Votrient 200 mg and 400 mg film coated tablets

1. Name Of The Medicinal Product

Votrient®

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 200 mg or 400 mg pazopanib (as hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

200 mg: Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side.

400 mg: Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Votrient is indicated for the first line treatment of advanced Renal Cell Carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease.

4.2 Posology And Method Of Administration

Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer agents.

Adults

The recommended dose of pazopanib is 800 mg once daily.

Dose modifications

Dose modification should be in 200 mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The dose of pazopanib should not exceed 800 mg.

Paediatric population

Pazopanib is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Elderly

There are limited data of the use of pazopanib in patients aged 65 years and older. In the RCC studies of pazopanib, overall no clinically significant differences in safety of pazopanib were observed between subjects aged at least 65 years and younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal impairment

Renal impairment is unlikely to have a clinically relevant effect on pazopanib pharmacokinetics given the low renal excretion of pazopanib and metabolites (see section 5.2). Therefore, no dose adjustment is required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients with creatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population.

Hepatic impairment

The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established (see section 4.4). Dosing recommendations in hepatically impaired patients are based on pharmacokinetic studies of pazopanib in patients with varying degrees of hepatic dysfunction (see section 5.2). Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring due to potentially increased exposure to the medicinal product. It is recommended that patients with mild abnormalities in liver parameters (defined as either normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or as an elevation of bilirubin (> 35 % direct) up to 1.5 x upper limit of normal (ULN) regardless of the ALT value) are treated initially with 800 mg pazopanib once daily. A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (defined as an elevation of bilirubin > 1.5 x to 3 x ULN regardless of the ALT values) (see section 5.2).

Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).

Method of administration

Pazopanib should be taken without food, at least one hour before or two hours after a meal (see section 5.2). Votrient film-coated tablets should be taken whole with water and not broken or crushed (see section 5.2).

4.3 Contraindications

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

Severe hepatic impairment.

4.4 Special Warnings And Precautions For Use

Hepatic effects

Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. The safety and pharmacokinetics of pazopanib have not been fully established in patients with pre-existing hepatic impairment. Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring. It is recommended that patients with mild abnormalities in liver parameters are treated initially with 800 mg pazopanib once daily. A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (see section 4.2). Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).

In clinical studies with pazopanib, increase in serum transaminases (ALT, AST) and bilirubin were observed (see section 4.8). In the majority of the cases, isolated increases in ALT and AST have been reported, without concomitant elevations of alkaline phosphatase or bilirubin.

Monitor serum liver tests before initiation of treatment with pazopanib and at least once every 4 weeks for the first 4 months of treatment, and as clinically indicated. Periodic monitoring should then continue after this time period.

• Patients with isolated transaminase elevations

• Patients with transaminases of > 8 X ULN should have pazopanib interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose and measure serum liver tests weekly for 8 weeks (see section 4.2). Following reintroduction of pazopanib, if transaminase elevations > 3 X ULN recur, then pazopanib should be discontinued.

• If transaminase elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN, bilirubin fractionation should be performed. If direct (conjugated) bilirubin is > 35 % of total bilirubin, pazopanib should be discontinued.

Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see section 4.5) and should be undertaken with caution and close monitoring.

Hypertension

In clinical studies with pazopanib, events of hypertension including newly diagnosed symptomatic episodes of elevated blood pressure (hypertensive crisis) have occurred. Blood pressure should be well controlled prior to initiating pazopanib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy (see section 4.8). Elevated blood pressure levels (systolic blood pressure

QT prolongation and Torsade de Pointes

In clinical studies with pazopanib, events of QT prolongation and Torsade de Pointes have occurred (see section 4.8). Pazopanib should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrythmics or other medicinal products that may prolong QT interval and those with relevant pre-existing cardiac disease. When using pazopanib, base line and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. calcium, magnesium, potassium) within normal range is recommended.

Arterial thrombotic events

In clinical studies with pazopanib, myocardial infarction, ischemic stroke, and transient ischemic attack were observed (see section 4.8). Pazopanib should be used with caution in patients who are at increased risk for any of these events. A treatment decision should be made based upon the assessment of individual patient's benefit/risk.

Haemorrhagic events

In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8). Pazopanib is not recommended in patients who had a history of haemoptysis, cerebral, or clinically significant gastrointestinal (GI) haemorrhage in the past 6 months. Pazopanib should be used with caution in patients with significant risk of haemorrhage.

Gastrointestinal perforations and fistula

In clinical studies with pazopanib, events of GI perforation or fistula have occurred (see section 4.8). Pazopanib should be used with caution in patients at risk for GI perforation or fistula.

Wound healing

No formal studies on the effect of pazopanib on wound healing have been conducted. Since Vascular Endothelial Growth Factor (VEGF) inhibitors may impair wound healing, treatment with pazopanib should be stopped at least 7 days prior to scheduled surgery. The decision to resume pazopanib after surgery should be based on clinical judgement of adequate wound healing. Pazopanib should be discontinued in patients with wound dehiscence.

Heart failure

The safety and pharmacokinetics of pazopanib in patients with moderate to severe heart failure has not been studied.

Hypothyroidism

In clinical studies with pazopanib, events of hypothyroidism have occurred (see section 4.8). Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism should be treated as per standard medical practice prior to the start of pazopanib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on pazopanib treatment. Laboratory monitoring of thyroid function should be performed periodically and managed as per standard medical practice.

Proteinuria

In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic urinanalysis during treatment is recommended and patients should be monitored for worsening proteinuria. Pazopanib should be discontinued if the patient develops Grade 4 proteinuria.

Infections

Cases of serious infections (with or without neutropenia), in some cases with fatal outcome, have been reported.

Combination with other systemic anti-cancer therapies

Clinical trials of pazopanib in combination with pemetrexed (non-small cell lung cancer (NSCLC)) and lapatinib (cervical cancer) were terminated early due to concerns over increased toxicity and/or mortality, and a safe and effective combination dose has not been established with these regimens.

Pregnancy

Pre-clinical studies in animals have shown reproductive toxicity (see section 5.3). If pazopanib is used during pregnancy, or if the patient becomes pregnant whilst receiving pazopanib, the potential hazard to the foetus should be explained to the patient. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with pazopanib (see section 4.6).

Interactions

Concomitant treatment with strong inhibitors of CYP3A4, P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib (see section 4.5). Selection of alternative concomitant medicinal products with no or minimal potential to inhibit CYP3A4, P-gp or BCRP should be considered.

Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure to pazopanib (see section 4.5).

Concomitant administration of pazopanib with uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) substrates (e.g. irinotecan) should be undertaken with caution since pazopanib is an inhibitor of UGT1A1.

Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of other medicinal products on pazopanib

In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.

CYP3A4, P-gp, BCRP Inhibitors: Pazopanib is a substrate for CYP3A4, P-gp and BCRP.

Co-administration of pazopanib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib.

Administration of 1,500 mg lapatinib (a substrate for and weak inhibitor of CYP3A4 and P-gp and a potent inhibitor of BCRP) with 800 mg pazopanib resulted in an approximately 50 % to 60 % increase in mean pazopanib AUC_(0-24) and C_max compared to administration of 800 mg pazopanib alone. Inhibition of P-gp and/or BCRP by lapatinib likely contributed to the increased exposure to pazopanib.

Concurrent administration of a single dose of pazopanib eye drops (at a low dose of 400 µg (80 µl of 5 mg/ml)) with the strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, in healthy volunteers resulted in a 2.2- and 1.5-fold increase in mean AUC_(0-t) and C_max values, respectively. Inhibition of P-gp and/or BCRP by ketoconazole likely contributed to the increased exposure to pazopanib. At present no dosing recommendations can be made for either potent specific inhibitors of CYP3A4 or ketoconazole.

Co-administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor, such as lapatinib, will result in an increase in plasma pazopanib concentrations. Co-administration with potent P-gp or BCRP inhibitors may also alter the exposure and distribution of pazopanib, including distribution into the central nervous systems (CNS).

Combination with strong CYP3A4, P-gp or BCRP inhibitors should therefore be avoided, or selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4, P-gp or BCRP is recommended.

CYP3A4, P-gp, BCRP Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Co-administration of pazopanib with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, including distribution into the CNS. Selection of an alternate concomitant medication with no or minimal enzyme or transporter induction potential is recommended.

Effects of pazopanib on other medicinal products

In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in cancer patients. Pazopanib resulted in an increase of approximately 30 % in the mean AUC and C_max of midazolam (CYP3A4 probe substrate) and increases of 33 % to 64 % in the ratio of dextrometrophan to dextrophan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate). Co-administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m² (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 25 % and 31 % in paclitaxel AUC and C_max, respectively.

Based on in vitro IC₅₀ and in vivo plasma C_max values, pazopanib metabolites GSK1268992 and GSK1268997 may contribute to the net inhibitory effect of pazopanib towards BCRP. Furthermore, inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract cannot be excluded. Care should be taken when pazopanib is co-administered with other oral BCRP and P-gp substrates.

In vitro, pazopanib inhibited human organic anion transporting polypeptide (OATP1B1). It cannot be excluded that pazopanib will affect the pharmacokinetics of substrates of OATP1B1 (e.g. statins, see “Effect of concomitant use of Pazopanib and Simvastatin” below).

Effect of concomitant use of Pazopanib and Simvastatin

Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Results from a meta-analysis using pooled data from clinical studies with pazopanib show that ALT > 3xULN was reported in 126 / 895 (14 %) of patients who did not use statins, compared with11/41 (27 %) of patients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue simvastatin (see section 4.4). In addition, concomitant use of pazopanib and other statins should be undertaken with caution as there are insufficient data available to assess their impact on ALT levels. It cannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g. atorvastatin, fluvastatin, pravastatin, rosuvastatin).

Effect of food on pazopanib

Administration of pazopanib with a high fat or low fat meal results in an approximately 2-fold increase in AUC and C_max. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of pazopanib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pazopanib should not be used during pregnancy unless the clinical condition of the women requires treatment with pazopanib. If pazopanib is used during pregnancy, or if the patient becomes pregnant while receiving pazopanib, the potential hazard to the foetus should be explained to the patient.

Women of childbearing potential should be advised to use adequate contraception and avoid becoming pregnant while receiving treatment with pazopanib.

Breast-feeding

The safe use of pazopanib during lactation has not been established. It is not known whether pazopanib is excreted in human milk. There are no animal data on the excretion of pazopanib in animal milk. A risk to the suckling child cannot be excluded. Breast feeding should be discontinued during treatment with pazopanib.

Fertility

Animal studies indicate that male and female fertility may be affected by treatment with pazopanib (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. A detrimental effect on such activities cannot be predicted from the pharmacology of pazopanib. The clinical status of the patient and the adverse event profile of pazopanib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should avoid driving or using machines if they feel dizzy, tired or weak.

4.8 Undesirable Effects

Pooled data from the pivotal RCC study (VEG105192, n=290), extension study (VEG107769, n=71) and the supportive Phase II study (VEG102616, n=225) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total n=586) in subjects with RCC (see section 5.1).

The most important serious adverse reactions were transient ischaemic attack, ischaemic stroke, myocardial ischaemia, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in < 1 % of treated patients.

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage, pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischemic stroke.

The most common adverse reactions (experienced by at least 10 % of the patients) of any grade included: diarrhoea, hair colour change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia, elevated alanine aminotransferase and elevated aspartate aminotransferase.

Treatment related adverse reactions, all grades, which were reported in RCC patients or during post marketing period are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised for the classification of frequency:

Very common
Common
Uncommon
Rare
Very rare	< 1/10,000
not known	(cannot be estimated from the available data)

Categories have been assigned based on absolute frequencies in the clinical study data. Post marketing data on safety and tolerability across all pazopanib clinical trials and from spontaneous reports have also been evaluated. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness.

Table 1: Treatment-related adverse reactions reported in RCC studies (n=586) or during post marketing period

System Organ Class	Frequency (all grades)	Adverse Reactions	All Grades n (%)	Grade 3 n (%)	Grade 4 n (%)
Infections and Infestations	Uncommon	Infections (with or without neutropenia)†	not known	not known	not known
Blood and lymphatic system disorders	Common	Thrombocytopenia	25 (4 %)	3 (< 1 %)	3 (< 1 %)
Common	Neutropenia	17 (3 %)	4 (< 1 %)	2 (< 1 %)
Common	Leukopenia	14 (2 %)	1 (< 1 %)	0
Endocrine disorders	Common	Hypothyroidism	23 (4 %)	0	0
Metabolism and nutrition disorders	Very common	Decreased appetitee	122 (21 %)	6 (1 %)	0
Uncommon	Hypophosphataemia	4 (< 1 %)	2 (< 1 %)	0
Uncommon	Hypomagnesaemia	3 (< 1 %)	0	0
Nervous system disorders	Very common	Dysgeusiac	92 (16 %)	0	0
Common	Headache	41 (7 %)	0	0
Common	Dizziness	19 (3 %)	0	1 (< 1 %)
Common	Lethargy	12 (2 %)	1 (< 1 %)	0
Common	Paraesthesia	12 (2 %)	2 (< 1 %)	0
Uncommon	Peripheral sensory neuropathy	5 (< 1 %)	0	0
Uncommon	Hypoaesthesia	4 (< 1 %)	0	0
Uncommon	Transient ischaemic attack	3 (< 1 %)	2 (< 1 %)	0
Uncommon	Cerebrovascular accident	1 (< 1 %)	0	1 (< 1 %)
Uncommon	Ischaemic stroke	1 (< 1 %)	0	0
Eye disorders	Uncommon	Eyelash discolouration	3 (< 1 %)	0	0
Cardiac disorders	Uncommon	Bradycardia	3 (< 1 %)	0	0
Uncommon	Cardiac dysfunction	4 (< 1 %)	1 (< 1 %)	1 (< 1 %)
Uncommon	Myocardial infarction	2 (< 1 %)	0	2 (< 1 %)
Uncommon	Myocardial ischaemia	1 (< 1 %)	1 (< 1 %)	0
Vascular disorders	Very common	Hypertension	225 (38 %)	34 (6 %)	0
Common	Hot flush	11 (2 %)	0	0
Uncommon	Flushing	5 (< 1 %)	0	0
Uncommon	Haemorrhage	1 (< 1 %)	0	0
Uncommon	Hypertensive crisis	1 (< 1 %)	0	1 (< 1 %)
Respiratory, thoracic and mediastinal disorders	Common	Epistaxis	16 (3 %)	0	0
Common	Dysphonia	15 (3 %)	0	0
Uncommon	Pulmonary embolism	4 (< 1 %)	1 (< 1 %)	3 (< 1 %)
Uncommon	Haemoptysis	3 (< 1 %)	0	0
Uncommon	Pulmonary haemorrhage	1 (< 1 %)	0	0
Gastrointestinal disorders	Very common	Diarrhoea	286 (49 %)	19 (3 %)	2 (< 1 %)
Very common	Nausea	161 (27 %)	3 (< 1 %)	0
Very common	Vomiting	89 (15 %)	7 (1 %)	1 (< 1 %)
Very common	Abdominal paina	60 (10 %)	8 (1 %)	0
Common	Dyspepsia	24 (4 %)	2 (< 1 %)	0
Common	Stomatitis	24 (4 %)	0	0
Common	Flatulence	20 (3 %)	0	0
Common	Abdominal distension	15 (3 %)	0	0
Uncommon	Mouth ulceration	4 (< 1 %)	1 (< 1 %)	0
Uncommon	Frequent bowel movements	3 (< 1 %)	0	0
Uncommon	Gastrointestinal haemorrhage	3 (< 1 %)	1 (< 1 %)	0
Uncommon	Rectal haemorrhage	3 (< 1 %)	1 (< 1 %)	0
Uncommon	Large intestine perforation	2 (< 1 %)	1 (< 1 %)	0
Uncommon	Mouth haemorrhage	2 (< 1 %)

Rogaine For Men Extra Strength Topical

Generic Name: minoxidil (Topical route)

min-OX-i-dil

Commonly used brand name(s)

In the U.S.

• Men's Rogaine


• Rogaine


• Rogaine For Men Extra Strength


• Women's Rogaine

In Canada

• Apo-Gain


• Gen-Minoxidol


• Hairgro


• Hair Regrowth Treatment


• Med Minoxidil


• Minox

Available Dosage Forms:

• Solution


• Foam

Therapeutic Class: Alopecia Agent

Uses For Rogaine For Men Extra Strength

Minoxidil applied to the scalp is used to stimulate hair growth in adult men and women with a certain type of baldness. The exact way that this medicine works is not known.

If hair growth is going to occur with the use of minoxidil, it usually occurs after the medicine has been used for several months and lasts only as long as the medicine continues to be used. Hair loss will begin again within a few months after minoxidil treatment is stopped.

In the U.S., this medicine is available without a prescription.

Before Using Rogaine For Men Extra Strength

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of topical minoxidil in children. Safety and efficacy have not been established ..

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of topical minoxidil in the elderly. However, studies have shown that the medicine works best in younger patients who have a short history of hair loss. Minoxidil has not been studied in patients older than 65 years of age .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Any other skin problems, an irritation, or a sunburn on the scalp—These conditions may cause too much topical minoxidil to be absorbed into the body and may increase the chance of side effects.

• Heart disease or


• Hypertension (high blood pressure)—Topical minoxidil has not been studied in patients who have these conditions, but more serious problems may develop for these patients if they use more medicine than is recommended over a large area and too much minoxidil is absorbed into the body.

Proper Use of minoxidil

This section provides information on the proper use of a number of products that contain minoxidil. It may not be specific to Rogaine For Men Extra Strength. Please read with care.

This medicine usually comes with patient instructions. It is important that you read the instructions carefully.

It is very important that you use this medicine only as directed. Do not use more of it and do not use it more often than your doctor ordered. To do so may increase the chance of it being absorbed through the skin. For the same reason, do not apply minoxidil to other parts of your body. Absorption into the body may affect the heart and blood vessels and cause unwanted effects.

Do not use any other skin products on the same skin area on which you use minoxidil. Hair coloring, hair permanents, and hair relaxers may be used during minoxidil therapy as long as the scalp is washed just before applying the hair coloring, permanent, or relaxer. Minoxidil should not be used 24 hours before and after the hair treatment procedure. Be sure to not double your doses of minoxidil to make up for any missed doses.

To apply minoxidil topical solution:

• Make sure your hair and scalp are completely dry before applying this medicine.


• Apply the amount prescribed to the area of the scalp being treated, beginning in the center of the area. Follow your doctor's instructions on how to apply the solution, using the applicator provided.


• Do not shampoo your hair for 4 hours after applying minoxidil.


• Immediately after using this medicine, wash your hands to remove any medicine that may be on them.


• Do not use a hairdryer to dry the scalp after you apply minoxidil solution. Blowing with a hairdryer on the scalp may make the treatment less effective.


• Allow the minoxidil to completely dry for 2 to 4 hours after applying it, including before going to bed. Minoxidil can stain clothing, hats, or bed linen if your hair or scalp is not fully dry after using the medicine.


• Avoid transferring the medicine while wet to other parts of the body. This can occur if the medicine gets on your pillowcase or bed linens or if your hands are not washed after applying minoxidil.

To apply minoxidil topical foam:

• Open the container by matching the arrow on can ring with the arrow on cap. Pull off the cap.


• Part the hair into one or more rows to expose the hair thinning area on the scalp.


• Hold the can upside down and press the nozzle to put foam on your fingers.


• Use your fingers to spread the foam over the hair loss area and gently massage into your scalp.


• Immediately after using this medicine, wash your hands to remove any medicine that may be on them .

If your scalp becomes abraded, irritated, or sunburned, check with your doctor before applying minoxidil.

Minoxidil topical foam or solution is for use on the scalp only. Keep this medicine away from the eyes, nose, and mouth. If you should accidentally get some in your eyes, nose, or mouth, flush the area thoroughly with cool tap water. If you are using the pump spray, be careful not to breathe in the spray .

Do not use the foam near heat or open flame, or while smoking. Do not puncture, break, or burn the aerosol can .

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For hair growth:
  
  • For topical solution dosage form:
    
    • Adults—Apply 1 milliliter (mL) to the scalp two times a day.
    
    
    • Children—Use and dose must be determined by the doctor.
    
    
  
  
  • For topical foam dosage form:
    
    • Adults—Apply half a capful to the scalp two times a day.
    
    
    • Children—Use and dose must be determined by your doctor .
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Flammable: Keep away from fire or flame.

Precautions While Using Rogaine For Men Extra Strength

It is important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

Tell your doctor if you notice continued itching, redness, or burning of your scalp after you apply minoxidil. If the itching, redness, or burning is severe, wash the medicine off and check with your doctor before using it again.

Hair loss may continue for 2 weeks after you start using minoxidil. Tell your doctor if your hair loss continues after 2 weeks. Also, tell your doctor if your hair growth does not increase after using minoxidil for 4 months.

Rogaine For Men Extra Strength Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Less common

• Itching or skin rash (continued)

Rare

• Acne at site of application


• burning of scalp


• facial hair growth


• increased hair loss


• inflammation or soreness at root of hair


• reddened skin


• swelling of face

Signs and symptoms of too much medicine being absorbed into the body—Rare

• Blurred vision or other changes in vision


• chest pain


• dizziness


• fainting


• fast or irregular heartbeat


• flushing


• headache


• lightheadedness


• numbness or tingling of hands, feet, or face


• swelling of face, hands, feet, or lower legs


• weight gain (rapid)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Rogaine For Men Extra Strength Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Rogaine For Men Extra Strength Topical resources

• Rogaine For Men Extra Strength Topical Side Effects (in more detail)
• Rogaine For Men Extra Strength Topical Use in Pregnancy & Breastfeeding
• Rogaine For Men Extra Strength Topical Drug Interactions
• 2 Reviews for Rogaine For Men Extra Strength Topical - Add your own review/rating

Compare Rogaine For Men Extra Strength Topical with other medications

• Alopecia

Kloramfenikol

Kloramfenikol may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Kloramfenikol

Chloramphenicol

Chloramphenicol is reported as an ingredient of Kloramfenikol in the following countries:

• Norway

International Drug Name Search

Puribel

Puribel may be available in the countries listed below.

Ingredient matches for Puribel

Allopurinol

Allopurinol is reported as an ingredient of Puribel in the following countries:

• Mexico

International Drug Name Search

Valcyte Powder for Oral Solution

1. Name Of The Medicinal Product

VALCYTE 50 mg/ml powder for oral solution.

2. Qualitative And Quantitative Composition

Each bottle contains 5.5 g valganciclovir hydrochloride per 12 g powder for oral solution.

Each ml of the reconstituted solution contains 50 mg valganciclovir (as hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for oral solution.

The powder is a granulate with a white to slightly yellow colour.

When the powder is dissolved, it forms a clear, colourless to brown solution.

4. Clinical Particulars

4.1 Therapeutic Indications

VALCYTE is indicated for the induction and maintenance treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).

VALCYTE is indicated for the prevention of CMV disease in CMV-negative patients who have received a solid organ transplant from a CMV-positive donor.

4.2 Posology And Method Of Administration

Caution – Strict adherence to dosage recommendations is essential to avoid overdose (see sections 4.4 and 4.9).

Valganciclovir is rapidly and extensively metabolised to ganciclovir after oral dosing. Oral valganciclovir 900 mg taken twice daily is therapeutically equivalent to intravenous ganciclovir 5 mg/kg taken twice daily. The ganciclovir systemic exposure following administration of 900 mg valganciclovir oral solution is equivalent to valganciclovir 900 mg tablets.

Standard dosage in adults

Induction treatment of CMV retinitis:

For patients with active CMV retinitis, the recommended dose is 900 mg valganciclovir twice a day for 21 days. Prolonged induction treatment may increase the risk of bone marrow toxicity (see section 4.4).

Maintenance treatment of CMV retinitis:

Following induction treatment, or in patients with inactive CMV retinitis, the recommended dose is 900 mg valganciclovir once daily. Patients whose retinitis worsens may repeat induction treatment; however, consideration should be given to the possibility of viral drug resistance.

Prevention of CMV disease in solid organ transplantation:

For kidney transplant patients, the recommended dose is 900 mg once daily , starting within 10 days of transplantation and continuing until 100 days post transplantation. Prophylaxis may be continued until 200 days post-transplantation (see sections 4.4, 4.8 and 5.1).

For patients who have received a solid organ transplant other than kidney, the recommended dose is 900 mg once daily, starting within 10 days of transplantation and continuing until 100 days post transplantation.

Special dosage instructions

Patients with renal impairment

Serum creatinine levels or creatinine clearance should be monitored carefully. Dosage adjustment is required according to creatinine clearance, as shown in the Table below (see sections 4.4 and 5.2).

An estimated creatinine clearance (ml/min) can be related to serum creatinine by the following formulae:

CrCl (ml/min)	Induction dose of valganciclovir	Maintenance/Prevention dose of valganciclovir
	900 mg twice daily	900 mg once daily
40 – 59	450 mg twice daily	450 mg once daily
25 – 39	450 mg once daily	225 mg once daily
10 – 24	225 mg once daily	125 mg once daily
<10	200 mg three times a week after dialysis	100 mg three times a week after dialysis

Patients undergoing haemodialysis:

Dosage adjustment is necessary for patients on haemodialysis (CrCl <10ml/min) (see sections 4.4 5.2) and a dosing recommendation is given in the Table above.

Patients with hepatic impairment

Safety and efficacy of VALCYTE have not been studied in patients with hepatic impairment (see sections 4.4 and 5.2).

Paediatric patients:

The safety and efficacy of Valcyte in paediatric patients have not been established in adequate and well-controlled clinical studies. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly patients:

Safety and efficacy of VALCYTE have not been established in this patient population.

Patients with severe leucopenia, neutropenia, anaemia, thrombocytopenia and pancytopenia:

see section 4.4 before initiation of therapy.

If there is a significant deterioration of blood cell counts during therapy with VALCYTE, treatment with haematopoietic growth factors and/or dose interruption should be considered (see section 4.4).

Method of administration

VALCYTE is administered orally, and whenever possible, should be taken with food (see section 5.2).

VALCYTE powder for oral solution requires reconstitution prior to oral administration (see section 6.6). Two oral dosing dispensers with graduations in 25 mg up to 500 mg are provided. It is recommended that patients use the dispenser.

4.3 Contraindications

VALCYTE is contraindicated in patients with hypersensitivity to valganciclovir, ganciclovir or to any of the excipients.

Due to the similarity of the chemical structure of VALCYTE and that of aciclovir and valaciclovir, a cross-hypersensitivity reaction between these drugs is possible. Therefore, VALCYTE is contraindicated in patients with hypersensitivity to aciclovir and valaciclovir.

VALCYTE is contraindicated during lactation (see section 4.6).

4.4 Special Warnings And Precautions For Use

Owing to the teratogenic character, the VALCYTE powder and reconstituted solution should be handled with caution. Inhalation should be avoided. If the powder or solution make direct contact with skin, the area should be washed thoroughly with soap and water. If the solution gets into the eye, the eye should be thouroghly washed with water immediately.

Prior to the initiation of valganciclovir treatment, patients should be advised of the potential risks to the foetus. In animal studies, ganciclovir was found to be mutagenic, teratogenic, aspermatogenic and carcinogenic, and a suppressor of female fertility. VALCYTE should, therefore, be considered a potential teratogen and carcinogen in humans with the potential to cause birth defects and cancers (see section 5.3). It is also considered likely that VALCYTE causes temporary or permanent inhibition of spermatogenesis. Women of child bearing potential must be advised to use effective contraception during treatment. Men must be advised to practise barrier contraception during treatment, and for at least 90 days thereafter, unless it is certain that the female partner is not at risk of pregnancy (see sections 4.6, 4.8 and 5.3).

Severe leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anaemia have been observed in patients treated with VALCYTE (and ganciclovir). Therapy should not be initiated if the absolute neutrophil count is less than 500 cells/μl, or the platelet count is less than 25000/μl, or the haemoglobin level is less than 8g/dl (see sections 4.2 and 4.8).

When extending prophylaxis beyond 100 days the possible risk of developing leucopenia and neutropenia should be taken into account (see sections 4.2, 4.8 and 5.1).

VALCYTE should be used with caution in patients with pre-existing haematological cytopenia or a history of drug-related haematological cytopenia and in patients receiving radiotherapy.

It is recommended that complete blood counts and platelet counts be monitored during therapy. Increased haematological monitoring may be warranted in patients with renal impairment. In patients developing severe leucopenia, neutropenia, anaemia and/or thrombocytopenia, it is recommended that treatment with haematopoietic growth factors and/or dose interruption be considered (see sections 4.2 and 4.8).

In patients with impaired renal function, dosage adjustments based on creatinine clearance are required (see sections 4.2 and 5.2).

Convulsions have been reported in patients taking imipenem-cilastatin and ganciclovir. VALCYTE should not be used concomitantly with imipenem-cilastatin unless the potential benefits outweigh the potential risks (see section 4.5).

Patients treated with VALCYTE and (a) didanosine, (b) drugs that are known to be myelosuppressive (e.g. zidovudine), or (c) substances affecting renal function, should be closely monitored for signs of added toxicity (see section 4.5).

The controlled clinical study using valganciclovir for the prophylactic treatment of CMV disease in transplantation, as detailed in section 5.1, did not include lung and intestinal transplant patients. Therefore, experience in these transplant patients is limited.

For patients on a sodium-controlled diet, this medicinal product contains a total of 0.188 mg/ml sodium.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drug interactions with valganciclovir

In-vivo drug interaction studies with VALCYTE have not been performed. Since valganciclovir is extensively and rapidly metabolised to ganciclovir; drug interactions associated with ganciclovir will be expected for valganciclovir.

Drug interactions with ganciclovir

Imipenem-cilastatin

Convulsions have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly. These drugs should not be used concomitantly unless the potential benefits outweigh the potential risks (see section 4.4).

Probenecid

Probenecid given with oral ganciclovir resulted in statistically significantly decreased renal clearance of ganciclovir (20%) leading to statistically significantly increased exposure (40%). These changes were consistent with a mechanism of interaction involving competition for renal tubular secretion. Therefore, patients taking probenecid and VALCYTE should be closely monitored for ganciclovir toxicity.

Zidovudine

When zidovudine was given in the presence of oral ganciclovir there was a small (17%), but statistically significant increase in the AUC of zidovudine. There was also a trend towards lower ganciclovir concentrations when administered with zidovudine, although this was not statistically significant. However, since both zidovudine and ganciclovir have the potential to cause neutropenia and anaemia, some patients may not tolerate concomitant therapy at full dosage (see section 4.4).

Didanosine

Didanosine plasma concentrations were found to be consistently raised when given with ganciclovir (both intravenous and oral). At ganciclovir oral doses of 3 and 6g/day, an increase in the AUC of didanosine ranging from 84 to 124% has been observed, and likewise at intravenous doses of 5 and 10 mg/kg/day, an increase in the AUC of didanosine ranging from 38 to 67% has been observed. There was no clinically significant effect on ganciclovir concentrations. Patients should be closely monitored for didanosine toxicity (see section 4.4).

Mycophenolate Mofetil

Based on the results of a single dose administration study of recommended doses of oral mycophenolate mofetil (MMF) and intravenous ganciclovir and the known effects of renal impairment on the pharmacokinetics of MMF and ganciclovir, it is anticipated that co-administration of these agents (which have the potential to compete for renal tubular secretion) will result in increases in phenolic glucuronide of mycophenolic acid (MPAG) and ganciclovir concentration. No substantial alteration of mycophenolic acid (MPA) pharmacokinetics is anticipated and MMF dose adjustment is not required. In patients with renal impairment to whom MMF and ganciclovir are co-administered, the dose recommendation of ganciclovir should be observed and the patients monitored carefully. Since both MMF and ganciclovir have the potential to cause neutropenia and leucopenia, patients should be monitored for additive toxicity.

Zalcitabine

No clinically significant pharmacokinetic changes were observed after concomitant administration of ganciclovir and zalcitabine. Both valganciclovir and zalcitabine have the potential to cause peripheral neuropathy and patients should be monitored for such events.

Stavudine

No clinically significant interactions were observed when stavudine and oral ganciclovir were given in combination.

Trimethoprim

No clinically significant pharmacokinetic interaction was observed when trimethoprim and oral ganciclovir were given in combination. However, there is a potential for toxicity to be enhanced since both drugs are known to be myelosuppressive and therefore both drugs should be used concomitantly only if the potential benefits outweigh the risks.

Other antiretrovirals

At clinically relevant concentrations, there is unlikely to be either a synergistic or antagonistic effect on the inhibition of either human immunodeficiency virus (HIV) in the presence of ganciclovir or CMV in the presence of a variety of antiretroviral drugs. Metabolic interactions with, for example, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are unlikely due to the lack of P450 involvement in the metabolism of either valganciclovir or ganciclovir.

Other potential drug interactions

Toxicity may be enhanced when valganciclovir is co-administered with, or is given immediately before or after, other drugs that inhibit replication of rapidly dividing cell populations such as occur in the bone marrow, testes and germinal layers of the skin and gastrointestinal mucosa. Examples of these types of drugs are dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations, nucleoside analogues and hydroxyurea.

Since ganciclovir is excreted through the kidney (section 5.2), toxicity may also be enhanced during co-administration of valganciclovir with drugs that might reduce the renal clearance of ganciclovir and hence increase its exposure. The renal clearance of ganciclovir might be inhibited by two mechanisms: (a) nephrotoxicity, caused by drugs such as cidofovir and foscarnet, and (b) competitive inhibition of active tubular secretion in the kidney by, for example, other nucleoside analogues.

Therefore, all of these drugs should be considered for concomitant use with valganciclovir only if the potential benefits outweigh the potential risks (see section 4.4).

4.6 Pregnancy And Lactation

There are no adequate data from the use of VALCYTE in pregnant women. Its active metabolite, ganciclovir, readily diffuses across the human placenta. Based on its pharmacological mechanism of action and reproductive toxicity observed in animal studies with ganciclovir (see section 5.3) there is a theoretical risk of teratogenicity in humans.

VALCYTE should not be used in pregnancy unless the therapeutic benefit for the mother outweighs the potential risk of teratogenic damage to the child.

Women of child-bearing potential must be advised to use effective contraception during treatment. Male patients must be advised to practise barrier contraception during, and for at least 90 days following treatment with VALCYTE unless it is certain that the female partner is not at risk of pregnancy (see section 5.3).

It is unknown if ganciclovir is excreted in breast milk, but the possibility of ganciclovir being excreted in the breast milk and causing serious adverse reactions in the nursing infant cannot be discounted. Therefore, breast-feeding must be discontinued (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Convulsions, sedation, dizziness, ataxia, and/or confusion have been reported with the use of VALCYTE and/or ganciclovir. If they occur, such effects may affect the patient's ability to drive and operate machinery.

4.8 Undesirable Effects

Valganciclovir is a prodrug of ganciclovir, which is rapidly and extensively metabolised to ganciclovir after oral administration. The undesirable effects known to be associated with ganciclovir use can be expected to occur with valganciclovir. All of the undesirable effects observed with valganciclovir clinical studies have been previously observed with ganciclovir. The most commonly reported adverse drug reactions following administration of valganciclovir in adults are neutropenia, anaemia and diarrhoea.

Valganciclovir is associated with a higher risk of diarrhoea compared to intravenous ganciclovir. In addition, valganciclovir is associated with a higher risk of neutropenia and leucopenia compared to oral ganciclovir.

Severe neutropenia (< 500 ANC/μl) is seen more frequently in CMV retinitis patients undergoing treatment with valganciclovir than in solid organ transplant patients receiving valganciclovir.

The frequency of adverse reactions reported in clinical trials with either valganciclovir, oral ganciclovir, or intravenous ganciclovir is presented in the Table below. The adverse reactions listed were reported in clinical trials in patients with AIDS for the induction or maintenance treatment of CMV retinitis, or in liver, kidney or heart transplant patients for the prophylaxis of CMV disease. The term (severe) in parenthesis in the Table indicates that the adverse reaction has been reported in patients at both mild/moderate intensity and severe/life-threatening intensity at that specific frequency.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Body System	Very Common (	Common (	Uncommon (	Rare (
Infections and infestations		Oral candidiasis, sepsis (bacteraemia, viraemia), cellulitis, urinary tract infection
Blood and lymphatic system disorders	(Severe) neutropenia, anaemia	(Severe) anaemia, (severe) thrombocytopenia, (severe) leucopenia, (severe) pancytopenia, ,	Bone marrow failure	Aplastic anaemia
Immune system disorders			Anaphylactic reaction
Metabolism and nutrition disorders		De creased appetite, anorexia
Psychiatric disorders		Depression, anxiety, confusion, abnormal thinking	Agitation, psychotic disorder, hallucination,
Nervous system disorders		Headache, insomnia, dysgeusia (taste disturbance), hypoaesthesia, paraesthesia, peripheral neuropathy, dizziness, convulsion	Tremor
Eye disorders		Macular oedema, retinal detachment, vitreous floaters, eye pain	Visual disturbance, conjunctivitis
Ear and labyrinth disorders		Ear pain	Deafness
Cardiac disorders			Arrhythmia
Vascular disorders			Hypotension
Respiratory, thoracic and mediastinal disorders	Dyspnoea	Cough
Gastrointestinal disorders	Diarrhea	Nausea, vomiting, abdominal pain, abdominal pain upper, dyspepsia, constipation, flatulence, dysphagia,	, Abdominal distension, mouth ulceration, pancreatitis
Hepatobiliary disorders		(Severe) hepatic function abnormal, blood alkaline phosphatase increased, aspartate aminotransferase increased	Alanine aminotransferase increased
Skin and subcutaneous tissue disorders		Dermatitis, night sweats, pruritus	Alopecia, urticaria, dry skin
Musculoskeletal and connective tissue disorders		Back pain, myalgia, arthralgia, muscle spasms
Renal and urinary disorders		Creatinine renal clearance decreased, renal impairment	Haematuria, renal failure
Reproductive system and breast disorders			Male infertility
General disorders and administration site conditions		Fatigue, pyrexia, chills, pain, chest pain, malaise, asthenia
Investigations		Weight decreased, blood creatinine increased

Severe thrombocytopenia may be associated with potentially life-threatening bleeding.

Paediatrics

There are very limited paediatric data on the exposure to valganciclovir(see also sections 5.1 and 5.2). Following is a summary of all adverse events which occurred in more than 10% (very common) of the total paedriatric population on treatment:

Body System	Very Common Adverse Events Reported in Clinical Trials
Blood and lymphatic system disorders	Anaemia, neutropenia
Vascular disorders	Hypertension
Respiratory, thoracic and mediastinal disorders	Upper respiratory tract infection
Gastrointestinal disorders	Diarrhoea, nausea , vomiting, constipation
General disorders and administration site conditions	Pyrexia , transplant rejection

4.9 Overdose

Overdose experience with valganciclovir

One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's degree of renal impairment (decreased creatinine clearance).

It is expected that an overdose of valganciclovir could also possibly result in increased renal toxicity (see section 4.2 and section 4.4).

Haemodialysis and hydration may be of benefit in reducing blood plasma levels in patients who receive an overdose of valganciclovir (see section 5.2)

Overdose experience with intravenous ganciclovir

Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during post-marketing experience. In some of these cases no adverse events were reported. The majority of patients experienced one or more of the following adverse events:

Haematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leucopenia, neutropenia, granulocytopenia

– Hepatotoxicity: hepatitis, liver function disorder

Renal toxicity: worsening of haematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine

– Gastrointestinal toxicity: abdominal pain, diarrhoea, vomiting

– Neurotoxicity: generalised tremor, convulsion

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B14

Mechanism of action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir. After oral administration, valganciclovir is rapidly and extensively metabolised to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine and inhibits replication of herpes viruses in vitro and in vivo. Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV-8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).

In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

Antiviral Activity

The in-vitro anti-viral activity, measured as IC₅₀ of ganciclovir against CMV, is in the range of 0.08μM (0.02μg/ml) to 14μM (3.5μg/ml).

The clinical antiviral effect of VALCYTE has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46% (32/69) of patients at study entry to 7% (4/55) of patients following four weeks of VALCYTE treatment.

Clinical efficacy

Treatment of CMV retinitis:

Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either VALCYTE 900 mg (twice daily) or intravenous ganciclovir 5 mg/kg (twice daily). The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and valganciclovir arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with VALCYTE given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with VALCYTE was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with VALCYTE was 219 (125) days.

Prevention of CMV disease in transplantation

A double-blind, double-dummy clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastro-intestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either VALCYTE (900 mg once daily) or oral ganciclovir (1000 mg three times daily) starting within 10 days of transplantation until Day 100 post-transplant. The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first 6 months post-transplant was 12.1% in the VALCYTE arm (n=239) compared with 15.2% in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm. The incidence of acute rejection in the first 6 months was 29.7% in patients randomised to valganciclovir compared with 36.0% in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8% of patients, in each arm.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg od) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo.

The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease¹, 12 Month ITT Population ^A

	Valganciclovir 900 mg od 100 Days N = 163	Valganciclovir 900 mg od 200 Days N = 155	Between Treatment Group Difference
Patients with confirmed or assumed CMV disease2	71 (43.6%) [35.8% ; 51.5%]	36 (23.2%) [16.8% ; 30.7%]	20.3% [9.9% ; 30.8%]
Patients with confirmed CMV disease	60 (36.8%) [29.4% ; 44.7%]	25 (16.1%) [10.7% ; 22.9%]	20.7% [10.9% ; 30.4%]

¹ CMV Disease is defined as either CMV syndrome or tissue invasive CMV. ² Confirmed CMV is a clinically confirmed case of CMV disease. Patients were assumed to have CMV disease if there was no week 52 assessment and no confirmation of CMV disease before this time point.

^A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Valcyte until Day 200 post-transplant compared to patients who received CMV prophylaxis with Valcyte until Day 100 post-transplant.

The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.2% (160/163) for the 100 day dosing regimen and 98.1% (152/155) for the 200 day dosing regimen. Up to 24 month post-transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post-transplant, one additional case has been reported in the 200 days dosing group.

Viral Resistance

Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:

Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2%, 6.5%, 12.8%, and 15.3% contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV disease in transplantation:

Active comparator study

Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9%) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9%.

Extending prophylaxis study from 100 to 200 days post-transplant

Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (>600 copies/mL) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.

Paediatrics

A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving valganciclovir once daily for up to 100 days according to a dosing algorithm produced exposures similar to that in adults (see section 5.2). Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults (see 4.8). These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients.

The pharmacokinetics and safety of single dose valganciclovir (dose range 14-16-20 mg/kg/dose) was studied in 24 neonates (aged 8-34 days) with symptomatic congenital CMV disease (see section 5.2). The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral valganciclovir, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for the most time of the study period. This treatment indication is not recommended presently for valganciclovir. The design of the study and obtained results are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Absorption

Valganciclovir is a prodrug of ganciclovir. It is well absorbed from the gastrointestinal tract and rapidly and extensively metabolised in the intestinal wall and liver to ganciclovir. Systemic exposure to valganciclovir is transient and low. The absolute bioavailability of ganciclovir from valganciclovir is approximately 60% across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below).

Valganciclovir in HIV positive, CMV positive patients:

Systemic exposure of HIV positive, CMV positive patients after twice daily administration of ganciclovir and valganciclovir for one week is:

Parameter	Ganciclovir (5 mg/kg, IV) n = 18	Valganciclovir (900 mg, p.o.) n = 25
Ganciclovir	Valganciclovir
AUC(0 - 12 h) (μg.h/ml)	28.6 ± 9.0	32.8 ± 10.1	0.37 ± 0.22
Cmax (μg/ml)	10.4 ± 4.9