Ganciclovir (Page 5 of 11)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous ganciclovir or ganciclovir capsules. 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.

Blood and lymphatic disorders: hemolytic anemia, agranulocytosis, granulocytopenia

Cardiac disorders: cardiac arrest, conduction disorder, torsade de pointes, ventricular tachycardia

Congenital, familial and genetic disorders: congenital anomaly

Endocrine disorders: inappropriate antidiuretic hormone secretion

Eye disorders: cataracts, dry eyes

Gastrointestinal disorders: intestinal ulcer

Hepatobiliary disorders: cholelithiasis, cholestasis, hepatic failure, hepatitis

Immune system disorders: anaphylactic reaction, allergic reaction, vasculitis

Investigations: blood triglycerides increased

Metabolism and nutrition disorders: acidosis, hypercalcemia, hyponatremia

Musculoskeletal and connective tissue disorders: arthritis, rhabdomyolysis

Nervous system disorders: dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, intracranial hypertension

Psychiatric disorders: irritability, hallucinations

Renal and urinary disorders: renal tubular disorder, hemolytic uremic syndrome

Reproductive system and breast disorders: infertility, testicular hypotrophy

Respiratory, thoracic and mediastinal disorders: bronchospasm, pulmonary fibrosis

Skin and subcutaneous tissues disorders: exfoliative dermatitis, Stevens-Johnson syndrome

Vascular disorders: peripheral ischemia

7 DRUG INTERACTIONS

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 ganciclovir for injection and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 6 [see Clinical Pharmacology (12.3)].

Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir

Name of the Concomitant Drug

Change in the Concentration of Ganciclovir or Concomitant Drug

Clinical Comment

Imipenem-cilastatin

Unknown

Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and

imipenem-cilastatin.

Cyclosporine or amphotericin B

Unknown

Monitor renal function when ganciclovir for injection is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2)].

Mycophenolate mofetil (MMF)

↔Ganciclovir (in patients with normal renal function)

↔MMF (in patients with normal renal function)

Based on increased risk, patients should be monitored for hematological and renal toxicity.

Other drugs associated with myelosuppresion or nephrotoxicity (e.g., dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/sulfamethoxazole, vinblastine, vincristine and zidovudine)

Unknown

Because of potential for higher toxicity, coadministration with ganciclovir for injection should be considered only if the potential benefits are judged to outweigh the risks

Didanosine

↔ Ganciclovir

↑ Didanosine

Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis).

Probenecid

↑ Ganciclovir

Ganciclovir for injection dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 exposure at the recommended human dose (RHD) [see Data]. Although placental transfer of ganciclovir has been shown to occur based on ex vivo experiments with human placenta and in at least one case report in a pregnant woman, no adequate human data are available to establish whether ganciclovir for injection poses a risk to pregnancy outcomes. The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

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 symptomatic infants is about 10% and approximately 50 to 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

Daily intravenous doses of ganciclovir were administered to pregnant mice (108 mg/kg/day) and rabbits (60 mg/kg/day), and also to female mice (90 mg/kg) prior to mating, during gestation, and during lactation. Fetal resorptions were present in at least 85% of rabbits and mice. Additional 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 pre/postnatal development studies in mice, there were maternal/fetal toxicity and embryolethality which included fetal effects of hypoplasia of the testes and seminal vesicles in the male offspring, as well as pathologic changes in the nonglandular region of the stomach. The systemic exposure (AUC) of ganciclovir during these studies was approximately 2 times (pregnant mice and rabbits) and 1.7 times (pre/postnatal mice) the exposure in humans at the RHD [see Nonclinical Toxicology (13.1)].

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