo
Vascular disorders
Not known	Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon	Cough
Gastrointestinal disorders
Uncommon	Abdominal pain
Hepato-biliary Disorders
Not known	Elevation of liver function values including increase of serum bilirubin.
Skin and subcutaneous tissue disorders
Not known	Angioedema, Rash, Pruritus
Musculoskeletal and connective tissue disorders
Not known	Myalgia
Renal and urinary disorders
Not known	Renal failure and impairment, Elevation of serum creatinine
General disorders and administration site conditions
Uncommon:	Fatigue

The safety profile seen in controlled-clinical studies in patients with post-myocardial infarction and/or heart failure varies from the overall safety profile seen in hypertensive patients. This may relate to the patients underlying disease. ADRs that occurred in post-myocardial infarction and/or heart failure patients are listed below:

• Post-myocardial infarction and/or heart failure

Blood and lymphatic system disorders
Not known	Thrombocytopenia
Immune system disorders
Not known	Hypersensitivity including serum sickness
Metabolism and nutrition disorders
Uncommon	Hyperkalaemia
Not known	Increase of serum potassium, hyponatraemia
Nervous system disorders
Common	Dizziness, Postural dizziness
Uncommon	Syncope, Headache
Ear and labyrinth system disorders
Uncommon	Vertigo
Cardiac disorders
Uncommon	Cardiac failure
Vascular disorders
Common	Hypotension, Orthostatic hypotension
Not known	Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon	Cough
Gastrointestinal disorders
Uncommon	Nausea, Diarrhoea
Hepatobiliary Disorders
Not known	Elevation of liver function values
Skin and subcutaneous tissue disorders
Uncommon	Angioedema
Not known	Rash, Pruritus
Musculoskeletal and connective tissue disorders
Not known	Myalgia
Renal and urinary disorders
Common	Renal failure and impairment
Uncommon	Acute renal failure, Elevation of serum creatinine
Not known	Increase in Blood Urea Nitrogen
General disorders and administration site conditions
Uncommon	Asthenia, Fatigue

4.9 Overdose

Symptoms

Overdose with Diovan may result in marked hypotension, which could lead to depressed levels of consciousness, circulatory collapse and/or shock.

Treatment

The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms; stabilisation of the circulatory condition is of prime importance.

If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken.

Valsartan is unlikely to be removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic groups: Angiotensin II Antagonists, plain ATC code: C09CA03.

Valsartan is an orally active, potent, and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT₁ receptor blockade with valsartan may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the AT₁ receptor. Valsartan does not exhibit any partial agonist activity at the AT₁ receptor and has much (about 20,000 fold) greater affinity for the AT₁ receptor than for the AT₂ receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Valsartan does not inhibit ACE (also known as kininase II), which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P < 0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.6 % versus 7.9 % respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5 % of trial subjects receiving valsartan and 19.0 % of those receiving a thiazide diuretic experienced cough compared to 68.5 % of those treated with an ACE inhibitor (P < 0.05).

Hypertension

Administration of Diovan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks and persist during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt withdrawal of Diovan has not been associated with rebound hypertension or other adverse clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE was reduced (p<0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups.

The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 µg/min; 20-700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/l). Patients were randomized to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that 160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.

Recent myocardial infarction

The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomised, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive heart failure and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction

Valsartan was as effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the valsartan (19.9 %), captopril (19.5 %), and valsartan+captopril (19.3 %) groups. Combining valsartan with captopril did not add further benefit over captopril alone. There was no difference between valsartan and captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying disease. Valsartan was also effective in prolonging the time to and reducing cardiovascular mortality, hospitalisation for heart failure, and recurrent myocardial infarction, resuscitated cardiac arrest, and non-fatal stroke (secondary composite endpoint.)

The safety profile of valsartan was consistent with the clinical course of patients treated in the post-myocardial infarction setting. Regarding renal function, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients, 4.8% of valsartan+captopril-treated patients, and 3.4% of captopril-treated patients. Discontinuations due to various types of renal dysfunction occurred in 1.1% of valsartan-treated patients, 1.3% in valsartan+captopril patients, and 0.8% of captopril patients. An assessment of renal function should be included in the evaluation of patients post-myocardial infarction.

There was no difference in all-cause mortality or cardiovascular mortality or morbidity when beta-blockers were administered together with the combination of valsartan + captopril, valsartan alone, or captopril alone. Irrespective of treatment, mortality was lower in the group of patients treated with a beta blocker, suggesting that the known beta blocker benefit in this population was maintained in this trial.

Heart failure

Val-HeFT was a randomised, controlled, multinational clinical trial of valsartan compared with placebo on morbidity and mortality in 5,010 NYHA class II (62%), III (36%) and IV (2%) heart failure patients receiving usual therapy with LVEF <40% and left ventricular internal diastolic diameter (LVIDD) >2.9 cm/m². Baseline therapy included ACE inhibitors (93%), diuretics (86%), digoxin (67%) and beta blockers (36%). The mean duration of follow-up was nearly two years. The mean daily dose of Diovan in Val-HeFT was 254 mg. The study had two primary endpoints: all cause mortality (time to death) and composite mortality and heart failure morbidity (time to first morbid event) defined as death, sudden death with resuscitation, hospitalisation for heart failure, or administration of intravenous inotropic or vasodilator agents for four hours or more without hospitalisation.

All cause mortality was similar (p=NS) in the valsartan (19.7%) and placebo (19.4%) groups. The primary benefit was a 27.5% (95% CI: 17 to 37%) reduction in risk for time to first heart failure hospitalisation (13.9% vs. 18.5%). Results appearing to favour placebo (composite mortality and morbidity was 21.9% in placebo vs. 25.4% in valsartan group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and valsartan.

In a subgroup of patients not receiving an ACE inhibitor (n=366), the morbidity benefits were greatest. In this subgroup all-cause mortality was significantly reduced with valsartan compared to placebo by 33% (95% CI: –6% to 58%) (17.3% valsartan vs. 27.1% placebo) and the composite mortality and morbidity risk was significantly reduced by 44% (24.9% valsartan vs. 42.5% placebo).

In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the valsartan (21.8%) and placebo (22.5%) groups. Composite mortality and morbidity risk was significantly reduced by 18.3% (95% CI: 8% to 28%) with valsartan compared with placebo (31.0% vs. 36.3%).

In the overall Val-HeFT population, valsartan treated patients showed significant improvement in NYHA class, and heart failure signs and symptoms, including dyspnoea, fatigue, oedema and rales compared to placebo. Patients treated with valsartan had a better quality of life as demonstrated by change in the Minnesota Living with Heart Failure Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan treated patients was significantly increased and LVIDD significantly reduced from baseline at endpoint compared to placebo.

5.2 Pharmacokinetic Properties

Absorption:

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.

Distribution:

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94–97%), mainly serum albumin.

Biotransformation:

Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.

Excretion:

Valsartan shows multiexponential decay kinetics (t_½α <1 h and t_½ß about 9 h). Valsartan is primarily eliminated by biliary excretion in faeces (about 83% of dose) and renally in urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

In Heart failure patients:

The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to that observed in healthy volunteers. AUC and C_max values of valsartan are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 l/h. Age does not affect the apparent clearance in heart failure patients.

Special populations

Elderly

A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.

Impaired renal function

As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Dose adjustment is therefore not required in patients with renal impairment (creatinine clearance >10 ml/min). There is currently no experience on the safe use in patients with a creatinine clearance <10 ml/min and patients undergoing dialysis, therefore valsartan should be used with caution in these patients (see sections 4.2 and 4.4). Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.

Hepatic impairment

Approximately 70% of the dose absorbed is eliminated in the bile, essentially in the unchanged form. Valsartan does not undergo any noteworthy biotransformation. A doubling of exposure (AUC) was observed in patients with mild to moderate hepatic impairment compared to healthy subjects. However, no correlation was observed between plasma valsartan concentration versus degree of hepatic dysfunction. Diovan has not been studied in patients with severe hepatic dysfunction (see sections 4.2, 4.3 and 4.4).

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose, polyvidone, sodium lauryl sulfate, crospovidone type A, magnesium stearate, gelatine, propylene glycol, colourings (E171, E172) and shellac.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Protect from moisture and heat. Store below 30°C.

6.5 Nature And Contents Of Container

PVC/PE/PVDC blister packs.

Diovan 160 mg capsules are supplied in packs 7, 28 or 98 capsules.

6.6 Special Precautions For Disposal And Other Handling

No specific instructions for use/handling.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Limited

Trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey GU16 7SR

United Kingdom

8. Marketing Authorisation Number(S)

PL 00101/0526

9. Date Of First Authorisation/Renewal Of The Authorisation

31 October 1997 / 03 November 2010

10. Date Of Revision Of The Text

21 March 2011

LEGAL CATEGORY

POM