Composition: Each film coated tablet contains
Memantine hydrochloride ………………. 5/10 mg
Additional ingredients:
Mannitol, microcrystalline cellulose PH 102, polyvinylpyrrolidone K-30, carmellose sodium, colloidal silicon dioxide, magnesium stearate, opadry pink 03F84827 & purified water.

INDICATIONS: Treatment of patients with moderate to severe Alzheimer’s disease.
DOSAGE AND ADMINISTRATION: Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines. The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient’s tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.
Denigma tablets should be administered orally once a day and should be taken at the same time every day. These tablets can be taken with or without food.
Adults:
Dose titration
Treatment Initiation Pack:
The recommended starting dose is 5 mg per day, which is stepwise increased over the first 4 weeks of treatment reaching the recommended maintenance dose as follows:
Week 1 (day 1-7):
The patient should take one 5 mg dose per day for 7 days. Week 2 (day 8-14): The patient should take one 10 mg dose per day for 7 days. Week 3 (day 15-21): The patient should take one 15 mg dose per day for 7 days. Week 4 (day 22-28): The patient should take one 20 mg dose per day for 7 days.
The maximum daily dose is 20 mg per day.
Maintenance dose
The recommended maintenance dose is 20 mg per day.
Elderly:
The recommended dose for patients over the age of 65 years is 20 mg per day as described above.
Children and adolescents under the age of 18 years: Denigma is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Renal impairment: In patients with mildly impaired renal function (creatinine clearance 50 – 80 ml/min) no dosage adjustment is required. In patients with moderate renal impairment (creatinine clearance 30 – 49 ml/min) daily dose should be 10 mg. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5 – 29 ml/min) daily dose should be 10 mg per day.
Hepatic impairment:
In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B) no dosage adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of Denigma is not recommended in patients with severe hepatic impairment.

ADVERSE EFFECTS:
Adverse reactions are ranked according to system organ class, using the following convention: very common (>1/10), common (>1/100 to < 1/10), uncommon (>1/1,000 to < 1/100), rare (>1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

INTERACTIONS WITH OTHER MEDICAL PRODUCTS:
Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur:
 The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dosage adjustment may be necessary.
 Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan. There is one published case report on a possible risk also for the combination of memantine and phenytoin.
 Other active substances such as such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels.
 There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT.
In post-marketing experience isolated cases with international normalized ratio (INR) increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase or sulphation in vitro.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE:
Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.
Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse drug reactions (mainly CNS-related) may be more frequent or more pronounced.
Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.
In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

PREGNANCY AND LACTATION Pregnancy:
For memantine, no clinical data on exposed pregnancies are available. The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
Lactation:
It is not known whether memantine is excreted in human breast milk but, taking into consideration the lipophilicity of the substance, this probably occurs. Women taking memantine should not breast-feed.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES Moderate to severe Alzheimer’s disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, Denigma has minor or moderate influence on the ability to drive and use machines, such that outpatients should take special care.

OVERDOSAGE: Only limited experience with overdose is available from clinical studies and post-marketing experience
CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients.

PHARMACOLOGIC PROPERTIES: Pharmacodynamics:

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
Pharmacokinetics:
Absorption: Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.
Distribution: Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5 – 1 µmol) with large interindividual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45% of memantine is bound to plasma-proteins.
Biotransformation: In man, about 80% of the circulating memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro.
In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, more than 99% being excreted renally.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m² and part of total renal clearance is achieved by tubular secretion.
Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalising gastric buffers.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.
Pharmacokinetic/pharmacodynamic relationship:
At a dose of memantine of 20 mg per day the cerebrospinal fluid (CSF) levels match the ki-value (ki = inhibition constant) of memantine, which is 0.5 µmol in human frontal cortex.
STORAGE CONDITION:
Store below 30°C.
Keep all medicines out of reach of children.
SHELF-LIFE:
36 months
PACKING:
-14049001461705
Alu-PVC/PVDC clear blister of 14 tablets. 1 or 10 blisters are packed in a carton box.
NAME AND ADDRESS OF MANUFACTURER: Kusum Healthcare Pvt. Ltd. A
SP 289(A), RIICO Indl. Area,
Chopanki, Bhiwadi (Rajasthan), India
DATE OF REVISION OF PACKAGE INSERT:
Not Applicable
Denigma 5 mg – MM Reg. No.: 1903AA 7574
Denigma 10 mg – MM Reg. No.: 1909AA 7701