Ganciclovir Capsules IP 250mg (Vitravene) Taj Pharma

Ganciclovir Capsules IP 250mg (Vitravene) Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT:

Ganciclovir Capsules IP 250mg (Vitravene) Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION:

Each hard gelatin capsule contains:
Ganciclovir IP                                               250mg
Excipients                                                          q.s.
Approved colours used in empty capsule shells

3. PHARMACEUTICAL FORM:

Capsule

Description:

An acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections.

4. CLINICAL PARTICULARS:

4.1. Therapeutic indications:

For induction and maintenance in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Also used in the treatment of severe cytomegalovirus (CMV) disease, including CMV pneumonia, CMV gastrointestinal disease, and disseminated CMV infections, in immunocompromised patients.

4.2. Dosage and administration:

Dosage: THE RECOMMENDED DOSE FOR Ganciclovir Capsules SHOULD NOT BE EXCEEDED.

For Treatment of CMV Retinitis in Patients with Normal Renal Function:

1. Induction Treatment

Ganciclovir Capsules should not be used for induction treatment.

2. Maintenance Treatment

Following induction treatment, the recommended maintenance dosage of Ganciclovir Capsules is 1000mg tid with food. Alternatively, the dosing regimen of 500 mg 6 times daily every 3 hours with food, during waking hours, may be used.

For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of ganciclovir, reinduction treatment is recommended.

For the Prevention of CMV Disease in Patients with Advanced HIV Infection andNormalRenal Function:

The recommended prophylactic dose of Ganciclovir Capsules is 1000 mg tid with food.

For the Prevention of CMV Disease in Transplant Recipients with Normal Renal Function:

The recommended prophylactic dosage of Ganciclovir Capsules is 1000 mg tid with food.

The duration of treatment with Ganciclovir Capsules in transplant recipients is dependent upon the duration and degree of immunosuppression. In a controlled clinical trial of liver allograft recipients, treatment with Ganciclovir Capsules was continued through week 14 posttransplantation (see indications and usage section for a more detailed discussion).

Renal Impairment:

In patients with renal impairment, the dose of Ganciclovir Capsules should be modified as shown below:

Creatinine clearance for females = 0.85 x male value

Patient Monitoring: Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see adverse events), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see dosage and administration).

Reduction of Dose: Dosage reductions in renally impaired patients should be considered for Ganciclovir Capsules (see Renal Impairment). Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see adverse events). Ganciclovir should not be administered in patients with severe neutropenia (ANC less than 500/µL) or severe thrombocytopenia (platelets less than 25,000/µL).

4.3. Contraindications:

Ganciclovir is contraindicated in patients with hypersensitivity to ganciclovir or acyclovir.

4.4. Warnings and Precautions:

Hematologic: Ganciclovir should not be administered if the absolute neutrophil count is less than 500 cells/µL or the platelet count is less than 25,000 cells/µL. Granulocytopenia (neutropenia), anemia and thrombocytopenia have been observed in patients treated with ganciclovir. The frequency and severity of these events vary widely in different patient populations (see adverse events).

Ganciclovir should, therefore, be used with caution in patients with pre-existing cytopenias or with a history of cytopenic reactions to other drugs, chemicals or irradiation. Granulocytopenia usually occurs during the first or second week of treatment but may occur at any time during treatment. Cell counts usually begin to recover within 3 to 7 days of discontinuing drug.

Impairment of Fertility: Animal data indicate that administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses and irreversible at higher doses (see precautions: Carcinogenesis, Mutagenesis and Impairment of Fertility). Although data in humans have not been obtained regarding this effect, it is considered probable that ganciclovir at the recommended doses causes temporary or permanent inhibition of spermatogenesis. Animal data also indicate that suppression of fertility in females may occur.

Teratogenesis: Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing potential should be advised to use effective contraception during treatment. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir (see Pregnancy; Teratogenic Effects: Category C).

Precautions

General

Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS SHOULD BE CONSIDERED FOR Ganciclovir Capsules. Such adjustments should be based on measured or estimated creatinine clearance values (see dosage and administration).

Information for Patients

All patients should be informed that the major toxicities of ganciclovir are granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications may be required, including discontinuation. The importance of close monitoring of blood counts while on therapy should be emphasized. Patients should be informed that ganciclovir has been associated with elevations in serum creatinine.

Patients should be instructed to take Ganciclovir Capsules with food to maximize bioavailability.

Patients should be advised that ganciclovir has caused decreased sperm production in animals and may cause infertility in humans. Women of childbearing potential should be advised that ganciclovir causes birth defects in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with ganciclovir. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with ganciclovir.

Patients should be advised that ganciclovir causes tumors in animals. Although there is no information from human studies, ganciclovir should be considered a potential carcinogen.

All HIV+ Patients: These patients may be receiving zidovudine (Retrovir*). Patients should be counseled that treatment with both ganciclovir and zidovudine simultaneously may not be tolerated by some patients and may result in severe granulocytopenia (neutropenia). Patients with AIDS may be receiving didanosine (Videx#). Patients should be counseled that concomitant treatment with both ganciclovir and didanosine can cause didanosine serum concentrations to be significantly increased.

HIV+ Patients with CMV Retinitis: Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may continue to experience progression of retinitis during or following treatment. Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with ganciclovir. Some patients will require more frequent follow-up.

Laboratory Testing

Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving ganciclovir (see adverse events), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Increased serum creatinine levels have been observed in trials evaluating ganciclovir. Patients should have serum creatinine or creatinine clearance values monitored carefully to allow for dosage adjustments in renally impaired patients (see dosage and administration).

4.5. Drug Interactions:

Didanosine: At an oral dose of 1000 mg of ganciclovir every 8 hours and didanosine, 200 mg every 12 hours, the steady-state didanosine AUC0-12 increased 111 ± 114% (range: 10% to 493%) when didanosine was administered either 2 hours prior to or concurrent with administration of ganciclovir (n = 12 patients, 23 observations). A decrease in steady-state ganciclovir AUC of 21 ± 17% (range: -44% to 5%) was observed when didanosine was administered 2 hours prior to administration of ganciclovir, but ganciclovir AUC was not affected by the presence of didanosine when the two drugs were administered simultaneously (n = 12). There were no significant changes in renal clearance for either drug.

Zidovudine: At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir AUC0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg every 4 hours (n = 12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range: -11% to 74%) in the presence of ganciclovir.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage.

Probenecid: At an oral dose of 1000 mg of ganciclovir every 8 hours (n = 10), ganciclovir AUC0-8 increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6 hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is consistent with an interaction involving competition for renal tubular secretion.

Imipenem-cilastatin: Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. These drugs should not be used concomitantly unless the potential benefits outweigh the risks.

Other Medications: It is possible that drugs that inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues, should be considered for concomitant use with ganciclovir only if the potential benefits are judged to outweigh the risks.

No formal drug interaction studies of ganciclovir and drugs commonly used in transplant recipients have been conducted.

4.6. Pregnancy, lactation and others:

Carcinogenesis, Mutagenesis

Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day (approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20 mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. No carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day (estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic sarcoma of the liver, ganciclovir- induced tumors were generally of epithelial or vascular origin. Although the preputial and clitoral glands, forestomach and harderian glands of mice do not have human counterparts, ganciclovir should be considered a potential carcinogen in humans.

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 mcg/mL, respectively. Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL.

Impairment of Fertility

Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily administration of doses ranging from 0.2 to 10 mg/kg.

Pregnancy: Teratogenic Effects: Pregnancy Category C

Ganciclovir has been shown to be embryotoxic in rabbits, mice and teratogenic in rabbits. Fetal resorptions were present in at least 85% of rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2 x the human exposure based on AUC comparisons), respectively.

Effects observed in rabbits included: fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.

Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use. There are no adequate and well-controlled studies in pregnant women. Ganciclovir should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Footnote: Compared with the single 5 mg/kg intravenous infusion, human exposure is doubled during the intravenous induction phase (5 mg/kg bid) and approximately halved during maintenance treatment with Ganciclovir Capsules (1000 mg tid). The cross-species dosage treatment should be multiplied by 2 for Ganciclovir Capsules.

Nursing Mothers

It is not known whether ganciclovir is excreted in human milk. However, many drugs are excreted in human milk and, because carcinogenic and teratogenic effects occurred in animals treated with ganciclovir, the possibility of serious adverse reactions from ganciclovir in nursing infants is considered likely (see Pregnancy: Teratogenic Effects: Pregnancy Category C). Mothers should be instructed to discontinue nursing if they are receiving ganciclovir. The minimum interval before nursing can safely be resumed after the last dose of ganciclovir is unknown.

Pediatric Use

Safety and efficacy of ganciclovir in pediatric patients have not been established. The use of ganciclovir in the pediatric population warrants extreme caution due to the probability of long-term carcinogenicity and reproductive toxicity. Administration to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.

Ganciclovir Capsules have not been studied in pediatric patients under age 13.

Geriatric Use

The pharmacokinetic profiles of ganciclovir in elderly patients have not been established. Since elderly individuals frequently have a reduced glomerular filtration rate, particular attention should be paid to assessing renal function before and during administration of ganciclovir (see dosage and administration).

Clinical studies of ganciclovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Ganciclovir is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see Use in Patients with Renal Impairment and dosage and administration)

Use in Patients with Renal Impairment

Ganciclovir should be used with caution in patients with impaired renal function because the half-life and plasma/serum concentrations of ganciclovir will be increased due to reduced renal clearance (see dosage and administration and adverse events: Renal Toxicity).

Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately 50%.

4.7. Undesirable effects:

Adverse events that occurred during clinical trials of Ganciclovir Capsules are summarized below, according to the participating study subject population.

Subjects with AIDS

Three controlled, randomized, phase 3 trials comparing ganciclovir-IV and Ganciclovir Capsules for maintenance treatment of CMV retinitis have been completed. During these trials, ganciclovir-IV or Ganciclovir Capsules were prematurely discontinued in 9% of subjects because of adverse events. In a placebo-controlled, randomized, phase 3 trial of Ganciclovir Capsules for prevention of CMV disease in AIDS, treatment was prematurely discontinued because of adverse events, new or worsening intercurrent illness, or laboratory abnormalities in 19.5% of subjects treated with Ganciclovir Capsules and 16% of subjects receiving placebo. Laboratory data and adverse events reported during the conduct of these controlled trials are summarized below.

Laboratory Data:

Selected Laboratory Abnormalities in Trials for Treatment of CMV Retinitis and Prevention of CMV Disease

Adverse events: The following table shows selected adverse events reported in 5% or more of the subjects in three controlled clinical trials during treatment with Ganciclovir Capsules (3000 mg/day) and in one controlled clinical trial in which Ganciclovir Capsules (3000 mg/day) were compared to placebo for the prevention of CMV disease.

The following events were frequently observed in clinical trials but occurred with equal or greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence, pneumonia, paresthesia, rash.

Retinal Detachment: Retinal detachment has been observed in subjects with CMV retinitis both before and after initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is unknown. Retinal detachment occurred in 8% of patients treated with Ganciclovir Capsules. Patients with CMV retinitis should have frequent ophthalmologic evaluations to monitor the status of their retinitis and to detect any other retinal pathology.

Transplant Recipients

There has been one controlled clinical trial of Ganciclovir Capsules for the prevention of CMV disease in transplant recipients. Laboratory data and adverse events reported during these trials are summarized below.

Laboratory Data: The following table shows the frequency of granulocytopenia (neutropenia) and thrombocytopenia observed:

The following table shows the frequency of elevated serum creatinine values in these controlled clinical trials:

In 3 out of 4 trials, patients receiving either ganciclovir-IV solution or Ganciclovir Capsules had elevated serum creatinine levels when compared to those receiving placebo. Most patients in these studies also received cyclosporine. The mechanism of impairment of renal function is not known. However, careful monitoring of renal function during therapy with Ganciclovir Capsules is essential, especially for those patients receiving concomitant agents that may cause nephrotoxicity.

General

Other adverse events that were thought to be “probably” or “possibly” related to Ganciclovir Capsules in controlled clinical studies in either subjects with AIDS or transplant recipients are listed below. These events all occurred in at least 3 subjects.

Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site inflammation, malaise, pain

Digestive System: abnormal liver function test, aphthous stomatitis, constipation, dyspepsia, eructation

Hemic and Lymphatic System: pancytopenia

Respiratory System: cough increased, dyspnea

Nervous System: abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth, insomnia, seizures, somnolence, thinking abnormal, tremor

Skin and Appendages: alopecia, dry skin

Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder

Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT increased, weight loss

Cardiovascular System: hypertension, phlebitis, vasodilatation

Urogenital System: creatinine clearance decreased, kidney failure, kidney function abnormal, urinary frequency

Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia

The following adverse events reported in patients receiving ganciclovir may be potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and sepsis.

Adverse Events Reported During Postmarketing Experience With Ganciclovir Capsules

The following events have been identified during postapproval use of the drug. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either the seriousness, frequency of reporting, the apparent causal connection or a combination of these factors:

acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest, cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly, dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia, hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia, inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension, irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve paralysis, peripheral ischemia, pulmonary fibrosis, renal tubular disorder, rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de Pointes, vasculitis, ventricular tachycardia.

4.8. Overdosage:

There have been no reports of overdosage with Ganciclovir Capsules. Doses as high as 6000 mg/day, given either as 1000 mg 6 times daily or as 2000 mg tid, did not result in overt toxicity other than transient neutropenia. Daily doses of more than 6000 mg have not been studied.

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered.

5. PHARMACOLOGICAL PROPERTIES:

5.1. Pharmacodynamic properties:

Ganciclovir is a synthetic nucleoside analogue of 2′-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (CMV), herpes simplex virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella zoster virus (VZV), however clinical studies have been limited to assessment of efficacy in patients with CMV infection. Ganciclovir is a prodrug that is structurally similar to acyclovir. It inhibits virus replication by its encorporation into viral DNA. This encorporation inhibits dATP and leads to defective DNA, ceasing or retarding the viral machinery required to spread the virus to other cells.

5.2. Pharmacokinetic properties:

Mechanism of Action

Ganciclovir’s antiviral activity inhibits virus replication. This inhibitory action is highly selective as the drug must be converted to the active form by a virus-encoded cellular enzyme, thymidine kinase (TK). TK catalyzes phosphorylation of ganciclovir to the monophosphate, which is then subsequently converted into the diphosphate by cellular guanylate kinase and into the triphosphate by a number of cellular enzymes. In vitro, ganciclovir triphosphate stops replication of herpes viral DNA. When used as a substrate for viral DNA polymerase, ganciclovir triphosphate competitively inhibits dATP leading to the formation of ‘faulty’ DNA. This is where ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed.

Absorption

Poorly absorbed systemically following oral administration. Bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9% (about 30% with a fatty meal).

Volume of Distribution

0.74 ± 0.15 L/kg

Metabolism

Little to no metabolism, about 90% of plasma ganciclovir is eliminated unchanged in the urine.

Route of Elimination

Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir.

Half-Life

2.5 to 3.6 hours (mean 2.9 hours) when administered intravenously in adults. 3.1 to 5.5 hours when administered orally in adults. Renal function impairment causes a marked increase in half-life (9 to 30 hours intravenously, 15.7 to 18.2 hours orally).

6. PHARMACEUTICAL PARTICULARS:

6.1. Incomaptibilities:
None stated.

6.2. Shelf life:
3 years

6.3. Storage and handling instructions:
Store in cool and dry place.

6.4. Packaging information:
Supplied in Bottles of 60, 90, 180, 1000.
Not all pack sizes may be marketed.

6.5. Special precautions for disposal and other handling:

Handling and Disposal: Caution should be exercised in the handling of Ganciclovir Capsules. Avoid direct contact with the skin or mucous membranes of the powder contained in Ganciclovir Capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water. Ganciclovir Capsules should not be opened or crushed.

Because ganciclovir shares some of the properties of antitumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published.

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At Plot No.: 220, Mahagujarat Industrial Estate,
At & Post: Moraiya, Tal – Sanand, Dist. Ahmedabad, Gujarat, INDIA.