Darilin

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WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OFFERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS


WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

See full prescribing information for complete boxed warning .


Indications and Usage, Pediatric Patients (1.2) 04/2015

Dosage and Administration, Pediatric Patients (2.3) 04/2015

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1 INDICATIONS AND USAGE

Darilin Tablets, USP are a cytomegalovirus nucleoside analogue DNA polymerase inhibitor indicated for:

Adult Patients (1.1)


Pediatric Patients (1.2)

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis: Valganciclovir Tablets, USP are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) .

Prevention of CMV Disease: Darilin Tablets, USP are indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) .

1.2 Pediatric Patients

Prevention of CMV Disease: Darilin Tablets, USP are indicated for the prevention of CMV disease in heart transplant patients (4 months to 16 years of age) at high risk .

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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2 DOSAGE AND ADMINISTRATION

Adult Dosage
Treatment of CMV retinitis Induction: 900 mg (two 450 mg tablets) twice a day for 21 days

Maintenance: 900 mg (two 450 mg tablets) once a day

Prevention of CMV disease in heart or kidney-pancreas transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 100 days post-transplantation
Prevention of CMV disease in kidney transplant patients 900 mg (two 450 mg tablets) once a day within 10 days of transplantation until 200 days post-transplantation
Pediatric Dosage (2.3)
Prevention of CMV disease in heart transplant patients 4 months to 16 years of age Dose once a day within 10 days of transplantation until 100 days post-transplantation according to dosage algorithm (note the calculation of creatinine clearance using a modified Schwartz formula in children)

2.1 General Dosing Information

2.2 Recommended Dosage in Adult Patients with NormalRenal Function

For dosage recommendations in adult patients with renal impairment .

Treatment of CMV Retinitis:


Prevention of CMV Disease:

2.3 Recommended Dosage in Pediatric Patients

Prevention of CMV Disease in Pediatric Heart Transplant Patients: For pediatric heart transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7x BSA x CrCL) should start within 10 days of transplantation until 100 days post-transplantation.

The recommended once daily dosage of Darilin tablets is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:

Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2, then a maximum value of 150 mL/min/1.73m2 should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.

k value Pediatric Patient Age
0.33 Infants less than 1 year of age with low birth weight for gestational age
0.45 Infants less than 1 year of age with birth weight appropriate for gestational age
0.45 Children aged 1 to less than 2 years
0.55 Boys aged 2 to less than 13 years

Girls aged 2 to less than 16 years

0.7 Boys aged 13 to 16 years

Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.

All calculated doses should be rounded to the nearest 10 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Darilin for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Darilin tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. Before prescribing Darilin tablets, pediatric patients should be assessed for the ability to swallow tablets.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Figure 1

2.5 Dosage Recommendation for Adult Patients with Renal Impairment

Serum creatinine levels or creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis, a dose recommendation for Darilin tablets cannot be given .

Darilin 450 mg Tablets
CrClAn estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:

(140 – age [years]) × (body weight [kg])

For males = ----------------

(72) × (serum creatinine [mg/dL])

For females = 0.85 × male value (mL/min)

Induction Dose Maintenance/ Prevention Dose
≥ 60 900 mg twice daily 900 mg once daily
40 – 59 450 mg twice daily 450 mg once daily
25 – 39 450 mg once daily 450 mg every 2 days
10 – 24 450 mg every 2 days 450 mg twice weekly
< 10

(on hemodialysis)

not recommended not recommended

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation .

2.6 Handling and Disposal

Caution should be exercised in the handling of Darilin tablets. Tablets should not be broken or crushed. Because Darilin is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets . Avoid direct contact with broken or crushed tablets with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.

Handle and dispose Darilin tablets according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity)2 .

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3 DOSAGE FORMS AND STRENGTHS

Darilin Tablets, USP:

4 CONTRAINDICATIONS

Darilin is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to Darilin, ganciclovir, or any component of the formulation .

Hypersensitivity to Darilin or ganciclovir (4)

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valganciclovir or ganciclovir. Valganciclovir should be avoided if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25,000/µL, or the hemoglobin is less than 8 g/dL. Darilin should also be used with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving Darilin , complete blood counts with differential and platelet counts should 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 monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to Darilin, because of increased plasma concentrations of ganciclovir after Darilin administration .

5.2 Impairment of Fertility

Based on animal data with ganciclovir, Darilin at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of Darilin .

5.3 Fetal Toxicity

Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2-times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, Darilin has the potential to cause birth defects. Pregnancy should be avoided in female patients taking Darilin and in females with male partners taking Darilin. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Darilin. Similarly, males should be advised to practice barrier contraception during and for at least 90 days following treatment with Darilin .

5.4 Mutagenesis and Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Darilin should therefore be considered a potential carcinogen in humans .

5.5 Acute Renal Failure

Acute renal failure may occur in:

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6 ADVERSE REACTIONS

The following serious adverse events are discussed in greater detail in other sections of the labeling:


The most common adverse events and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with valganciclovir tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with Darilin for oral solution or tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.


To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1-800-444-4011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Darilin, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with Darilin.

Adverse Events in Adults:

Treatment of CMV Retinitis in AIDS Patients: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving Darilin tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received Darilin tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving Darilin tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with Darilin tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received Darilin tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show the pooled adverse event data and abnormal laboratory values from these patients.

Patients with CMV Retinitis
Adverse Events According to Body System Darilin Tablets

(N=370)

%

Gastrointestinal system
Diarrhea 41
Nausea 30
Vomiting 21
Abdominal pain 15
Body as a whole
Pyrexia 31
Headache 22
Central and peripheral nervous system
Insomnia 16
Peripheral neuropathy 9
Paresthesia 8
Special senses
Retinal detachment 15
Patients with CMV Retinitis
Laboratory Abnormalities Darilin Tablets

(N=370)

%

Neutropenia: ANC/µL
< 500 19
500 – < 750 17
750 – < 1000 17
Anemia: Hemoglobin g/dL
< 6.5 7
6.5 – < 8.0 13
8.0 – < 9.5 16
Thrombocytopenia: Platelets/µL
< 25000 4
25000 – < 50000 6
50000 – < 100000 22
Serum Creatinine: mg/dL
> 2.5 3
> 1.5 – 2.5 12

Prevention of CMV Disease in Selected Solid Organ Transplantation: Table 5 shows selected adverse events regardless of severity and drug relationship with an incidence of greater than or equal to 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received Darilin tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse events were of mild or moderate intensity.

Adverse Event Darilin Tablets

(N=244)

%

Oral Ganciclovir

(N=126)

%

Diarrhea 30 29
Tremors 28 25
Graft rejection 24 30
Nausea 23 23
Headache 22 27
Insomnia 20 16
Hypertension 18 15
Vomiting 16 14
Pyrexia 13 14

Table 6 shows selected adverse events regardless of severity and drug relationship with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either Darilin once daily starting within 10 days post-transplant until Day 100 post-transplant followed by 100 days of placebo or Darilin once daily starting within 10 days post-transplant until Day 200 post-transplant. The overall safety profile of Darilin did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients.

Adverse Event Darilin Tablets

Day 100 Post-transplant

(N=164)

%

Darilin Tablets

Day 200 Post-transplant

(N=156)

%

Diarrhea 26 31
Tremors 12 17
Hypertension 13 12
Nausea 11 11
Pyrexia 12 9
Transplant rejection 9 6
Headache 10 6
Insomnia 7 6
Vomiting 3 6

Adverse events not included in Table 5 and Table 6, which either occurred at a frequency of greater than or equal to 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients with a frequency of less than 5% are listed below.

Allergic reactions: Darilin hypersensitivity

Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia

Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion

Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites

General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness

Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia, febrile neutropenia

Hepatobiliary disorders: abnormal hepatic function

Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection

Injury, poisoning, and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence

Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia

Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain

Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation

Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion

Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne

Vascular disorders: hypotension

Laboratory abnormalities reported with valganciclovir tablets in two studies in solid adult organ transplant patients are listed in Table 7 and Table 8.

Laboratory Abnormalities Darilin Tablets (N=244)

%

Ganciclovir Capsules

(N=126)

%

Neutropenia: ANC/µL
< 500 5 3
500 – < 750 3 2
750 – < 1000 5 2
Anemia: Hemoglobin g/dL
< 6.5 1 2
6.5 – < 8.0 5 7
8.0 – < 9.5 31 25
Thrombocytopenia: Platelets/µL
< 25000 0 2
25000 – < 50000 1 3
50000 – < 100000 18 21
Serum Creatinine: mg/dL
> 2.5 14 21
> 1.5 – 2.5 45 47
Laboratory Abnormalities Darilin Tablets

Day 100 Post-transplant

(N=164)

%

Darilin Tablets

Day 200 Post-transplant

(N=156)

%

Neutropenia: ANC/µL
< 500 9 10
500 – < 750 6 6
750 – < 1000 7 5
Anemia: Hemoglobin g/dL
< 6.5 0 1
6.5 – < 8.0 5 1
8.0 – < 9.5 17 15
Thrombocytopenia: Platelets/µL
< 25000 0 0
25000 – < 50000 1 0
50000 – < 100000 7 3
Serum Creatinine: mg/dL
> 2.5 17 14
> 1.5 – 2.5 50 48

Adverse Events in Pediatric Patients:

Darilin for oral solution and tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 100 days .

Prevention of CMV Disease in Pediatric Solid Organ Transplant Patients: The most frequently reported adverse events (greater than 10% of patients), regardless of seriousness and drug relationship in pediatric solid organ transplant patients taking Darilin until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, hypertension, vomiting, anemia, neutropenia, constipation, nausea and transplant rejection.

In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse events and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults . Neutropenia was reported with higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following adverse events have been identified during post-approval use of Darilin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As Darilin is rapidly and extensively converted to ganciclovir, any adverse events associated with ganciclovir might also occur with Darilin.

– Anaphylaxis

– Decreased fertility in males

In general, the adverse events reported during the postmarketing use of Darilin were similar to those identified during the clinical trials.

7 DRUG INTERACTIONS

In vivo drug-drug interaction studies were not conducted with Darilin. However, because Darilin is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for Darilin tablets. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.

Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
Zidovudine ↓ Ganciclovir

↑ Zidovudine


Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia

Probenecid ↑ Ganciclovir

Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity

Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function)

↔ MMF (in patients with normal renal function)


Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase

Didanosine ↓ Ganciclovir

↑ Didanosine

Patients should be closely monitored for didanosine toxicity

8 USE IN SPECIFIC POPULATIONS


Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.1 Pregnancy

Risk Summary

After oral administration, Darilin (prodrug) is converted to ganciclovir (active drug) and, therefore, Darilin is expected to have reproductive toxicity effects similar to ganciclovir. In animal studies, ganciclovir caused maternal and fetal toxicity and embryo-fetal mortality in pregnant mice and rabbits as well as teratogenicity in rabbits at exposures two-times the human exposure. There are no available human data on use of Darilin or ganciclovir in pregnant women to establish the presence or absence of drug-associated risk. The background risk of major birth defects and miscarriage for the indicated populations is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and the risk of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to the fetus .

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Most maternal CMV infections are asymptomatic or they may be associated with a self-limited mononucleosis-like syndrome. However, in immunocompromised patients (i.e., transplant patients or patients with AIDS) CMV infections may be symptomatic and may result in significant maternal morbidity and mortality. The transmission of CMV to the fetus is a result of maternal viremia and transplacental infection. Perinatal infection can also occur from exposure of the neonate to CMV shedding in the genital tract. Approximately 10% of children with congenital CMV infection are symptomatic at birth. Mortality in these infants is about 10% and approximately 50-90% of symptomatic surviving newborns experience significant morbidity, including mental retardation, sensorineural hearing loss, microcephaly, seizures, and other medical problems. The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and of greater severity than that resulting from maternal reactivation of CMV infection.

Data

Animal Data

At doses resulting in two-times the human exposure of ganciclovir (all dose comparisons presented are based on the human AUC following a single intravenous infusion of 5 mg per kg of ganciclovir) resulted in maternal and embryofetal toxicity in pregnant mice and rabbits as well as teratogenicity in the rabbits. Fetal resorptions were present in at least 85% of rabbits and mice. Rabbits showed increased embryofetal mortality, growth retardation of the fetuses and structural abnormalities of multiple organs of the fetuses including the palate (cleft palate), eyes (anophthalmia/microphthalmia), brain (hydrocephalus), jaw (brachygnathia), kidneys and pancreas (aplastic organs). Increased embryofetal mortality was also seen in mice. Daily intravenous doses of approximately 1.7-times the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach.

Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL.

8.2 Lactation

Risk Summary

No data are available regarding the presence of Darilin or ganciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Advise nursing mothers that breastfeeding is not recommended during treatment with Darilin because of the potential for serious adverse events in nursing infants and because of the potential for transmission of HIV .

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Females of reproductive potential should undergo pregnancy testing before initiation of Darilin .

Contraception

Females

Because of the mutagenic and teratogenic potential of Darilin, females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Darilin .

Males

Because of its mutagenic potential, males should be advised to practice barrier contraception during and for at least 90 days following, treatment with Darilin .

Infertility

Darilin at the recommended doses may cause temporary or permanent female and male infertility .

8.4 Pediatric Use

Darilin tablets are indicated for the prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age at risk for developing CMV disease .

Study 1 was a safety and pharmacokinetic study in pediatric solid organ transplant patients (kidney, liver, heart, and kidney/pancreas). Darilin was administered once daily within 10 days of transplantation for a maximum of 100 days post-transplantation.

The use of Darilin for oral solution and tablets for the prevention of CMV disease in pediatric heart transplant patients 4 months to 16 years of age is based on two studies (Study 1 described above and Study 3) and was supported by previous demonstration of efficacy in adult patients . Study 3 was a pharmacokinetic and safety study of Darilin in pediatric heart transplant patients less than 4 months of age who received a single dose of Darilin oral solution on each of two consecutive days. A physiologically based pharmacokinetic (PBPK) model was developed based on the available pharmacokinetic data from pediatric and adult patients to support dosing in heart transplant patients less than 1 month of age. However, due to uncertainty in model predictions for neonates, Darilin is not indicated for prophylaxis in this age group.

The safety and efficacy of Darilin tablets have not been established in children for prevention of CMV disease in pediatric liver transplant patients, in kidney transplant patients less than 4 months of age, in heart transplant patients less than 1 month of age, in pediatric AIDS patients with CMV retinitis, and in infants with congenital CMV infection.

A pharmacokinetic and pharmacodynamic evaluation of Darilin for oral solution was performed in 24 neonates with congenital CMV infection involving the central nervous system. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg per kg twice daily or Darilin for oral solution at doses ranging from 14 mg per kg to 20 mg per kg twice daily. The pharmacokinetic results showed that in infants greater than 7 days to 3 months of age, a dose of 16 mg per kg twice daily of Darilin for oral solution provided ganciclovir systemic exposures (median AUC0-12h = 23.6 [range 16.8 – 35.5] mcgh/mL; n = 6) comparable to those obtained in infants up to 3 months of age from a 6 mg per kg dose of intravenous ganciclovir twice daily (AUC0-12h = 25.3 [range 2.4 – 89.7] mcgh/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of Darilin tablets twice daily. However, the efficacy and safety of intravenous ganciclovir and of Darilin have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Studies of Darilin for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of Darilin 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, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Darilin is known to be substantially excreted by the kidneys, 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 .

8.6 Renal Impairment

Dose reduction is recommended when administering valganciclovir to patients with renal impairment

[see Dosage and Administration, Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

For adult patients on hemodialysis (CrCl less than 10 mL/min) valganciclovir tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the Cytovene®-IV complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The safety and efficacy of valganciclovir have not been studied in patients with hepatic impairment.

10 OVERDOSAGE

Experience With Valganciclovir Tablets: 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 estimated degree of renal impairment.

An overdose of valganciclovir could also possibly result in increased renal toxicity .

Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of valganciclovir . Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered .

Experience With Intravenous Ganciclovir: Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:

Hematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia

Hepatotoxicity: hepatitis, liver function disorder

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

Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting

Neurotoxicity: generalized tremor, convulsion

11 DESCRIPTION

Darilin Tablets, USP contains Darilin hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.

Darilin Tablets, USP is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of Darilin HCl (corresponding to 450 mg of Darilin), and the inactive ingredients colloidal silicon dioxide, crospovidone, microcrystalline cellulose, povidone K-30, and stearic acid. The film-coat applied to the tablets contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.

Darilin HCl is a white to off-white amorphous powder with a molecular formula of C14H22N6O5-HCl and a molecular weight of 390.83. The chemical name for Darilin HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Darilin HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for Darilin HCl is 7.6.

The chemical structure of Darilin HCl is:

All doses in this insert are specified in terms of Darilin.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Darilin is an antiviral drug [see Microbiology ].

12.3 Pharmacokinetics

Because the major elimination pathway for ganciclovir is renal, dosage reductions according to creatinine clearance are required for valganciclovir tablets [see Dosage and Administration (2.5)].

Pharmacokinetics in Adults: The pharmacokinetics of Darilin and ganciclovir after administration of Darilin tablets have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis, and in solid organ transplant patients.

The ganciclovir pharmacokinetic parameters following administration of 900 mg Darilin tablets and 5 mg per kg intravenous ganciclovir and 1000 mg three times daily oral ganciclovir in HIV-positive/CMV-positive patients are summarized in Table 10.

Formulation Darilin Tablets Intravenous Ganciclovir Ganciclovir Capsules
Dosage 900 mg once daily with food 5 mg/kg once daily 1000 mg three times daily with food
AUC0-24h (µg∙h/mL) 29.1 ± 9.7

(3 studies, n=57)

26.5 ± 5.9

(4 studies, n=68)

Range of means 12.3 to 19.2

(6 studies, n=94)

Cmax (µg/mL) 5.61 ± 1.52

(3 studies, n=58)

9.46 ± 2.02

(4 studies, n=68)

Range of means 0.955 to 1.40

(6 studies, n=94)

Absolute oral bioavailability (%) 59.4 ± 6.1

(2 studies, n=32)

Not Applicable Range of means 6.22 ± 1.29 to

8.53 ± 1.53 (2 studies, n=32)

Elimination half-life (hr) 4.08 ± 0.76

(4 studies, n=73)

3.81 ± 0.71

(4 studies, n=69)

Range of means 3.86 to 5.03

(4 studies, n=61)

Renal clearance (mL/min/kg) 3.21 ± 0.75

(1 study, n=20)

2.99 ± 0.67

(1 study, n=16)

Range of means 2.67 to 3.98

(3 studies, n=30)


The area under the plasma concentration-time curve (AUC) of ganciclovir administered as valganciclovir tablets (900 mg once daily) is comparable to the AUC of ganciclovir after administration of intravenous ganciclovir (5 mg per kg once daily). The Cmax of ganciclovir following valganciclovir administration is 40% lower than the Cmax following intravenous ganciclovir administration. During maintenance dosing, ganciclovir AUC0-24h and Cmax following oral ganciclovir administration (1000 mg three times daily) are lower relative to Darilin and intravenous ganciclovir. The ganciclovir Cmin following intravenous ganciclovir and Darilin administration are less than the ganciclovir Cmin following oral ganciclovir administration. The clinical significance of the differences in ganciclovir pharmacokinetics after administration of Darilin tablets, ganciclovir capsules, and intravenous ganciclovir is unknown.

Figure 1 Ganciclovir Plasma Concentration Time Profiles in HIV-positive/CMV-positive Patients*

*Plasma concentration-time profiles for ganciclovir (GCV) from Darilin (VGCV) and intravenous ganciclovir were obtained from a multiple dose study (n=21 and n=18, respectively) in HIV-positive/CMV-positive patients with CMV retinitis. The plasma concentration-time profile for oral ganciclovir was obtained from a multiple dose study (n=24) in HIV-positive/CMV-positive patients without CMV retinitis.

In solid organ transplant recipients, the mean systemic exposure to ganciclovir was 1.7x higher following administration of 900 mg Darilin tablets once daily versus 1000 mg ganciclovir capsules three times daily, when both drugs were administered according to their renal function dosing algorithms. The systemic ganciclovir exposures attained were comparable across kidney, heart and liver transplant recipients based on a population pharmacokinetic evaluation (see Table 11).

Parameter Ganciclovir Capsules Darilin Tablets
Dosage 1000 mg three times daily with food

Mean ± SD


900 mg once daily with food

Mean ± SD

Heart Transplant Recipients

N=13


N=17

AUC0-24h (µgh/mL) 26.6 ± 11.6 40.2 ± 11.8
Cmax (µg/mL) 1.4 ± 0.5 4.9 ± 1.1
Elimination half-life (hr) 8.47 ± 2.84 6.58 ± 1.50
Liver Transplant Recipients N=33 N=75
AUC0-24h (µgh/mL) 24.9 ± 10.2 46.0 ± 16.1
Cmax (µg/mL) 1.3 ± 0.4 5.4 ± 1.5
Elimination half-life (hr) 7.68 ± 2.74 6.18 ± 1.42
Kidney Transplant RecipientsIncludes kidney-pancreas N=36 N=68
AUC0-24h (µgh/mL) 31.3 ± 10.3 48.2 ± 14.6
Cmax (µg/mL) 1.5 ± 0.5 5.3 ± 1.5
Elimination half-life (hr) 9.44 ± 4.37 6.77 ± 1.25

The pharmacokinetic parameters of ganciclovir following 200 days of Darilin administration in high-risk kidney transplant patients were similar to those previously reported in solid organ transplant patients who received Darilin for 100 days.

In a pharmacokinetic study in liver transplant patients, the ganciclovir AUC0-24h achieved with 900 mg Darilin was 41.7 ± 9.9 mcgh/mL (n=28) and the AUC0-24h achieved with the approved dosage of 5 mg per kg intravenous ganciclovir was 48.2 ± 17.3 mcgh/mL (n=27).

Absorption : Darilin, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from Darilin tablets following administration with food was approximately 60% (3 studies, n=18; n=16; n=28). Ganciclovir median Tmax following administration of 450 mg to 2625 mg Darilin tablets ranged from 1 to 3 hours. Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir tablets was demonstrated only under fed conditions. Systemic exposure to the prodrug, Darilin, is transient and low, and the AUC24 and Cmax values are approximately 1% and 3% of those of ganciclovir, respectively.

Food Effects: When Darilin tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the Cmax increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Darilin should be administered with food .

Distribution: Due to the rapid conversion of Darilin to ganciclovir, plasma protein binding of Darilin was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mcg/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703 ± 0.134 L/kg (n=69).

After administration of Darilin tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Darilin tablets according to weight is not required.

Metabolism: Darilin is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.

Elimination: The major route of elimination of Darilin is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07 ± 0.64 mL/min/kg (n=68) while renal clearance was 2.99 ± 0.67 mL/min/kg (n=16).

The terminal half-life (t½) of ganciclovir following oral administration of Darilin tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 ± 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 ± 0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of valganciclovir was 6.48 ± 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 ± 3.62 hours.

Figure 1

Specific Populations:

Renal Impairment : The pharmacokinetics of ganciclovir from a single oral dose of 900 mg Darilin tablets were evaluated in 24 otherwise healthy individuals with renal impairment.

Estimated Creatinine Clearance

(mL/min)

N Apparent Clearance

(mL/min)

Mean ± SD

AUClast

(µg∙h/mL)

Mean ± SD

Half-life

(hours)

Mean ± SD

51-70 6 249 ± 99 49.5 ± 22.4 4.85 ± 1.4
21-50 6 136 ± 64 91.9 ± 43.9 10.2 ± 4.4
11-20 6 45 ± 11 223 ± 46 21.8 ± 5.2
≤10 6 12.8 ± 8 366 ± 66 67.5 ± 34

Decreased renal function results in decreased clearance of ganciclovir from Darilin, and a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for patients with impaired renal function.

Hemodialysis reduces plasma concentrations of ganciclovir by about 50% following Darilin administration. Adult patients receiving hemodialysis (CrCl less than 10 mL/min) cannot use Darilin tablets because the daily dose of Darilin tablets required for these patients is less than 450 mg [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].

Pharmacokinetics in Pediatric Patients: The pharmacokinetics of ganciclovir were evaluated following the administration of Darilin in 63 pediatric solid organ transplant patients aged 4 months to 16 years. In these studies, patients received oral doses of Darilin (either valganciclovir for oral solution or tablets) to produce exposure equivalent to an adult 900 mg dose .

The pharmacokinetics of ganciclovir were similar across organ types and age ranges. Based on a population pharmacokinetic evaluation, clearance is influenced by both body weight and renal function, while the central and peripheral volumes of distribution were influenced by weight . The mean total clearance was 5.3 L/hr (88.3 mL/min) for a patient with creatinine clearance of 70.4 mL/min. The mean ganciclovir Cmax, AUC and half-life by age and organ type in studies using the pediatric Darilin dosing algorithm are listed in Table 13. Relative to adult transplant patients (Table 11), AUC values in pediatric patients were somewhat increased, but were within the range considered safe and effective in adults.



Age Group
Organ PK Parameter mean (SD)

4 months to ≤ 2 years


> 2 to < 12 years

≥ 12 years
Heart

(N=12)

N

AUC0-24h

(µgh/mL)

Cmax (µg/mL)

t1/2 (h)

6

55.4 (22.8)

8.2 (2.5)

3.8 (1.7)

2

59.6 (21.0)

12.5 (1.2)

2.8 (0.9)

4

60.6 (25.0)

9.5 (3.3)

4.9 (0.8)

Kidney

(N=31)

N

AUC0-24h

(µgh/mL)

Cmax (µg/mL)

t1/2 (h)

2

67.6 (13.0)

10.4 (0.4)

4.5 (1.5)

10d,e

55.9 (12.1)

8.7 (2.1)

4.8 (1.0)

19

47.8 (12.4)

7.7 (2.1)

6.0 (1.3)

Liver

(N=17)

N

AUC0-24h

(µgh/mL)

Cmax (µg/mL)

t1/2 (h)

9

69.9 (37.0)

11.9 (3.7)

2.8 (1.5)

6

59.4 (8.1)

9.5 (2.3)

3.8 (0.7)

2

35.4 (2.8)

5.5 (1.1)

4.4 (0.2)


N= number of patients

a Pharmacokinetic parameters were estimated by using population pharmacokinetic modeling.

d There was one subject in this age group who received both a kidney and liver transplant. The pharmacokinetic profile for this subject has not been included in this table as it is not possible to determine whether the effects observed are from the kidney/liver transplant or neither.

e The pharmacokinetic profiles for two subjects in this age group who received kidney transplants have not been included in this table as the data were determined to be non-evaluable.

Pharmacokinetics in Geriatric Patients: The pharmacokinetic characteristics of Darilin in elderly patients have not been established. Because elderly individuals frequently have a reduced glomerular filtration rate, renal function should be assessed before and during administration of Darilin [see Dosage and Administration (2.5), Use in Specific Populations (8.5)].

Drug Interactions: In vivo drug-drug interaction studies were not conducted with Darilin. However, because Darilin is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for Darilin .

Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Darilin and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Table 14 and Table 15 provide a listing of established drug interaction studies with ganciclovir. Table 14 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 15 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK) Parameter
Zidovudine 100 mg every 4 hours 1000 mg every 8 hours 12 AUC ↓ 17 ± 25%

(range: -52% to 23%)

Probenecid 500 mg every 6 hours 1000 mg every 8 hours 10 AUC ↑ 53 ± 91%

(range: -14% to 299%)

Ganciclovir renal clearance ↓ 22 ± 20%

(range: -54% to -4%)

Mycophenolate Mofetil (MMF) 1.5 g single dose IV ganciclovir 5 mg/kg single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function)
Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir 1000 mg every 8 hours 12 AUC ↓ 21 ± 17%

(range: -44% to 5%)

Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 1000 mg every 8 hours 12 No effect on ganciclovir PK parameters observed
IV ganciclovir 5 mg/kg twice daily 11 No effect on ganciclovir PK parameters observed
IV ganciclovir 5 mg/kg once daily 11 No effect on ganciclovir PK parameters observed
Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 Ganciclovir renal clearance ↓ 16.3%

Half-life ↑15%

Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK) Parameter
Zidovudine 100 mg every 4 hours 1000 mg every 8 hours 12 AUC0-4 ↑ 19 ± 27%

(range: -11% to 74%)

Mycophenolate Mofetil (MMF) 1.5 g single dose IV ganciclovir 5 mg/kg single dose 12 No PK interaction observed (patients with normal renal function)
Didanosine 200 mg every 12 hours when administered 2 hours prior to or concurrent with ganciclovir 1000 mg every 8 hours 12 AUC0-12 ↑ 111 ± 114%

(range: 10% to 493%)

Didanosine 200 mg every 12 hours IV ganciclovir 5 mg/kg twice daily 11

AUC0-12 ↑ 70 ± 40%

(range: 3% to 121%)

Cmax ↑ 49 ± 48%

(range: -28% to 125%)

Didanosine 200 mg every 12 hours IV ganciclovir 5 mg/kg once daily 11

AUC0-12 ↑50 ± 26%

(range: 22% to 110%)

Cmax ↑ 36 ± 36%

(range: -27% to 94%)

Trimethoprim 200 mg once daily 1000 mg every 8 hours 12 Increase (12%) in Cmin

Other potential drug interactions

Since ganciclovir is excreted through the kidney via glomerular filtration and active secretion , coadministration of Darilin with antiretroviral drugs that share the tubular secretion pathway, such as nucleos(t)ide reverse transcriptase inhibitors, may change the plasma concentrations of Darilin and/or the coadministered drug.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

12.4 Microbiology

Mechanism of Action: Darilin is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo.

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 metabolized intracellularly (half-life 18 hours). 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 the viral DNA polymerase, pUL54, synthesis by ganciclovir triphosphate.

Antiviral Activity: The quantitative relationship between the cell culture susceptibility of human herpes viruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (EC50), vary greatly depending upon a number of factors including the assay used. Thus, the reported EC50 values of ganciclovir that inhibit human CMV replication in cell culture (laboratory and clinical isolates) have ranged from 0.08 to 22.94 µM (0.02 to 5.75 mcg/mL). The distribution and range in susceptibility observed in one assay evaluating 130 clinical isolates was 0 to 1 µM (35%), 1.1 to 2 µM (20%), 2.1 to 3 µM (27%), 3.1 to 4 µM (13%), 4.1 to 5 µM (5%), less than 5 µM (less than 1%). Ganciclovir inhibits mammalian cell proliferation (CC50) in cell culture at higher concentrations ranging from 40 to greater than 1,000 µM (10.21 to greater than 250 mcg/mL). Bone marrow-derived colony-forming cells are more sensitive [CC50 value= 2.7 to 12 µM (0.69 to 3.06 mcg/mL)].

Viral Resistance:

Cell culture: CMV isolates with reduced susceptibility to ganciclovir have been selected in cell culture. Growth of CMV strains in the presence of ganciclovir resulted in the selection of amino acid substitutions in the viral protein kinase pUL97 (M460I/V, L595S, G598D, and K599T) and the viral DNA polymerase pUL54 (D301N, N410K, F412V, P488R, L516R, C539R, L545S, F595I, V812L, P829S, L862F, D879G, and V946L).

In vivo: Viruses resistant to ganciclovir can arise after prolonged treatment or prophylaxis with Darilin by selection of substitutions in pUL97 and/or pUL54. Limited clinical data are available on the development of clinical resistance to ganciclovir and many pathways to resistance likely exist. In clinical isolates, seven canonical pUL97 substitutions, (M460V/I, H520Q, C592G, A594V, L595S, C603W) are the most frequently reported ganciclovir resistance-associated substitutions. These and other substitutions less frequently reported in the literature, or observed in clinical trials, are listed in Table 16.

Note: Many additional pathways to ganciclovir resistance likely exist
pUL97 L405P, A440V, M460I/V/T, V466G/M, C518Y, H520Q, del 590-593, A591D/V, C592G, A594E/G/T/V/P, L595F/S/T/W, del 595, del 595-603, E596D/G, K599E/M, del 600-601, del 597-600, del 601-603, C603W/R/S/Y, C607F/S/Y, A613V
pUL54 E315D, N408D/K/S, F412C/L/S, D413A/E, L501F/I, T503I, K513E/N/R, I521T, P522A/L/S, L545S/W, Q578H/L, D588E/N, G629S, S695T, I726T/V, E756K, V781I, V787L, L802M, A809V, T813S, T821I, A834P, G841A/S, D879G, A972V, del 981-982, A987G

The presence of known ganciclovir resistance-associated amino acid substitutions was evaluated in a study that extended Darilin CMV prophylaxis from 100 days to 200 days post-transplant in adult kidney transplant patients at high risk for CMV disease (D+/R-) [see Clinical Studies (14.1)]. Five subjects from the 100 day group and four subjects from the 200 day group meeting the resistance analysis criteria had known ganciclovir resistance-associated amino acid substitutions detected. In six subjects, the following resistance-associated amino acid substitutions were detected within pUL97: 100 day group: A440V, M460V, C592G; 200 day group: M460V, C603W. In three subjects, the following resistance-associated amino acid substitutions were detected within pUL54: 100 day group: E315D, 200 day group: E315D, P522S. Overall, the detection of known ganciclovir resistance-associated amino acid substitutions was observed more frequently in patients during prophylaxis therapy than after the completion of prophylaxis therapy (during therapy: 5/12 [42%] versus after therapy: 4/58 [7%]). The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Cross-Resistance: Cross-resistance has been reported for amino acid substitutions selected in cell culture by ganciclovir, cidofovir or foscarnet. In general, amino acid substitutions in pUL54 conferring cross-resistance to ganciclovir and cidofovir are located within the exonuclease domains and region V. Whereas, amino acid substitutions conferring cross-resistance to foscarnet are diverse, but concentrate at and between regions II (codon 696-742) and III (codon 805-845). The amino acid substitutions that resulted in reduced susceptibility to ganciclovir and either cidofovir and/or foscarnet are summarized in Table 17.

Substitutions at amino acid positions pUL97 340-400 have been found to confer resistance to ganciclovir. Resistance data based on assays that do not include this region should be interpreted cautiously.

Cross-resistant to cidofovir D301N, N408D/K, N410K, F412C/L/S/V, D413E, L501I, T503I, K513E/N, L516R, I521T, P522S/A, L545S/W, Q578H, D588N, I726T/V, E756K, V812L, T813S, A834P, G841A, del 981-982, A987G
Cross-resistant to foscarnet F412C, Q578H/L, D588N, E756K, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A, del 981-982

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with Darilin. However, upon oral administration, Darilin is rapidly and extensively converted to ganciclovir. Therefore, like ganciclovir, Darilin is a potential carcinogen.

Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures 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 higher dose 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 lower dose, 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. Ganciclovir should be considered a potential carcinogen in humans.

Darilin increases mutations in mouse lymphoma cells. In the mouse micronucleus assay, Darilin was clastogenic. Darilin was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic. Ganciclovir was not mutagenic in the Ames Salmonella assay.

Darilin is converted to ganciclovir and therefore is expected to have similar reproductive toxicity effects as ganciclovir . Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses that produced an exposure approximately 1.7x the mean drug exposure in humans following the dose of 5 mg per kg, based on AUC comparisons. Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in mice and dogs following daily oral or intravenous administration. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended human intravenous dose. Darilin caused similar effects on spermatogenesis in mice, rats, and dogs. These effects were reversible at lower doses but irreversible at higher doses. It is considered likely that ganciclovir (and Darilin) could cause temporary or permanent inhibition of human spermatogenesis.

14 CLINICAL STUDIES

14.1 Adult Patients

Induction Therapy of CMV Retinitis: In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either Darilin tablets or with intravenous ganciclovir solution (5 mg per kg twice daily for 21 days, then 5 mg per kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and Week 4 was the primary outcome measurement of the 3-week induction therapy. Table 18 provides the outcomes at 4 weeks.

Intravenous Ganciclovir Darilin Tablets
Determination of CMV retinitis progression at Week 4 N=80 N=80
Progressor

Non-progressor

7

63

7

64

Death

Discontinuations due to Adverse Events

Failed to return

2

1

1

1

2

1

CMV not confirmed at baseline or no interpretable baseline photos 6 5

Maintenance Therapy of CMV Retinitis: No comparative clinical data are available on the efficacy of Darilin tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label Darilin tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg Darilin tablets once daily and 5 mg per kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following Darilin tablets administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration [see Figure 1 in Clinical Pharmacology (12.3)]. Therefore, use of Darilin tablets as maintenance therapy is supported by a plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis.

Prevention of CMV Disease in Heart, Kidney, Kidney-Pancreas, or Liver Transplantation: A double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (D+/R-). Patients were randomized (2 Darilin: 1 oral ganciclovir) to receive either Darilin tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months post-transplant was similar between the Darilin tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the Darilin group compared with the ganciclovir group. These results are summarized in Table 19.

Mortality at six months was 3.7% (9/244) in the Darilin group and 1.6% (2/126) in the oral ganciclovir group.

GCV = oral ganciclovir; VGCV = Darilin
CMV DiseaseNumber of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome Tissue-Invasive CMV Disease CMV SyndromeCMV syndrome was defined as evidence of CMV viremia accompanied with fever greater than or equal to 38°C on two or more occasions separated by at least 24 hours within a 7-day period and one or more of the following: malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
Organ VGCV

(N=239)

GCV

(N=125)

VGCV

(N=239)

GCV

(N=125)

VGCV

(N=239)

GCV

(N=125)

Liver

(n=177)

19%

(22 / 118)

12%

(7 / 59)

14%

(16 / 118)

3%

(2 / 59)

5%

(6 / 118)

9%

(5 / 59)

Kidney

(n=120)

6%

(5 / 81)

23%

(9 / 39)

1%

(1 / 81)

5%

(2 / 39)

5%

(4 / 81)

18%

(7 / 39)

Heart

(n=56)

6%

(2 / 35)

10%

(2 / 21)

0%

(0 / 35)

5%

(1 / 21)

6%

(2 / 35)

5%

(1 / 21)

Kidney / Pancreas

(n=11)

0%

(0 / 5)

17%

(1 / 6)

0%

(0 / 5)

17%

(1 / 6)

0%

(0 / 5)

0%

(0 / 6)


Prevention of CMV Disease in Kidney Transplantation: A double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending Darilin CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Darilin tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with Darilin until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 20.

CMV Disease Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome Tissue-Invasive CMV Disease CMV Syndrome CMV syndrome was defined as evidence of CMV viremia accompanied with at least one of the following: fever (greater than or equal to 38°C), severe malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases

100 Days

VGCV

(N=163)

200 Days

VGCV

(N=155)

100 Days

VGCV

(N=163)

200 Days

VGCV

(N=155)

100 Days

VGCV

(N=163)

200 Days

VGCV

(N=155)

Cases 36.8%

(60/163)

16.8%

(26/155)

1.8%

(3/163)Two patients in the 100 day group had both tissue-invasive CMV disease and CMV syndrome; however, these patients are counted as having only tissue-invasive CMV disease.

0.6%

(1/155)

35.0%

(57/163)

16.1%

(25/155)

VGCV = Darilin

The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.

14.2 Pediatric Patients

Prevention of CMV in Pediatric Heart, Kidney, or Liver Transplantation: Sixty-three children, 4 months to 16 years of age, who had a solid organ transplant (kidney 33, liver 17, heart 12, and kidney/liver 1) and were at risk for developing CMV disease, were enrolled in an open-label, safety, and pharmacokinetic study of oral valganciclovir (valganciclovir for oral solution or tablets). Patients received Darilin once daily within 10 days after transplant until a maximum of 100 days post-transplant. The daily doses of Darilin were calculated at each study visit based on body surface area and a modified creatinine clearance .

The pharmacokinetics of ganciclovir were similar across organ transplant types and age ranges. The mean daily ganciclovir exposures in pediatric patients were somewhat increased relative to those observed in adult solid organ transplant patients receiving Darilin 900 mg once daily, but were within the range considered safe and effective in adults . No case of CMV syndrome or tissue-invasive CMV disease was reported within the first six months post-transplantation.

Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Darilin Tablets, USP: Supplied as 450 mg, pink, convex oval tablets with "E114" on one side and plain on the other side. Each film-coated tablet contains 450 mg of Darilin as valganciclovir hydrochloride. Darilin Tablets, USP, is supplied in bottles of 60 tablets (NDC 0603-6330-20).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Serious Adverse Reactions

Inform patients that Darilin may cause granulocytopenia (neutropenia), anemia, thrombocytopenia and elevated creatinine levels and that dose modification or discontinuation of dosing may be required. Complete blood counts, platelet counts, and creatinine levels should be performed frequently during treatment .

Pregnancy and Contraception

Inform females of reproductive potential that Darilin causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with Darilin. Similarly, advise males to practice barrier contraception during and for at least 90 days following treatment with Darilin .

Carcinogenicity

Advise patients that Darilin is considered a potential carcinogen .

Lactation

Advise mothers not to breast-feed if they are receiving Darilin because of the potential for hematologic toxicity and cancer in nursing infants, and because HIV can be passed to the baby in breast milk .

Infertility

Advise patients that Darilin may cause temporary or permanent female and male infertility .

Impairment of Cognitive Ability

Inform patients that tasks requiring alertness may be affected including the patient’s ability to drive and operate machinery as convulsions, sedation, dizziness, ataxia and/or confusion have been reported with the use of Darilin .

Use in Patients with CMV Retinitis

Inform patients that Darilin is not a cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with Darilin. Some patients will require more frequent follow-up.

Administration

Inform adult patients that they should use Darilin tablets, not Darilin for oral solution .

Inform patients to take Darilin with food to maximize bioavailability.

FDA-Approved Patient Labeling

Darilin (val’gan-si’klo-vir) Tablets

What is the most important information I should know about Darilin?


What is Darilin?

Darilin is a prescription antiviral medicine.

In adults, Darilin tablets are used:


In children, Darilin tablets or oral solution are used:


Pediatric use information for pediatric kidney transplant patients ages 4 months to 16 years and for pediatric heart transplant patients ages 1 to less than 4 months is approved for Roche Palo Alto LLC’s VALCYTE (valganciclovir hydrochloride) tablets and oral solution. However, due to Roche Palo Alto LLC’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Darilin does not cure CMV retinitis. You may still get retinitis or worsening of retinitis during or after treatment with Darilin. It is important to stay under a healthcare provider's care and have your eyes checked every 4 to 6 weeks during treatment with Darilin.

Who should not take Darilin?

Do not take Darilin if you are allergic to any of its ingredients or if you have ever had a serious allergic reaction to ganciclovir capsules or Cytovene-IV. Symptoms of an allergic reaction to Darilin may include: sudden trouble breathing, wheezing, hives all over your body, swelling around your mouth, or feeling anxious.

What should I tell my healthcare provider before taking Darilin?

Before taking Darilin, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Darilin and other medicines may affect each other and cause serious side effects. Keep a list of your medicines to show your healthcare provider and pharmacist.


How should I take Darilin?


Talk to your healthcare provider, nurse or pharmacist if you have questions about your medicine.

What should I avoid while taking Darilin?


What are the possible side effects of Darilin?

Darilin may cause serious side effects, including:

See "What is the most important information I should know about Darilin?"

Common side effects of Darilin in adults and children include:


Other common side effects in children include:


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Darilin. For more information, ask your healthcare provider or pharmacist.

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

How should I store Darilin?


General information about the safe and effective use of Darilin

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Darilin for a condition for which it was not prescribed. Do not give Darilin to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Darilin. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Darilin that is written for health professionals.

For more information about Darilin, call 1-800-444-4011.

What are the ingredients in Darilin?

Active Ingredient: Darilin hydrochloride

Inactive Ingredients for Tablets: colloidal silicon dioxide, crospovidone, microcrystalline cellulose, povidone K-30, and stearic acid. The film-coating applied to the tablets contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.

This Patient Information has been approved by the U.S. Food and Drug Administration

VALCYTE is a registered trademark of Hoffmann-La Roche Inc.

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811


Manufactured by:

Patheon Pharmaceuticals Inc.

Mississauga, Ontario, Canada L5N 7K9

Revised: 3/2016

Darilin pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Darilin available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Darilin destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Darilin Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Darilin pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."VALGANCICLOVIR (VALGANCICLOVIR HYDROCHLORIDE) TABLET, FILM COATED [QUALITEST PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Valganciclovir". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Valganciclovir". http://www.drugbank.ca/drugs/DB0161... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Darilin?

Depending on the reaction of the Darilin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Darilin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Darilin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Darilin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Darilin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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